Impact of omega-3 polyunsaturated fatty acids on vascular function and blood pressure: Relevance for cardiovascular outcomes.

AIMS: To overview the effects of omega-3 polyunsaturated fatty acids (PUFA) on blood vessels and blood pressure (BP) and their relevance for cardiovascular prevention. DATA SYNTHESIS: The importance of omega-3 PUFA for the cardiovascular system has come under the spotlight during the last decades. These fatty acids are present in variable amounts in cell membranes of mammal species, and their content affects a variety of cellular functions. Evidence obtained in animal and human studies suggests that omega-3 PUFA affect many steps of the atherosclerotic process. In blood vessels, omega-3 PUFA improve endothelial function; promote vasodilatation through relaxation of smooth muscle cells; exert antioxidant, anti-inflammatory, and antithrombotic actions; delay development of plaques and increase their stability; and decrease wall stiffening. Omega-3 PUFA might affect BP, and studies conducted with ambulatory monitoring suggest that supplementation with these fatty acids decreases the average 24-h BP levels. This effect on BP is related to the pretreatment membrane content of omega-3 PUFA, and this might explain some inconsistencies among intervention trials. Meta-analyses indicate that omega-3 PUFA have a mild but significant BP lowering effect. While encouraging results were initially obtained with the use of omega-3 PUFA supplements in secondary prevention trials, meta-analyses have not confirmed the ability of these fatty acids to decrease the risk of coronary heart and cerebrovascular disease. CONCLUSIONS: Omega-3 PUFA are associated with significant improvement in vascular function and lowering of BP. However, the evidence currently supporting the role of these fatty acids in cardiovascular prevention is weak and needs further investigation.

Mineralocorticoid Receptor Antagonists and Clinical Outcomes in Primary Aldosteronism: As Good as Surgery?

Primary aldosteronism (PA) is detected with increasing frequency in hypertensive patients and is associated with excess cardiovascular, renal, and metabolic complications. For these reasons, appropriate choices for treatment of this endocrine condition are mandatory. Adrenalectomy is safely performed in PA patients when adrenal venous sampling (AVS) demonstrates lateralized aldosterone secretion. AVS, however, is a complex procedure and even among worldwide referral centers there are substantial discrepancies for interpretation of results. Also, in the majority of PA patients with lateralized aldosterone secretion, hypertension may persist after adrenalectomy requiring use of additional antihypertensive agents. Treatment with mineralocorticoid receptor antagonists (MRAs) is currently recommended for PA patients with bilateral adrenal disease, but these agents effectively decrease blood pressure also in patients with unilateral disease, although concern remains for possible sex-related side effects. Prospective studies indicate that MRAs have therapeutic values comparable to surgery in the long-term, inasmuch as they effectively correct metabolic abnormalities and subclinical organ damage and reduce the risk of cardiovascular events and renal disease progression. This article overviews the clinical outcomes obtained in patients with PA with use of MRAs.

Aldosterone and Left Ventricular Remodeling.

Experimental and clinical evidence obtained in the last 2 decades clearly indicates that protracted exposure to inappropriately elevated aldosterone levels causes significant changes in left ventricular structure and function. Animal studies have demonstrated that aldosterone induces myocardial inflammatory changes and fibrosis in the presence of a high salt diet. Moreover, the effects of aldosterone on the heart have been investigated in different clinical conditions. These conditions include systolic and diastolic heart failure, essential hypertension, and primary aldosteronism that offers a unique clinical model to study the cardiac effects of excess aldosterone because these effects are isolated from those of the renin-angiotensin axis. A relatively clear picture is emerging from these studies with regard to aldosterone-related changes in left ventricular mass and geometry. Conversely, no direct effect of aldosterone on left ventricular diastolic function can be demonstrated and improvement of diastolic function obtained in some studies that have employed mineralocorticoid receptor blockers could result from left ventricular mass reduction. Animal experiments demonstrate that effects of aldosterone on the left ventricle require high salt intake to occur, but the evidence of this contribution of salt to aldosterone-induced cardiac changes in humans remains weaker and needs further research. The article reviews the results of clinical studies addressing the role of aldosterone in regulation of LV remodeling and diastolic function, and focuses on the possible relevance of salt intake.

Carotid artery stiffness is related to hyperinsulinemia and insulin-resistance in middle-aged, non-diabetic hypertensive patients.

BACKGROUND AND AIMS: Glycometabolic abnormalities are frequently found in hypertension and could affect the mechanical properties of carotid arteries. The aim of the study was to investigate the relationship of glucose tolerance, plasma insulin, and insulin sensitivity with carotid distensibility in middle-aged, non-diabetic hypertensive patients free of cardiac and vascular complications. METHOD AND RESULTS: In 93 patients with grade 1-2, uncomplicated, primary hypertension and 68 matched normotensive controls we measured plasma glucose and insulin at fast and after an oral glucose load (OGTT), calculated the HOMA-index as a marker of insulin sensitivity, and assessed distensibility of common carotid arteries by B-mode ultrasonography. Hypertensive patients were hyperinsulinemic and insulin-resistant as compared to normotensive controls. Hypertensive patients with impaired fasting glucose and/or impaired glucose tolerance had comparable distensibility of carotid arteries. Patients with decreased carotid distensibility were older and had higher body mass, fasting and post-OGTT plasma insulin, HOMA-index, and carotid IMT than the remaining patients, but no differences in glycated hemoglobin, and fasting or post-OGTT plasma glucose. Carotid coefficient of distensibility was inversely related and ß-stiffness directly related with fasting and post-OGTT plasma insulin, and HOMA-index. Multivariate logistic regression showed that age and post-OGTT plasma insulin levels predicted carotid artery stiffening independent of body mass index, sex, blood pressure, and plasma glucose levels. CONCLUSIONS: The study demonstrates that decreased insulin sensitivity and the related hyperinsulinemia but not hyperglycemia could contribute to carotid artery stiffening in middle-aged, non-diabetic hypertensive patients free of cardiovascular complications.

Ambulatory arterial stiffness indices and non-alcoholic fatty liver disease in essential hypertension.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) has been found to be strongly related to an increased arterial stiffness in patients with essential hypertension, suggesting a pathophysiologic link between major cardiovascular and metabolic abnormalities associated with liver steatosis and the functional and structural alterations of the arterial wall. The aim of our study was to investigate, in a group of essential hypertensive patients without additional cardiovascular risk factors, the relationship between NAFLD and arterial stiffness. METHODS AND RESULTS: Sixty-eight consecutive patients with essential hypertension underwent 24-h ambulatory blood pressure monitoring (ABPM) and were separated according to the presence (n = 40) or absence (n = 28) of NAFLD at liver ultrasonography. The Ambulatory Arterial Stiffness Index (AASI) and Symmetric AASI (Sym-AASI) were derived from ABPM tracings. Patients with diabetes, obesity, hyperlipidaemia or other risk factors for cardiovascular or liver disease were excluded. Hypertensive patients were compared with a normotensive control group.The two hypertensive groups had comparable age, sex distribution and clinic/ABPM blood pressure levels. In hypertensive patients with NAFLD, body mass index, fasting glucose, insulin, homeostasis model of assessment of insulin resistance index and triglyceride levels were higher, whereas plasma adiponectin was lower than in patients without NAFLD. In hypertensive patients, AASI and Sym-AASI were higher (P < 0.001) than in normotensive subjects, but both indices of vascular stiffness were comparable in patients with and without NAFLD. CONCLUSIONS: In essential hypertensive patients without additional cardiovascular risk factors, NAFLD is associated with insulin resistance but not with increased arterial stiffness.

Predictive factors of left ventricular mass changes after treatment of primary aldosteronism.

A variety of abnormalities that occur in patients with primary aldosteronism indicate the capability of elevated aldosterone to induce cardiac damage over that induced by hypertension itself. This study investigates factors that can predict structural and functional changes of the heart after treatment of primary aldosteronism in a post-hoc analysis of 54 patients who were enrolled in a long-term follow-up study that was conducted after either adrenalectomy or treatment with spironolactone. Cardiac ultrasound assessment was performed before treatment and after with an average follow-up of 6.4 years. During follow-up, blood pressure decreased significantly and comparably in both treatment groups. In both treatment groups, left ventricular mass decreased significantly with a trend to improved diastolic filling profile and no changes in ventricular geometry. At univariate analysis, changes in left ventricular mass induced by treatment of primary aldosteronism were directly related with changes in systolic blood pressure and pretreatment plasma aldosterone levels measured both at baseline and after an intravenous saline load. This relationship was maintained when patients treated with adrenalectomy and spironolactone were analyzed separately. Multivariate regression analysis showed that changes in systolic blood pressure and pretreatment aldosterone levels were independent predictors of left ventricular mass changes after treatment. This study strongly supports a role of aldosterone in promoting left ventricular hypertrophy that is independent of the hypertension-related hemodynamic load and suggests a practical way to predict left ventricular mass changes following surgical and medical treatment of primary aldosteronism.

Aldosterone and the heart: from basic research to clinical evidence.

Recent views suggest that long-term exposure to elevated aldosterone concentrations might result in cardiac, vascular, renal, and metabolic sequelae that occur independent of the blood pressure level. Indirect evidence of the untoward effects of aldosterone on the heart has been clearly established in clinical studies that have tested the effects of mineralocorticoid receptor antagonists in the treatment of systolic heart failure. As it has become clear in recent years, the interaction between aldosterone and the heart has to deal with additional actions of the hormone on specific cell types, cellular mechanisms, and molecules that are involved in regulation of tissue responses, leading to hypertrophy, remodeling, and fibrosis. The majority of these effects are mediated by activation of the mineralocorticoid receptors that are expressed in cardiomyocytes and cardiac fibroblasts, and mediate the genomic effects of the hormone. Evidence of interactions between aldosterone and the heart that occur independent of the renal effects of aldosterone, however, is not limited to the context of systolic heart failure and observations obtained in other disease states have led, together with findings of animal studies, to a better understanding of the potential benefits of aldosterone antagonists. In this narrative overview, we highlight the most recent findings that have been obtained in experimental animal models and in clinical conditions that include, in addition to systolic heart failure, primary aldosteronism, essential hypertension, diastolic heart failure, and arrhythmia.

Low serum 25-hydroxyvitamin D levels are associated with left ventricular hypertrophy in essential hypertension.

BACKGROUND AND AIM: Low serum 25-hydroxyvitamin D [25(OH)D] levels may have an important role in predisposing to hypertension and myocardial disease. We investigated the relationship between 25(OH)D and left ventricular (LV) structure and function, assessed by echocardiography, in a series of patients with essential hypertension (EH). METHODS AND RESULTS: Sixty-two newly diagnosed never-treated patients (32 male/30 female), aged 18-65 years, with grade 1-2 hypertension, no diabetes, no obesity, no hyperlipidemia, and no cardiopulmonary, renal, or hepatic disease, were studied. Twenty-four healthy normotensive sex-, age-, BMI-matched subjects served as controls. Hypertensive patients with 25(OH)D deficiency, defined as serum 25(OH)D levels <50 nmol/L, had higher prevalence of LV hypertrophy (LVH) than their 25(OH)D-sufficient counterparts (57.1 vs 17.6%, P = 0.02); no differences between the two groups were found in blood pressure levels as well as in other biochemical and hormone parameters. There was an inverse correlation between LV mass index and 25(OH)D levels (r = -0.366, P < 0.003) and a direct correlation between LV mass index and BMI (r = 0.333, P < 0.006) in the entire hypertensive population. The two variables remained independently associated with LVH at multivariable logistic regression analysis (OR 1.05, P < 0.005 and OR 1.25, P = 0.03, respectively). Prevalence of 25(OH)D deficiency was similar in EH patients and controls (45.1 vs 41.6%, P = 0.89), whereas no correlation between echocardiographic parameters and hormone levels was found. CONCLUSIONS: In the absence of major cardiovascular risk factors, 25(OH)D deficiency is a frequent finding in EH patients and is independently associated with LVH.

Mineralocorticoid antagonists treatment versus surgery in primary aldosteronism.

Recent evidence indicates a greater frequency of primary aldosteronism (PA) among patients with hypertension than the previously accepted prevalence. PA was once considered a relatively benign form of hypertension associated with low incidence of organ complications. Recent views, however, suggest that long-term exposure to increased aldosterone levels might result in cardiovascular, renal, and metabolic sequelae that occur independently of the blood pressure level. Cross-sectional comparisons with patients with essential hypertension have demonstrated that patients with PA are at higher risk of cardiovascular events, have more frequent left ventricular hypertrophy and diastolic dysfunction, have greater urinary albumin losses as a marker of a hemodynamic intrarenal adaptation, and are insulin resistant. Some of these findings have been corroborated by the results of short-term, follow-up studies where it was shown that unilateral adrenalectomy or treatment with mineralocorticoid receptor (MR) antagonists are effective in correcting hypertension and hypokalemia. Normalization of blood pressure and correction of hypokalemia, however, are not the only goals in managing PA and effective prevention of organ complications is mandatory in these patients. The relative efficacy of adrenalectomy and MR antagonists, in the long-term, on the cardiovascular, renal, and metabolic outcomes still needs evaluation, being the aldosterone-induced tissue damage the main factor that could justify the cost of increasing efforts in screening of disease and differentiation of subtypes. In this narrative review, we summarize the results obtained with either surgical or medical treatment of PA and outline the findings of long-term, prospective studies on the effects of treatment on cardiovascular and renal outcomes and on insulin sensitivity.

Non-alcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in essential hypertension.

BACKGROUND AND AIM: Insulin resistance is recognized as the pathophysiological hallmark of non-alcoholic fatty liver disease (NAFLD). A relation between insulin sensitivity and left ventricular morphology and function has been reported in essential hypertension, where a high prevalence of NAFLD has been recently found. We investigated the inter-relationship between left ventricular morphology/function, metabolic parameters and NAFLD in 86 never-treated essential hypertensive patients subdivided in two subgroups according to the presence (n = 48) or absence (n = 38) of NAFLD at ultrasonography. METHODS AND RESULTS: The two groups were similar as to sex, age and blood pressure levels. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for liver disease. Body mass index, waist circumference, triglycerides, glucose, insulin, homeostasis model of assessment index for insulin resistance (HOMA-IR), aspartate aminotransferase and alanine aminotransferase were higher and adiponectin levels were lower in patients with NAFLD than in patients without NAFLD, and were associated with NAFLD at univariate analysis. Patients with NAFLD had similar prevalence of left ventricular hypertrophy compared to patients without NAFLD, but a higher prevalence of diastolic dysfunction (62.5 vs 21.1%, P < 0.001), as defined by E/A ratio <1 and E-wave deceleration time >220 ms. Diastolic dysfunction (P = 0.040) and HOMA-IR (P = 0.012) remained independently associated with NAFLD at backward multivariate analysis. CONCLUSIONS: Non-alcoholic fatty liver disease was associated with insulin resistance and abnormalities of left ventricular diastolic function in a cohort of patients with essential hypertension, suggesting a concomitant increase of metabolic and cardiac risk in this condition.

Increased fibrinogen levels and hemostatic abnormalities in patients with arteriolar nephrosclerosis: association with cardiovascular events.

Increased plasma fibrinogen levels and hemostatic abnormalities suggestive of a prothrombotic state are present in patients with end-stage renal failure and could contribute to increased cardiovascular morbidity in these patients. We investigated the relationship between abnormalities of the hemostatic system and the degree of renal failure and whether these abnormalities are associated with increased prevalence of cardiovascular events in patients with arteriolar nephrosclerosis. In 425 patients recruited at a hypertension clinic we assessed the renal function by creatinine clearance, urinary protein excretion, and microalbuminuria, the prevalence of atherosclerotic disease, and measured prothrombin time, activated partial thromboplastin time. fibrinogen, prothrombin fragment 1+2 (F1+2), D-dimer, and antithrombin. Early impairment of renal function (creatinine clearance, 30 to 89 ml/min per 1.73 m2 of body surface area) caused by arteriolar nephrosclerosis was found in 172 patients. Patients with early renal failure were significantly older and had significantly greater values of blood pressure, plasma fibrinogen, F1+2, and D-dimer than patients with normal renal function. Elevated D-dimer and fibrinogen levels were independently associated with the presence of decreased creatinine clearance. Log fibrinogen, log F1+2, and log D-dimer were inversely correlated with creatinine clearance. The prevalence of coronary artery, cerebrovascular, and peripheral vascular disease was significantly greater in patients with mild renal failure than in those with normal renal function. Elevated levels of fibrinogen and D-dimer were associated with the presence of atherosclerotic disease independent of renal function and other risk factors. In conclusion, changes in hemostatic parameters occur early in the course of renal failure in patients with arteriolar nephrosclerosis, suggesting a prothrombotic state that may contribute to the risk for atherosclerotic disease at all levels of renal function.

Abnormalities of coagulation in hypertensive patients with reduced creatinine clearance.

PURPOSE: The prothrombotic state that occurs in uremic patients may increase their cardiovascular risk. We studied hypertensive patients with mild-to-moderate impairment of renal function to determine if they had evidence of abnormalities in the coagulation system. SUBJECTS AND METHODS: Renal function was assessed in 382 patients with essential hypertension, in whom 24-hour creatinine clearance, urinary protein excretion, and microalbuminuria were measured. We evaluated the function of the coagulation system by measurement of platelet counts, prothrombin time, partial thromboplastin time, and plasma antithrombin III, fibrinogen, D-dimer, and prothrombin fragment 1 + 2 levels. RESULTS: Impaired renal function, defined as a creatinine clearance of 30 to 89 mL per minute per 1.73 m(2) of body surface area, was found in 168 (44%) of the patients. Age, blood pressure, duration of hypertension, and plasma levels of fibrinogen, D-dimer, prothrombin fragment 1 + 2, and lipoprotein(a) were significantly greater in these patients than in those with normal renal function; these differences persisted after adjustment for potential confounders. Creatinine clearance was significantly and inversely correlated with levels of plasma fibrinogen (Spearman's rho = -0.26, P <0.001), D-dimer (rho = -0.33, P <0.001), and prothrombin fragment 1 + 2 (rho = -0.20, P <0.001). Levels of plasma fibrinogen (P = 0.009) and D-dimer (P = 0.003) were correlated with renal function independent of age, blood pressure, duration of hypertension, triglyceride level, urinary protein excretion, and erythrocyte sedimentation rate. Lipoprotein(a) levels were correlated with fibrinogen (rho = 0.16, P = 0.003) and D-dimer (rho = 0.26, P <0.001) levels. CONCLUSIONS: Increased plasma levels of fibrinogen, D-dimer, and prothrombin fragment 1 + 2 are present in hypertensive patients with mildly decreased creatinine clearance, suggesting that the coagulation system is activated in these patients.

Micronucleus yield and colorimetric test as indicators of damage in patients' lymphocytes after 131I therapy.

UNLABELLED: To estimate the absorbed dose received by patients who underwent 131I therapy, a modified compartmental model of the International Commission on Radiological Protection (ICRP) was used. The activity in plasma and micronucleus (MN) frequency (MN test) were measured before and after therapy. To evaluate whether a correlation exists between lymphocytes and absorbed dose, a colorimetric test, based on the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT test), was used. METHODS: Twenty patients who underwent 131I therapy were studied. Activity was measured in plasma, and isolated lymphocytes were collected to perform the MN and MTT tests. RESULTS: The mean MN frequency observed in unexposed patient lymphocytes was comparable with that of healthy subjects. 131I therapy induces a small increase in MN, and a good correlation with the bone marrow absorbed dose was obtained (P = 0.040). A consistent decrease in phytostimulation observed after therapy (MTT test) correlated significantly with bone marrow absorbed dose (P = 0.0085). CONCLUSION: The MTT test appears to be more reliable than the MN test for evaluating lymphocyte damage induced by 131I therapy.

Lipoprotein (a), haemostatic variables and cardiovascular damage in hypertensive patients.

OBJECTIVE: Lipoproteins and coagulation factors are independent predictors of atherothrombotic events in the general population and their interaction may contribute to the development of cardiovascular damage. This study was designed to assess relationships between lipoproteins, haemostatic variables, and atherosclerotic complications in hypertensive patients. METHODS: In 389 untreated essential hypertensive patients recruited at a hypertension clinic, we measured plasma lipids, apolipoproteins, lipoprotein (a), apolipoprotein (a) isoforms, fibrinogen, and parameters that directly reflect the coagulation activation. Hypertensive patients were compared to 92 normotensive controls. RESULTS: Univariate analysis showed log lipoprotein (a) concentrations to be significantly correlated with age (P< 0.02), apolipoprotein B (P< 0.02), plasma fibrinogen (P< 0.001), and fibrin D-dimer (P< 0.001) levels, but not with body mass index, blood pressure, dietary fat intake, cholesterol, triglycerides, apolipoprotein Al, prothrombin fragment 1 + 2, and antithrombin III. The relationship of lipoprotein (a) with fibrinogen and D-dimer was present in both sexes, whereas the relationship of lipoprotein (a) with age and apolipoprotein B was found only in males. Multiple regression analysis showed that both fibrinogen and D-dimer were independently related with lipoprotein (a). Elevated fibrinogen, D-dimer, and lipoprotein (a) levels were significantly and independently associated with clinical evidence of atherosclerotic disease. To investigate whether the relationships of lipoprotein (a) with coagulation parameters are genetically determined, we analysed apolipoprotein (a) phenotypes in a subset of 188 hypertensive patients. While lipoprotein (a) levels were inversely correlated with apolipoprotein (a) isoform protein size, both fibrinogen and D-dimer concentrations were comparable in patients with apolipoprotein (a) isoforms of different size. CONCLUSIONS: This study demonstrates a relationship between lipoprotein (a) and clotting variables in hypertensive patients that may contribute to atherosclerotic damage in these patients. There is no evidence of a genetic background for this relationship.

Relationship of fibrinogen levels and hemostatic abnormalities with organ damage in hypertension.

Elevated plasma levels of fibrinogen and activated coagulation pathways are risk factors of cardiovascular disease in the general population. In a cross-sectional study of a case series, we investigated the relationship between fibrinogen and hemostatic markers with target-organ damage (TOD) in patients with arterial hypertension. Prothrombin time, partial thromboplastin time, fibrinogen, fibrin D-dimer, prothrombin fragment 1+2 (F1+2), and antithrombin III were measured in 352 untreated patients with mild to moderate essential hypertension and 92 normotensive controls. Staging of TOD was assessed according to W.H.O. guidelines by clinical evaluation and laboratory tests including measurements of creatinine clearance, proteinuria, ophthalmoscopy, electrocardiography, echocardiography, and ultrasound examination of major arteries. F1+2 concentrations were significantly greater in hypertensive patients than normotensive controls and were positively correlated with blood pressure. Age, blood pressure levels, duration of hypertension, smoking, HDL-cholesterol, triglycerides, and plasma fibrinogen, fibrin D-dimer, and F1+2 levels were significantly related to the presence and severity of TOD in univariate analysis. Plasma fibrinogen and D-dimer levels were related to organ damage independent of age, blood pressure, duration of hypertension, and smoking status. Separate analysis indicated significant association of fibrinogen and D-dimer levels with cardiac, cerebrovascular, peripheral vascular, and renal damage. In conclusion, elevated plasma levels of fibrinogen and a prothrombotic state are associated with the presence and severity of TOD in patients with essential hypertension and may contribute to the development of atherosclerotic disease in these patients.

Lipoprotein(a) and apolipoprotein(a) isoforms and proteinuria in patients with moderate renal failure.

BACKGROUND: Atherosclerotic diseases are a major cause of death in patients with renal failure. Increased serum concentrations of lipoprotein(a) [Lp(a)] have been established as a genetically controlled risk factor for these diseases and have been demonstrated in patients with moderate renal failure, suggesting that this lipoprotein contributes to the increased cardiovascular risk seen in these patients. Variable alleles at the apolipoprotein(a) [apo(a)] gene locus are the main determinants of the serum Lp(a) level in the general population. The purpose of this study was to investigate apo(a) isoforms in patients with moderate renal failure and mild proteinuria (less than 1.0 g/day). METHODS: In 250 consecutive subjects recruited at a hypertension clinic, we assessed the renal function by 24-hour creatinine clearance, proteinuria, and microalbuminuria, as well as the prevalence of atherosclerotic disease, and we also measured apo(a) isoforms, serum albumin, and Lp(a) concentrations. RESULTS: Moderate impairment of renal function (creatinine clearance, 30 to 89 ml/min per 1.73 m2 of body surface area) was found in 97 patients. Lp(a) levels were significantly greater in patients with moderate renal failure (21.7+/-23.9 mg/dl) as compared with patients with normal renal function (15.6+/-16.4 mg/dl, P<0.001), and an inverse correlation was observed between log Lp(a) and creatinine clearance (r = -0.181, P <0.01). However, no difference was found in the frequency of low molecular weight apo(a) isoforms between patients with normal (25.5%) and impaired (27.8%) renal function. Only patients with the smallest size apo(a) isoforms exhibited significantly elevated levels of Lp(a), whereas the large-size isoforms had similar concentrations in patients with normal and impaired renal function. No significant relationship was found between serum Lp(a) and proteinuria. Clinical and laboratory evidence of one or more events attributed to atherosclerosis was found in 9.8% of patients with normal renal function and 25.8% of patients with moderate renal failure (P<0.001). CONCLUSIONS: These results indicate that renal failure per se or other genes beside the apo(a) gene locus are responsible for the elevation of serum Lp(a) levels in patients with moderate impairment of renal function. The elevation of Lp(a) levels occurs independently of the level of proteinuria and may contribute to the risk for atherosclerotic disease in these patients.

Increased serum lipoprotein(a) levels in patients with early renal failure.

BACKGROUND: Elevated serum lipoprotein(a) levels have been found in patients with end-stage renal disease and in patients undergoing dialysis, suggesting that this lipoprotein contributes to the increased cardiovascular risk seen in these patients. It is not known whether lipoprotein(a) levels are elevated in the early phases of renal disease. OBJECTIVE: To evaluate levels of lipoprotein(a) and other lipids and the prevalence of atherosclerotic disease in patients with early renal failure. DESIGN: Cross-sectional study. SETTING: Hypertension clinic of a university medical center. PATIENTS: 257 patients with normal renal function and 160 patients with early impairment of renal function (creatinine clearance, 30 to 89 mL/min per 1.73 m2 of body surface area). MEASUREMENTS: Renal function was assessed by 24-hour creatinine clearance, proteinuria, and microalbuminuria. Cardiovascular disease status was also assessed. Serum lipoprotein(a), lipids, apolipoproteins, and apolipoprotein(a) isoforms were measured. RESULTS: Age, blood pressure, and serum lipoprotein(a) levels were greater in patients with early renal failure than in those with normal renal function and were independently associated with the presence of decreased creatinine clearance. Serum lipoprotein(a) and creatinine clearance were inversely correlated. The prevalence of coronary artery, cerebrovascular, and peripheral vascular disease was greater in patients with early renal failure than in those with normal renal function. The frequency distribution of apolipoprotein(a) isoforms was similar in patients with normal and those with impaired renal function. CONCLUSIONS: Serum lipoprotein(a) levels are elevated in patients with early impairment of renal function and are associated with greater prevalence of cardiovascular disease. An inverse correlation between serum lipoprotein(a) level and creatinine clearance and a frequency distribution of apolipoprotein(a) isoforms similar to that of normal patients point to decreased renal catabolism as a probable mechanism of lipoprotein(a) elevation in patients with early renal failure.

Glucose metabolism and insulin receptor binding and mRNA levels in tissues of Dahl hypertensive rats.

Increased insulinemic response to an oral glucose load has been demonstrated in Dahl salt-sensitive hypertensive rats. To determine whether this abnormality is mediated at the level of the insulin receptor, we compared insulin receptor binding and mRNA levels in tissues of Dahl salt-sensitive rats (DS) and in their normotensive controls, Dahl salt-resistant rats (DR). To evaluate possible influences of dietary sodium intake, rats were fed either low (0.07% NaCl) or high salt (7.5% NaCl) chow until the DS became hypertensive, and then were killed by decapitation. Fasting plasma glucose and plasma insulin levels did not differ between DR and DS rats and were not affected by salt intake. In response to an oral glucose load, plasma glucose had a similar increase in DR and DS rats, but the increase in plasma insulin was significantly greater in DS rats. Scatchard analysis of binding was obtained from in situ autoradiographic studies performed in frozen skeletal muscle and kidney sections, and insulin receptor mRNA levels were measured by slot-blot hybridization. Number and affinity of insulin receptors were comparable in skeletal muscle and kidney of DR and DS rats and, in both groups, binding parameters were not affected by dietary sodium chloride. Hepatic and renal insulin receptor mRNA levels were also comparable in DR and DS rats fed either low or high salt chow. Thus, increased plasma insulin response to oral glucose load is associated with normal insulin receptor binding and gene expression in peripheral tissues in rats with Dahl hypertension. A postreceptor defect is likely responsible for the decreased sensitivity to insulin in this model of genetic hypertension.

Peripheral blood lymphocyte decrease and micronucleus yields during radiotherapy.

PURPOSE: To investigate the relationship between lymphocyte decrease and cytogenetic response in individual patients undergoing radiotherapy. MATERIALS AND METHODS: Peripheral blood lymphocytes obtained from 35 patients with pelvic and from 14 with head and neck tumours before and during radiotherapy were PHA-stimulated in vitro and the cultures prepared for the cytokinesis-block micronucleus test. For some patients only, the micronucleus test was carried out after 2 Gy in vitro X-irradiation, and 3-aminobenzamide (2 mM) was used to calculate the 3AB-index. RESULTS: The initially observed individual variation in the decrease of lymphocytes disappeared with increasing number of radiation exposures, reaching a stable level at about 500/microl lymphocytes in the blood. The slope of the relationship between the reciprocal of the lymphocyte decrease ratio and equivalent dose indicates the radiosensitivity of the lymphocyte pool in individual patients. The micronucleus test performed on lymphocytes obtained from patients during radiotherapy (in vivo) provided a lower cytogenetic response than the in vitro micronucleus yield for the same dose, so it was possible to calculate the cytogenetic recovery factor k. A correlation was found between the 3AB-index calculated before radiotherapy, and the recovery factor k. CONCLUSIONS: The 3AB-index, the micronucleus frequency after 2 Gy in vitro X-irradiation, and the cytogenetic recovery factor are proposed as predictive of individual response to radiotherapy.