Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension

BACKGROUND : Hypertension is a complex trait with an ill-defined genetic predisposition, in which adrenergic mechanisms seem to be involved even at the early stages. Chromogranin A is a pro-hormone stored and released with catecholamines by exocytosis; its fragment catestatin, formed in vivo, inhibits further catecholamine release as an antagonist at the physiologic trigger for secretion, the neuronal nicotinic cholinergic receptor. METHODS : We measured catestatin by radioimmunoassay in n = 277 subjects stratified by blood pressure (n = 61 hypertensive, n = 216 normotensive), and if normotensive by genetic risk of developing hypertension: family history positive (n = 176) versus negative (n = 40). Maximum likelihood analysis tested for bimodality. Involvement of catestatin in pathophysiology was probed by measurements of catecholamines and leptin, and the hemodynamic responses to environmental (cold) stress. RESULTS : The normotensive offspring of patients with hypertension already had diminished catestatin (P = 0.024), and family history was a better predictor of catestatin than age, ethnicity or gender (P = 0.014). Greater catestatin variance among family history-positive individuals (P = 0.021) suggested heterogeneity in this group, and a bimodal distribution (P < 0.001) identified 4.3% of individuals in a lower mode of catestatin values, all with positive family histories (P = 0.05). Catestatin correlated inversely with body mass index (r = -0.215, r(2) = 0.046, n = 276, P < 0.001) and plasma leptin (r = -0.203, r(2) = 0.041, n = 212, P = 0.003), while body mass index and leptin correlated directly (r = 0.59, r(2) = 0.350, n = 212, P < 0.001). Family history-positive individuals had greater epinephrine excretion (P = 0.037) in addition to diminished catestatin, suggesting an inhibitory effect of catestatin on chromaffin cells in vivo. Low plasma catestatin predicted enhanced pressor response to a sympathoadrenal stressor (cold stress; r = -0.184, r(2) = 0.034, n = 211, P = 0.007), suggesting an adrenergic mechanism whereby diminished catestatin might predispose to later development of hypertension. In white subjects, diminished catestatin also predicted greater systemic vascular resistance responses to cold stress (r = -0.307, r(2) = 0.094, n = 75, P = 0.007), a relationship not found in Blacks (r = 0.122, r(2) = 0.015, n = 94, P = 0.243). CONCLUSIONS : We conclude that catestatin is diminished early in the course of development of hypertension, even in the normotensive offspring of patients with the disease. Low catestatin predicts augmented adrenergic pressor responses, suggesting a mechanism whereby diminished catestatin might increase the risk for later development of hypertension.     

Circulating amylin in human essential hypertension: heritability and early increase in individuals at genetic risk

BACKGROUND: Human essential hypertension is a complex trait with poorly understood genetic determination. Insulin resistance is frequently associated with this trait. OBJECTIVE: To determine whether a potentially pathogenic feature of the insulin-resistant state, circulating amylin (islet amyloid polypeptide, co-released with insulin from pancreatic islet beta-cells), is already increased in prehypertensive individuals (normotensive persons at genetic risk of hypertension because of family history), whether such individuals already differ in their amylin response to beta-cell stimulation, and whether plasma amylin concentration is heritable. Such features could establish increased circulating amylin as a hereditary 'intermediate phenotype' useful in genetic analyses of hypertension. METHODS: Plasma amylin and insulin were measured in 283 medication-free individuals stratified by blood pressure status (82 hypertensive and 201 normotensive), and genetic risk (family history) of hypertension. Differences in means were tested by ANOVA, variances by F test, and frequency distributions by maximum likelihood analysis. Co-release of amylin and insulin was provoked by intravenous infusion of mixed amino acids. The effect of antihypertensive treatment was evaluated after monotherapy with either angiotensin converting enzyme inhibition or calcium-channel blockade in hypertension. RESULTS: Plasma amylin was increased in hypertension (P= 0.027), and body mass index was a strong predictor of increased circulating amylin (P = 0.0001). Plasma amylin and plasma renin activity were not correlated (P = 0.395), and effective antihypertensive monotherapy with either angiotensin converting enzyme inhibition or calcium-channel blockade did not affect either amylin (P = 0.87-0.97) or insulin (P= 0.55-0.59). Among normotensive individuals, those at genetic risk of hypertension (with positive family history) already had increased concentrations of amylin (P< 0.001), despite exhibiting no difference in blood pressure or body mass index compared with the family-history-negative group; however, among normotensive individuals, both family history (P = 0.043) and body mass index (P= 0.0059) were significant predictors of increased concentrations of amylin. By maximum likelihood analysis, plasma amylin was distributed heterogeneously in the normotensive individuals, with two modes best explaining the distribution (chi2 = 77.4, P< 0.001), and family-history-positive individuals completely accounting for the upper mode (chi2 = 4.63, P = 0.031). Family-history-positive normotensive individuals showed greater plasma amylin concentrations both before and during beta-cell stimulation by amino acid infusion (P = 0.014). Black (n = 111) and white (n = 172) individuals did not differ in mean (P = 0.946) or variance (P = 0.172) of plasma amylin concentrations. CONCLUSIONS: These results suggest that plasma amylin concentration is in part determined by heredity. Both basal and stimulated plasma amylin excess may identify a subgroup of individuals bearing an inherited predisposition to hypertension. Measurement of amylin might identify a useful 'intermediate phenotype' in the genetic analysis of essential hypertension and its relationship to insulin resistance.     

Neural mechanisms of genetic risk for impulsivity and violence in humans

Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.     

Renal proximal tubule sodium transport and genetic mechanisms of essential hypertension

Renal sodium re-absorption is a closely regulated process serving to maintain both extracellular fluid volume and arterial blood pressure. Proteins participating in sodium re-absorption and its regulation are therefore important candidate proteins whose genes may contain sequence variation contributing to the inherited tendency for increased arterial blood pressure (essential hypertension). Important insight has come from rare forms of single-gene hypertension in human subjects and from polygenic animal models of genetic hypertension. Both indicate the primacy of altered renal function in the genesis of hypertension, and suggest that genes contributing to the disease are members of the subset of genes expressed in the kidney. This review examines evidence for abnormalities in renal sodium re-absorption in hypertension and focuses on the proximal tubule as a site of relevant dysfunction. Identification of the proteins participating in renal sodium re-absorption and its regulation, particularly those involved in the renal pressure-natriuresis mechanism, will allow gene cloning and sequencing which in turn may lead to the identification of novel gene sequence variation participating in hypertension.     

Left ventricular mass and glomerular hyperfiltration in essential hypertension

OBJECTIVE: to assess the early involvement to target organs in never treated essential hypertensives (HT). METHODS: effective renal plasma flow (ERPF, 131I-Hippurate) and glomerular filtration rate (GFR, 99mTc-DTPA) were estimated in 80 mild HT. Left ventricular mass (LVM, M-mode echocardiography), sodium intake (24h UNaV) and urinary kallikrein (Kall) were also measured. Hyperfiltering patients (HF, GFR = 155 +/- 3 ml/min: 1.73 m2, n = 21) were defined by comparison with age-matched normotensive. HF patients were pair-matched for age, sex and blood pressure level with normofiltering hypertensives (NF, GFR = 112 +/- 3, n = 21). RESULTS: are expressed as mean +/- sem [table: see text] CONCLUSION: These results suggest that a high Na intake is associated with hyperfiltration and higher LVMI in subjects with never treated essential hypertension of short duration.     

Arrhythmic risk in essential hypertension: late potentials

AIM: A higher incidence of cardiac death exists in patients with essential hypertension, and it is higher still in those with ventricular arrhythmia. The purpose of noninvasive diagnostic imaging in hypertensive patients is to determine those with a greater risk for arrhythmia. In previous studies on hypertension, one of the inclusion criteria is diastolic blood pressure <95 mmHg, which, however, is a low selectivity criterion. Instead, our study emphasizes the need to evaluate the incidence of ventricular arrhythmia in hypertensive patients not yet receiving drug therapy and to formulate the diagnosis based on 24-h ambulatory arterial blood pressure monitoring, which represents a more selective criterion than the diastolic pressure value proposed by the World Health Organization (WHO). METHODS: A total of 128 consecutive patients with essential hypertension classified according to WHO criteria underwent 24-h monitoring, 85 (66.4%) of which presented with a mean 24-h arterial pressure >135/85 mmHg. These patients were then evaluated using mono- and two-dimensional echocardiography and 24-h dynamic Holter monitoring to detect arrhythmias and the presence of left ventricular later potentials. RESULTS: Left ventricular hypertrophy was present in 60 (70.6%) patients and absent in 25 (29.4%). Based on the Lown classification of ventricular arrhythmia, 20 (23.5%) patients had Grade I arrhythmia, 5 (5.9%) Grade II, 4 (4.7%) Grade III, 9 (10.6%) Grade IVA, 20 (23.5%) Grade IVB, 12 (14.1%) Grade V, 15 (17.6%) clinically unremarkable arrhythmia, and 17 (20%) had late potentials because they tested positive to at least 2 out of three criteria, and 2 patients were positive to all 3 criteria. CONCLUSION: Our study findings demonstrated a significant correlation between left ventricular hypertrophy and grade of arrhythmia (r=0.552; p<0.0001) and late potentials (r=0.405; p<0.001). The presence of late potentials was also found to correlate significantly with grade of arrhythmia (r=0.593; p<0.001). These patients present with a more severe stage of the disease and should therefore receive more aggressive treatment to prevent sudden cardiac death resulting from arrhythmia.     

The genetic basis of essential hypertension

During the last few years the studies on the genetic basis of essential hypertension (EH) have been numerous, allowing however only a partial understanding of the underlying molecular mechanisms. The most used techniques were the candidate gene approach, genome-wide scanning, the intermediate phenotype approach and comparative-genomics in animal models. The renin-angiotensin-aldosterone system may play a prominent role in the genesis of hypertension, and polymorphisms of the genes coding for angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 and 2 receptors, and aldosterone synthase have been widely studied. Other mechanisms may involve the KLK 1 gene of tissue kallikrein, gene variants of endothelial nitric oxide synthase and polymorphisms of the endothelin-1 gene. Finally, a number of studies have highlighted the potential contribution of polymorphisms of genes coding for inflammatory cytokines, adrenergic receptors and intracellular G proteins, which can activate Na+/K+ exchangers. Further important information might derive from proteomic analysis and the study of mitochondrial genome. Overall, results have often been discordant, sometimes suggesting a different expression of the same gene variants in different populations. EH is a highly polygenic condition, caused by the combination of small changes in the expression of many genes, in conjunction with a variable collection of environmental factors.     

原发性高血压患者肾小球滤过率减退相关因素分析

目的 :探讨原发性高血压 (EH)患者肾小球滤过率减退的相关因素。方法 :95例EH患者均进行放射性核素肾动态显像 ,根据肾小球滤过率 (GFR)有无减退分成两组 ,并进行年龄、病程、血脂、尿素氮 (BUN)、血肌酐 (Cr)、血尿酸 (UA)、纤维蛋白原 (Fib)、尿微量白蛋白 (MAU)、尿α1 微球蛋白 (α1 MG)、最大收缩压 (SBP max)、最大舒张压 (DBPmax)及肾有效血浆流量 (ERPF)的组间比较 ,同时进行多元回归统计分析。结果 :EH患者GFR下降组在年龄、病程、血Cr、肾有效血浆流量、尿α1 MG、SBPmax、DBPmax方面与GFR正常组比较差异均有显著性意义 (P <0 .0 1) ,总胆固醇、三酰甘油两组间未见明显差异 (P >0 .0 5 )。多元回归分析显示 :GFR水平与ERPF水平呈正相关 ,与舒张压呈负相关 (P <0 .0 1)。结论 :EH患者GFR减退是多种因素作用的结果     

Primary aldosteronism and essential hypertension: Assessment of cardiovascular risk at diagnosis and after treatment

Background and aimsPrimary aldosteronism (PA), the most frequent form of secondary hypertension, is characterized by a higher rate of cardiovascular (CV) events than essential hypertension (EH).Aim of the study was to evaluate the cardiovascular risk according to the ESH/ESC 2007 guidelines, in patients with PA and with EH, at diagnosis and after treatment.Methods and resultsWe prospectively studied 102 PA patients (40 with aldosterone producing adenoma-APA and 62 with idiopathic hyperaldosteronism-IHA) and 132 essential hypertensives at basal and after surgical or medical treatment (mean follow-up period 44 months for PA and 42 months for EH).At baseline evaluation the stratification of CV risk was significantly different: the predominant risk category was the high CV risk (50% in total PA, 53% in PA matched for blood pressure values and 55% in EH), but the very high risk category was twice in PA than in EH patients (36% in total PA and 33% in matched PA vs. 17% in EH, p < 0.05). The worse risk profile of PA was due to a higher prevalence of glycemic alterations, metabolic syndrome and left ventricular hypertrophy (LVH) (p < 0.05).After adequate treatment, the CV risk was significantly reduced becoming comparable in PA and in EH patient due to a reduction of hypertension grading, prevalence of metabolic syndrome, hypertension persistence and LVH (p < 0.05).ConclusionPatients with PA present a high CV risk, which is in part reversible after specific treatment, due both to the reduced blood pressure values and to the improvement of end-organ damage.     

Echocardiographic evaluation of coronary flow reserve in patients with essential hypertension

BACKGROUND: In patients with essential arterial hypertension (EAH) the left heart ventricular hypertrophy (LVH) causes structural and functional alterations of the coronary vessels that can alter the coronary blood flow reserve. The aim of this study is to evaluate in hypertensive patients with or without LVH versus normotensive subjects, the blood flow and the coronary vasodilatation capability and the coronary blood flow reserve in basal conditions and during dipiridamole i.v. infusion. METHODS: Eighty patients have been selected by ECG, echo color Doppler, transesophageal echocardiography: 50 were hypertensive patients with and without LVH, from mild to moderate to severe and 30 were normotensive subjects. The enrolled patients underwent a first transesophageal echocardiography, before and during infusion of 0.86 mg/kg of dipiridamole in growing doses, 0.56 in four minutes followed after three minutes by 0.30 mg/kg. The observation lasted 18 months, and no patients left the study. RESULTS: The coronary resistances in hypertensive patients were significintally reduced during dipiridamole infusion, maintaining their level higher compared to the normal controls. The reduced coronary vasodilatation capability in hypertensive subjects could be due to an increase of the basal vessel tone and/or a reduced compliance of the coronary resistances. The coronary blood flow reserve is significantly reduced in all hypertensive studied, included those without LVH. It is suggested that this is secondary to increase of the coronary blood flow and tone. CONCLUSIONS: In conclusion essential arterial hypertension is the cause of early anatomical and functional coronary alterations leading hypertensive subjects to risk for coronary events before LVH.     

Renal functional reserve in humans. Effect of protein intake on glomerular filtration rate

This study was designed to investigate the effect of protein intake on glomerular filtration rate, and to demonstrate and evaluate the functional reserve of the kidney. Normal subjects ingesting a protein diet had a significantly higher creatinine clearance than a comparable group of normal subjects ingesting a vegetarian diet. A progressive increment in protein intake in normal volunteers resulted in a significant increase in creatinine clearance. Diurnal variations in creatinine clearance were found. These daily variations correlated well with the periods of food intake. The capacity of the kidney to increase its level of function with protein intake suggests a renal function reserve. In short-term studies, the effect of a protein load on glomerular filtration rate was evaluated. Normal subjects showed an increase in glomerular filtration rate two and a half hours after protein load to a maximal glomerular filtration rate of 171.0 +/- 7.7 ml per minute. In patients with a reduced number of nephrons, renal functional reserve may be diminished or absent.     

Risk factors for glomerular injury in rats with genetic hypertension

Systemic and glomerular hypertension, hyperlipidemia, and massive proteinuria have been described as risk factors for the development of focal glomerulosclerosis (FGS). Previous studies have shown that Dahl salt-sensitive (S) rats with severe hypertension have elevated glomerular pressures and develop extensive FGS. In the present study, we determined whether Dahl S rats exhibit other risk factors for FGS. Dahl S rats were found to have elevated serum triglycerides at six weeks of age, compared to Dahl salt-resistant (R) rats. Between six and 24 weeks, systemic hypertension and progressive increases in both serum lipids and albuminuria occurred in Dahl S rats fed high salt (4% NaCl) chow. No changes in blood pressure or serum lipids occurred in Dahl R rats fed high salt. At 30 weeks, the incidence of FGS was 20 times greater in hypertensive Dahl S than in Dahl R. In a separate study, we compared risk factors for FGS in Dahl S rats and spontaneously hypertensive rats (SHR). The magnitude of glomerular capillary pressure, serum lipid levels, and urine albumin excretion were measured in male Dahl S rats and male SHR between 12 and 20 weeks of age. Normal values for the various parameters were established in a group of normotensive male Sprague-Dawley rats. For this study, all rats were fed standard chow containing 0.6% NaCl. Blood pressure was elevated (P less than .01) in Dahl S (142 +/- 2 mm Hg) and in SHR (173 +/- 3 mm Hg) compared to the Sprague-Dawley rats (117 +/- 3 mm Hg). Glomerular capillary pressure, however, was similar in all three groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Prediction of genetic risk for hypertension

Although genetic epidemiological studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. Large-scale association studies that examine many gene polymorphisms simultaneously are required to predict genetic risk for hypertension. The population of the present study comprised 1940 unrelated Japanese individuals, including 1067 subjects with hypertension (574 men, 493 women) and 873 controls (533 men, 340 women). The genotypes for 33 single nucleotide polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that 2 polymorphisms (825C-->T in the G protein beta3 subunit gene and 190G-->A in the CC chemokine receptor 2 gene) were significantly associated with hypertension in men and that one polymorphism (-238G-->A in the tumor necrosis factor alpha gene) was significantly associated with hypertension in women. These results suggest that 2 and 1 genes may be susceptibility loci for hypertension in Japanese men and women, respectively, and that genotyping of these polymorphisms may prove informative for prediction of the genetic risk for hypertension.     

Prediction of genetic risk for hypertension

BACKGROUND: Although genetic epidemiological studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. Large-scale association studies that examine many gene polymorphisms simultaneously are required to predict genetic risk for hypertension. METHODS and RESULTS: The population of the present study comprised 1,940 unrelated Japanese individuals, including 1,067 subjects with hypertension (574 men, 493 women) and 873 controls (533 men, 340 women). The genotypes for 33 single nucleotide polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that two polymorphisms (825C -> T in the G protein beta3 subunit gene and 190G -> A in the CC chemokine receptor 2 gene) were significantly associated with hypertension in men and that one polymorphism (-238G -> A in the tumor necrosis factor- alpha gene) was significantly associated with hypertension in women. CONCLUSION: These results suggest that two and one genes may be susceptibility loci for hypertension in Japanese men and women, respectively, and that genotyping of these polymorphisms may prove informative for prediction of the genetic risk for hypertension.     

Renin as a risk factor in essential hypertension: More evidence

When patients with essential hypertension are classified into three major subgroups according to their plasma renin levels, they appear to exhibit different physiologic and epidemiologic characteristics. The present study extends previous observations which have suggested that low renin patients are relatively protected from development of heart attacks and strokes.Low renin patients despite the fact that they are older, exhibit lower blood urea levels than patients in the other two groups. These data are in keeping with the idea that low renin patients have relatively less renal vascular involvement.Young hypertensive blacks, known to be most prone to severe hypertension with vascular complications, practically always fall into the normal renin subgroup, whereas, in contrast, a vast majority of those blacks above the age of 50, with relatively milder hypertensive disease, exhibit low renin levels.These new findings which further associate vascular sequellae with the normal or high renin state provide more support for the concept that low renin patients have a relatively benign type of hypertensive disease.Nonhomogeneity of the low renin hypertensive population and differences in methodologic and physiologic approaches used to define such patients may provide the basis for conflicting observations from certain laboratories.