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Background Hyperhomocysteinemia and the metabolic syndrome are established cardiovascular risk factors and are frequently associated with hypertension. The relationship of plasma homocysteine (Hcy) with the metabolic syndrome and insulin resistance, however, is debated and studies in hypertensive patients are limited. In this study, we have investigated the association of Hcy with the metabolic syndrome and cerebro- cardiovascular events in hypertension. Methods In 562 essential hypertensive patients who underwent accurate assessment of fasting and postload glucose metabolism, insulin sensitivity, and renal function, we measured plasma levels of Hcy, vitamin B12, folate, and fibrinogen and assessed the prevalence of the metabolic syndrome and of coronary heart and cerebrovascular disease (CVD). Results Patients with the metabolic syndrome had significantly higher plasma Hcy levels. After correction for covariates, increasing Hcy levels were associated with an increasing prevalence of the metabolic syndrome, coronary heart disease, and CVD. Plasma Hcy was directly correlated with age, waist circumference, fasting glucose, triglyceride, uric acid, and fibrinogen levels, and homeostatic model assessment index and inversely with creatinine clearance and high-density lipoprotein cholesterol, vitamin B12, and folate levels. Logistic regression analysis showed an independent association of Hcy levels with age, male gender, vitamin B12 and folate levels, and the metabolic syndrome. Logistic regression indicated also an independent association of Hcy with cerebro-cardiovascular disease that was independent of the metabolic syndrome. Conclusions Elevated plasma Hcy is associated with the metabolic syndrome in hypertensive patients. Prevalence of events increases with increasing plasma Hcy levels suggesting a contribution of Hcy to cerebro-cardiovascular diseases in these patients.

Background Primary aldosteronism (PA) is associated with an increase in left ventricular (LV) mass beyond the amount needed to compensate the hypertension-related workload. Available evidence suggests effectiveness of surgical treatment of PA in decreasing LV mass, whereas data on medical treatment are controversial. We have conducted a meta-analysis of long-term follow-up studies on surgical and medical treatment of PA to compare the effects of treatments on LV mass. Methods Medline and Cochrane searches were performed including the following words: hyperaldosteronism, left ventricular mass, mineralocorticoid receptor antagonists, surgery, adrenalectomy, and follow-up studies. Studies published within 2013 focusing on cardiac effects of treatment and follow-up longer than 6 months were selected. Data extraction was performed independently by 2 authors. Results Of 61 retrieved articles, 4 were included in the analysis. These studies enrolled 355 patients with PA who had an average follow-up of 4.0 years after unilateral adrenalectomy (n = 178) or treatment with mineralocorticoid receptor antagonists (n = 177). Despite greater effect of surgery over medical treatment in reducing blood pressure, meta-analysis of the selected studies demonstrated no significant difference in LV mass change between patients with PA who were treated with mineralocorticoid receptor antagonists or adrenalectomy (standard mean difference = 0.130; 95% confidence interval = -0.085 to 0.345; P = 0.24; I2 = 0%). Conclusions Available evidence indicates that reduction of LV mass is not different in PA patients treated with adrenalectomy or mineralocorticoid receptor antagonists.

Background Studies on fish oil effects on ambulatory blood pressure (ABP) are inconclusive. We evaluated fish effects on fatty acid composition of red blood cell (RBC) membrane and ABP values and tested the hypothesis that the starting membrane fatty acid composition affects the ability to incorporate additional polyunsaturated fatty acids (PUFA) and decrease blood pressure. Methods In 55 hypertensive patients, we measured RBC membrane fatty acid by gas chromatography and performed ABP monitoring. Patients received nutritional counseling and 3 weekly meals of trout rich in PUFA. In 42 patients, RBC membrane fatty acid and ABP were reassessed after 6 months. Results At baseline, the PUFA/saturated fatty acid (SFA) ratio of RBC membrane (PUFA/SFA) was inversely related to 24-hour, daytime, and nighttime systolic and pulse pressure, a relationship that was independent of covariables. At follow-up, the PUFA/SFA ratio increased in 20 (48%) of 42 patients. Patients with increased PUFA/SFA ratio at follow-up had lower baseline PUFA/SFA ratio than patients without such increase. Fish meal supplementation decreased 24-hour systolic and diastolic pressure only in patients who had increased PUFA/SFA ratio, a change that was more prominent during the nighttime. The change in PUFA/SFA was inversely and independently related to the change in 24-hour systolic and pulse pressure, and a logistic regression analysis indicated low baseline PUFA/SFA ratio as the only independent predictor of PUFA/SFA increase and blood pressure decrease. Conclusions The ability of fish meals to increase membrane PUFA content and decrease blood pressure in hypertensive patients depends upon the starting membrane fatty acid composition.

To investigate the relationships between the sympathetic nervous system (SNS) and parameters of glucose metabolism in arterial hypertension, daily urinary excretion of catecholamines and plasma glucose, insulin, and C-peptide response to an oral glucose load (OGL) have been evaluated in 77 untreated patients with mild-to-moderate essential hypertension and in 31 normotensive controls. Urinary excretion of norepinephrine (UNE) was positively correlated with body mass index and with plasma glucose levels both at fast and after OGL. No correlations were found between urinary excretion of catecholamines and plasma insulin and C-peptide levels both at fast and in response to OGL. Because the frequency distribution of UNE was bimodal, hypertensive subjects were separated into two subgroups using an arbitrary cutoff, and the parameters of glucose metabolism were compared. Subjects with UNE205 microg/day had greater levels of fasting glucose and greater glycemic response to OGL than subjects with UNE205 microg/day, whereas no significant differences between the groups were found in fasting and stimulated plasma insulin and C-peptide. Thus, activation of SNS is related to glucose tolerance but not hyperinsulinemia and insulin hypersecretion in essential hypertension. Plasma glucose levels, independent of insulin, may contribute to the relationship between SNS activity and blood pressure in essential hypertension.

Angiotensin II (Ang II) may act as an angiogenic and growth promoting factor in different tissues. To assess the role of Ang II in compensatory renal growth following unilateral nephrectomy (UNX), we measured renin, angiotensinogen, and Ang II type 1 (AT1) receptor mRNA levels, as well as Ang II receptor density, in two groups of Sprague-Dawley rats 7 days after either sham operation or UNX. Half of each group received either no treatment or an angiotensin-converting enzyme inhibitor (100 mg/dL captopril in the drinking water, initiated at the time of the intervention). Following UNX, the ratio of kidney weight to body weight (KW/BW) in untreated animals was greater than in rats undergoing sham UNX (0.46 ± 0.01 v 0.37 ± 0.01%, P < .01). Neither renal renin, nor renal or hepatic angiotensinogen mRNA levels, determined by slot blot hybridization, changed significantly after UNX. Ang II receptor density in glomeruli, determined using an 125I-Sar1-IIe8 Ang II in situ receptor binding assay on frozen kidney sections, did not change significantly after UNX, nor did renal AT1 receptor mRNA. In captopril-treated rats, KW/BW was greater in UNX than in sham operated rats (0.44 ± 0.01 v 0.37 ± 0.01%, P < .01), similar to results in untreated animals. Renal and hepatic angiotensinogen mRNA levels were not affected by captopril treatment and did not change further in response to UNX. Captopril treatment increased renin mRNA in both sham operated and UNX rats as compared with untreated controls, but had no significant effect on Ang II receptor density and AT1 receptor mRNA; and no change was observed in either variable as a consequence of UNX. Thus, compensatory renal hypertrophy following UNX occurred in the absence of measurable changes in components of the renin-angiotensin system, and despite functionally significant inhibition of this system by captopril. These data do not support a critical role for Ang II in compensatory renal hypertrophy.

BACKGROUND Changes in left ventricular (LV) diastolic filling anticipate diastolic heart failure and are frequently detected in patients with hypertension or diabetes. We tested the hypothesis that increased fasting and postload glucose levels are associated with diastolic dysfunction as assessed by tissue Doppler imaging (TDI) in hypertensive patients. METHODS In 104 untreated, nondiabetic, hypertensive patients free of cardiovascular complications, we measured glucose and insulin at fast and after an oral glucose load, calculated the Homeostatic Model Assessment (HOMA) index, and performed electrocardiogram (ECG), conventional echocardiography, and TDI. RESULTS Thirty-one patients who had impaired fasting glucose/impaired glucose tolerance had more frequent LV strain at ECG and worse TDI markers of diastolic function than patients with normal plasma glucose but no differences in variables LV mass, LV geometry, systolic function, and early-/late-wave transmitral diastolic velocity. TDI detected diastolic dysfunction in 46 patients who were older and had greater body mass index, blood pressure, fasting and postload glucose, insulin, HOMA index, LV mass, and left atrial diameter than patients with preserved diastolic function. Variables of diastolic function measured at TDI were significantly related with age, body mass index, LV mass, and fasting and postload plasma glucose. Stepwise regression analysis showed that the relationship of markers of diastolic dysfunction with both fasting and postload glucose levels was independent of possible confounders. CONCLUSIONS Initially abnormal fasting and postload glucose levels are associated with more prominent diastolic impairment in uncomplicated hypertensive patients, suggesting that hyperglycemia might increase the risk of diastolic heart failure even in the absence of diabetes.

Primary aldosteronism (PA) is one of the common forms of curable hypertension. Recent views have suggested that PA is far from being relatively benign, as it was previously thought, but it is associated with a variety of cardiovascular and renal sequelae that reflect the capability of inappropriately elevated aldosterone to induce tissue damage over that induced by hypertension itself. The evidence supporting these views has been obtained from experiments conducted in hypertensive animal models and studies involving patients with PA. Preclinical studies have also indicated that aldosterone causes cardiovascular and renal tissue damage only in the context of inappropriate salt status. It has been suggested that untoward effects of high-salt intake are dependent on activation of mineralocorticoid receptors (MRs) that might result from increased oxidative stress and changes in the intracellular redox potential. Unilateral adrenalectomy or treatment with MR antagonists are the current options for treating an aldosterone-producing adenoma (APA) or idiopathic adrenal hyperplasia (IHA). Treatments are effective in correcting hypertension and hypokalemia, and currently available information on their capability to prevent cardiovascular events and deterioration of renal function indicates that surgery and medical treatment are equally beneficial in the long term.

Background components of the renin–angiotensin–aldosterone system (RAAS) and a prothrombotic state are predictors of cardiovascular events in hypertensive patients. A relationship between the RAAS and the coagulation/fibrinolytic systems has been demonstrated, but its clinical relevance in hypertension is unclear. We investigated the relationships of the RAAS and the hemostatic system with hypertensive organ damage. methodS Plasma components of the RAAS and parameters that directly assess the activation of coagulation and fibrinolysis were measured in 247 essential hypertensive patients in whom the extent of organ damage had been characterized at the cardiac, renal, and vascular level. reSult S Positive association with increasing plasma renin activity (PRA) was demonstrated for plasma fibrinogen, d-dimer, and plasminogen activator inhibitor-1 (PAI-1) levels. PRA was directly correlated with plasma aldosterone, fibrinogen, d-dimer, and PAI-1. The relationship of PRA with fibrinogen and PAI-1 remained significant after correction for age, gender, duration of hypertension, and smoking status. Plasma aldosterone levels were directly correlated with fibrinogen, d-dimer, and PAI-1, whereas plasma angiotensinconverting enzyme was not related with any of the coagulation parameters. Elevated PRA, aldosterone, fibrinogen, d-dimer, prothrombin fragment 1+2, and PAI-1 levels were associated with clinical and/or instrumental evidence of hypertension-related cardiac and renal damage. Both fibrinogen and PAI-1 were independent predictors of the presence of organ damage and their inclusion in a multivariate model eliminated PRA and aldosterone as independent predictors. concluSionS A strong and independent association exists between renin, aldosterone, and markers of a prothrombotic state in essential hypertension. This relationship might contribute to the development of hypertensive organ damage.

BACKGROUND Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity in hypertension. Current evidence suggests a contribution to LVH of plasma aldosterone levels that are inappropriately elevated for the salt status. The aim of this study was to investigate whether inappropriate modulation of aldosterone production by a saline load is associated with left ventricular (LV) mass in hypertensive patients. METHODS In 90 hypertensive patients free of clinically relevant cardiovascular complications in whom secondary forms of hypertension were ruled out, we performed a standard intravenous saline load (0.9% NaCl, 2 l in 4 hours) with measurement of plasma aldosterone and active renin at baseline and end of infusion. Bi-dimensional echocardiography was performed for the assessment of cardiac morphology and function. RESULTS LVH was present in 19% of patients who had significantly worse renal function and higher body mass, blood pressure, and plasma aldosterone levels measured both at baseline and after the saline load than patients without LVH. LV mass was directly related to age, body mass, systolic blood pressure, duration of hypertension, baseline, and post-saline load plasma aldosterone levels and inversely to glomerular filtration. Multivariate regression analysis showed independent correlation of LV mass with body mass, systolic blood pressure, and plasma aldosterone levels measured after intravenous saline load, but not at baseline. CONCLUSIONS In patients with hypertension, aldosterone levels measured after intravenous saline load are related to LV mass independent of age, body mass, and blood pressure, suggesting that limited ability of salt to modulate aldosterone production could contribute to LVH.