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Purpose Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio. Methods In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions. Results Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables. Conclusion We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.

Sodium and potassium appear to interact with each other in their effects on blood pressure with potassium supplementation having a greater blood pressure lowering-effect when sodium intake is high. Whether the effect of sodium reduction on blood pressure varies according to potassium intake levels is unclear. We carried out a systematic review and meta-analysis to examine the impact of baseline potassium intake on blood pressure response to sodium reduction in randomized trials in adult populations, with sodium and potassium intake estimated from 24-h urine samples. We included 68 studies involving 5708 participants and conducted univariable and multivariable meta-regression. The median intake of baseline potassium was 67.7 mmol (Interquartile range: 54.6–76.4 mmol), and the mean reduction in sodium intake was 128 mmol (95% CI: 107–148). Multivariable meta-regression that included baseline 24-h urinary potassium excretion, age, ethnicity, baseline blood pressure, change in 24-h urinary sodium excretion, as well as the interaction between baseline 24-h urinary potassium excretion and change in 24-h urinary sodium excretion did not identify a significant association of baseline potassium intake levels with the blood pressure reduction achieved with a 50 mmol lowering of sodium intake (p > 0.05 for both systolic and diastolic blood pressure). A higher starting level of blood pressure was consistently associated with a greater blood pressure reduction from reduced sodium consumption. However, the nonsignificant findings may subject to the limitations of the data available. Additional studies with more varied potassium intake levels would allow a more confident exclusion of an interaction.

MicroRNAs (miRNAs) are short sequences of non-coding RNA that play an important role in the regulation of gene expression and thereby in many physiological and pathological processes. Furthermore, miRNAs are released in the extracellular space, for example in vesicles, and are detectable in various biological fluids, such as serum, plasma, and urine. Over the last years, it has been shown that miRNAs are crucial in the development of several cardiovascular diseases (CVDs). This review discusses the (patho)physiological implications of miRNAs in CVD, ranging from cardiovascular risk factors (i.e., hypertension, diabetes, dyslipidemia), to atherosclerosis, myocardial infarction, and cardiac remodeling. Moreover, the intriguing possibility of their use as disease-specific diagnostic and prognostic biomarkers for human CVDs will be discussed in detail. Finally, as several approaches have been developed to alter miRNA expression and function (i.e., mimics, antagomirs, and target-site blockers), we will highlight the miRNAs with the most promising therapeutic potential that may represent suitable candidates for therapeutic intervention in future translational studies and ultimately in clinical trials. All in all, this review gives a comprehensive overview of the most relevant miRNAs in CVD and discusses their potential use as biomarkers and even therapeutic targets.

Microvascular dysfunction (MVD) is considered a crucial pathway in the development and progression of cardiometabolic and renal disease and is associated with increased cardiovascular mortality. MVD often coexists with or even precedes macrovascular disease, possibly due to shared mechanisms of vascular damage, such as inflammatory processes and oxidative stress. One of the first events in MVD is endothelial dysfunction. With the use of different physiologic or pharmacologic stimuli, endothelium-dependent (micro) vascular reactivity can be studied. This reactivity depends on the balance between various mediators, including nitric oxide, endothelin, and prostanoids, among others. The measurement of microvascular (endothelial) function is important to understand the pathophysiologic mechanisms that contribute to MVD and the role of MVD in the development and progression of cardiometabolic/renal disease. Here, we review a selection of direct, noninvasive techniques for measuring human microcirculation, with a focus on methods, interpretation, and limitations from the perspective of chronic cardiometabolic and renal disease.

Background Altered regulation of extracellular matrix (ECM) composition by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) may contribute to arterial stiffening. We investigated associations between circulating MMP-1, -2, -3, -9, -10 and TIMP-1, and carotid-femoral pulse wave velocity (cfPWV) and pulse pressure (PP), as markers of arterial stiffness in type 1 diabetic patients. Methods Individuals with type 1 diabetes from three different cohorts were included in this study: EURODIAB Prospective Complications study (n = 509), LEACE (n = 370) and PROFIL (n = 638). Linear regression analyses were used to investigate cross-sectional associations between circulating levels of MMP-1, -2, -3, -9, -10, and TIMP-1 and cfPWV (n = 614) as well as office PP (n = 1517). Data on 24-h brachial and 24-h central PP were available in 638 individuals from PROFIL. Analyses were adjusted for age, sex, duration of diabetes, HbA1c, mean arterial pressure (MAP), and eGFR, and additionally for other cardiovascular risk factors and presence of vascular complications. Results After adjustment for potential confounders and presence of vascular complications, circulating MMP-3 was associated with cfPWV [β per 1 SD higher lnMMP3 0.29 m/s (0.02; 0.55)]. In addition, brachial and central 24-h PP measurements in PROFIL were significantly associated with MMP-2 [(1.40 (0.47:2.33) and 1.43 (0.63:2.23)]. Pooled data analysis showed significant associations of circulating levels of MMP-1 and MMP-2 with office PP [β per 1 SD higher lnMMP-1 and lnMMP-2 = − 0.83 mmHg (95% CI − 1.50; − 0.16) and = 1.33 mmHg (0.55; 2.10), respectively]. Conclusions MMPs-1, -2, and -3 are independently associated with markers of arterial stiffening in patients with type 1 diabetes and may become therapeutic targets. Electronic supplementary material The online version of this article (doi:10.1186/s12933-017-0620-9) contains supplementary material, which is available to authorized users.

Hyperoxia and slow breathing acutely improve autonomic function in type-1 diabetes. However, their effects on arterial function may reveal different mechanisms, perhaps potentially useful. To test the effects of oxygen and slow breathing we measured arterial function (augmentation index, pulse wave velocity), baroreflex sensitivity (BRS) and oxygen saturation (SAT), during spontaneous and slow breathing (6 breaths/min), in normoxia and hyperoxia (5 L/min oxygen) in 91 type-1 diabetic and 40 age-matched control participants. During normoxic spontaneous breathing diabetic subjects had lower BRS and SAT, and worse arterial function. Hyperoxia and slow breathing increased BRS and SAT. Hyperoxia increased blood pressure and worsened arterial function. Slow breathing improved arterial function and diastolic blood pressure. Combined administration prevented the hyperoxia-induced arterial pressure and function worsening. Control subjects showed a similar pattern, but with lesser or no statistical significance. Oxygen-driven autonomic improvement could depend on transient arterial stiffening and hypertension (well-known irritative effect of free-radicals on endothelium), inducing reflex increase in BRS. Slow breathing-induced improvement in BRS may result from improved SAT, reduced sympathetic activity and improved vascular function, and/or parasympathetic-driven antioxidant effect. Lower oxidative stress could explain blunted effects in controls. Slow breathing could be a simple beneficial intervention in diabetes.

Aims: Eastern Finns have higher risk of coronary heart disease (CHD) and carotid intima-media thickness than western Finns although current differences in CHD risk factors are minimal. Left ventricular (LV) mass and diastolic function predict future cardiovascular events but their east–west differences are unknown. We examined the association of eastern/western baseline origin with LV mass and diastolic function. Methods : The study population included 2045 subjects of the Cardiovascular Risk in Young Finns Study with data from the baseline survey (1980) and the latest follow-up (2011) when echocardiography was performed at the age of 34–49 years. Results: Subjects with eastern baseline origin had in 2011 higher LV mass (139±1.0 vs. 135±1.0 g, p=0.006) and E/e′-ratio indicating weaker LV diastolic function (4.86±0.03 vs. 4.74±0.03, p=0.02) than western subjects. Results were independent of age, sex, area of examination and CHD risk factors such as blood pressure and BMI (LV mass indexed with height: p

Background Ethnic disparities in cardiovascular morbidity and mortality are widely documented in the literature. Recently, research has shown that decreased parasympathetic cardiac modulation is associated with the established and emerging risk factors for cardiovascular disease (CVD) and stroke. In consideration of the disproportionate CVD risk and disease profile of African Americans (AAs), it is plausible that decreased cardiac parasympathetic functioning may partially explain these disparities. In the present systematic review and meta-analysis, we assess the available evidence for a reliable ethnic difference in tonic vagally mediated heart rate variability (HRV), an indicator of parasympathetic cardiac modulation.Methods A systematic literature search was conducted yielding studies comparing tonic HRV in AAs and European Americans. Adjusted standardized effect sizes (Hedges g) were calculated using a mixed-effects model, with restricted maximum likelihood estimation for 17 studies containing appropriate measures of vagally mediated HRV.Results Meta-analysis results suggest that AAs have greater HRV than do European Americans (Hedges g = 0.93, 95% confidence interval = 0.25-1.62), even after consideration of several covariates including health status, medication use, and subgroup stratification by sex and age.Conclusions These findings suggest that decreased vagally mediated HRV is not likely to account for the persistent health disparities experienced by AAs with respect to CVD risk and burden. These disparities underscore the need for continued research addressing socioethnic cardiovascular differences and the biobehavioral mechanisms involved.

Item does not contain fulltext Arterial stiffness is an important pathophysiological factor linking cardiovascular disease and kidney disease. Controversy exists as to whether arterial stiffness causes renal function decline, or kidney dysfunction leads to stiffening or whether the association is mutual. We aimed to investigate the longitudinal association between arterial stiffness and annual rate of renal function decline. We prospectively investigated in a primary care population whether carotid-femoral pulse wave velocity (PWV) was associated with estimated glomerular filtration rate (eGFR) and annual decline in eGFR in participants aged 40 years without overt kidney disease. Baseline data on PWV and eGFR were available for 587 participants; follow-up measurements with a mean duration of 5.6 years were available for 222 patients. PWV, female gender and mean arterial pressure were independently associated with eGFR at baseline, although age confounded this association. More importantly, baseline PWV, age and eGFR were independent predictors of renal function decline. Stratification for age showed that the effect of PWV on rate of eGFR decline was amplified with advancing age. On the other hand, baseline eGFR did not determine annual change in PWV, suggesting a unidirectional association between arterial stiffness and eGFR. Arterial stiffness amplifies age-related renal function decline, suggesting that arterial stiffness plays a causal role in the development of renal damage, at least at later stages of age-related renal function decline, possibly through impaired renal autoregulation and increased arterial blood pressure pulsatility.

Purpose: Beta-blocker use is common in the cases with coronary artery bypass surgery. According to the literature, beta-blockers have positive effects but may cause erectile dysfunction (ED). The most commonly used beta-blockers in ischemic cardiac disease are nebivolol and metoprolol. In our clinic, we aimed to compare the effects of nebivolol and metoprolol succinate on ED in the sexually active cases with coronary artery bypass surgery. Methods: In our clinic, a total of 119 patients with coronary artery bypass surgery were included in the study. International Index of Erectile Function (IIEF-5) Test was used to evaluate whether the patients had ED and to grade the cases. Results: No significant difference was found in terms of anti-ischemic efficacy between metoprolol succinate and nebivolol in the postoperative period; however, the incidence of any grade ED was % 85.96 in Group 1, % 83.87 in Group 2. This difference was considered as statistically significant (p = 0.036). Conclusion: Beta-blocker use increases the risk of ED in cases with ischemic cardiac disease. We suggest that the complaints of ED could be less frequent with nebivolol use in sexually active cases with ischemic cardiac disease. Namik Kemal UniversityNamik Kemal University Namik Kemal University provided financial support for the study as a scientific research project.

Background: Elevated homocysteine levels are a risk indicator for cardiovascular disease, fractures and cognitive decline. Previous studies indicated associations between homocysteine levels and medication use, including antihypertensive, lipid-lowering and antidiabetic medication. However, results were often contradictory and inconclusive. Our objective was to study the associations established previously in more detail by sub-classifying medication groups, and investigate the potential mediating role of vitamin B12 and folate status. Materials and Methods: Baseline data from the B-PROOF (B-vitamins for the PRevention Of Osteoporotic Fractures) study were used. We included 2,912 participants aged ≥65 years, with homocysteine levels of 12-50 μmol/L and creatinine levels ≤150 μmol/L, for whom self-reported medication data were available. We used multivariable linear regression models and analysis of covariance to assess the association between medication use and plasma homocysteine levels, and the potential mediation by serum vitamin B 12 and folate. Results: The mean age was 74 years (standard deviation, 6.5), 50 % were women, and median homocysteine levels were 14 μmol/L [interquartile range, 13-17 μmol/L]. Higher mean homocysteine levels were observed in users vs. non-users for diuretics (15.2 vs. 14.9, p = 0.043), high-ceiling sulphonamide diuretics (16.0 vs. 14.9, p < 0.001), medication acting via the renin-angiotensin system (15.2 vs. 14.9, p = 0.029) and metformin (15.6 vs. 15.1, p = 0.006). Non-selective β-blocker use was associated with lower mean homocysteine levels (14.4 vs. 15.0, p = 0.019). Only this association was mediated by an underlying association with vitamin B 12 and folate levels. Conclusion: The associations between homocysteine levels and medication use appear to be fairly modest. Our results suggest that medication use is unlikely to contribute to clinically relevant changes in plasma homocysteine levels. © 2014 Springer International Publishing.

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) OBJECTIVES: Considering that changes in the maternal environment may result in changes in progeny, the aim of this study was to investigate the influence of sleep restriction during the last week of pregnancy on renal function and autonomic responses in male descendants at an adult age. METHODS: After confirmation of pregnancy, female Wistar rats were randomly assigned to either a control or a sleep restriction group. The sleep-restricted rats were subjected to sleep restriction using the multiple platforms method for over 20 hours per day between the 14 th and 20 th day of pregnancy. After delivery, the litters were limited to 6 offspring that were designated as offspring from control and offspring from sleep-restricted mothers. Indirect measurements of systolic blood pressure (BPi), renal plasma flow, glomerular filtration rate, glomerular area and number of glomeruli per field were evaluated at three months of age. Direct measurements of cardiovascular function (heart rate and mean arterial pressure), cardiac sympathetic tone, cardiac parasympathetic tone, and baroreflex sensitivity were evaluated at four months of age. RESULTS: The sleep-restricted offspring presented increases in BPi, glomerular filtration rate and glomerular area compared with the control offspring. The sleep-restricted offspring also showed higher basal heart rate, increased mean arterial pressure, increased sympathetic cardiac tone, decreased parasympathetic cardiac tone and reduced baroreflex sensitivity. CONCLUSIONS: Our data suggest that reductions in sleep during the last week of pregnancy lead to alterations in cardiovascular autonomic regulation and renal morpho-functional changes in offspring, triggering increases in blood pressure. Escola Paulista de Medicina - UNIFESP, Departamento de Fisiologia, São Paulo/SP, Brazil Escola Paulista de Medicina - UNIFESP, Departamento de Psicobiologia, São Paulo/SP, Brazil Centro Universitário São Camilo, São Paulo/SP, Brazil Escola Paulista de Medicina - UNIFESP, Departamento de Fisiologia, São Paulo/SP, Brazil Escola Paulista de Medicina - UNIFESP, Departamento de Psicobiologia, São Paulo/SP, Brazil FAPESP: 2013-23622-7 Web of Science

Atherosclerotic damage to the kidney is one of the most prevalent causes of chronic kidney disease and ultimately kidney failure. It frequently coincides with atherosclerotic damage to the heart, the brain and the lower extremities. In fact, the severity of the damage in the various end organs runs in parallel. As damage to the kidney is easy to measure by monitoring albuminuria and eGFR, and as the early phases of kidney damage frequently precede the alarming symptomatology in the heart, brain and peripheral vasculature, we argue that the nephrologist should consider taking the lead in better organizing early detection and management of CKD. The nephrologist can guide the general practitioner and general health care workers to offer better preventive care to the subjects at risk of progressive atherosclerotic end-organ damage.

High sodium intake limits the antihypertensive and antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors in patients with CKD; however, whether dietary sodium also associates with progression to ESRD is unknown. We conducted a post hoc analysis of the first and second Ramipril Efficacy in Nephropathy trials to evaluate the association of sodium intake with proteinuria and progression to ESRD among 500 CKD patients without diabetes who were treated with ramipril (5 mg/d) and monitored with serial 24-hour urinary sodium and creatinine measurements. Urinary sodium/creatinine excretion defined low (100 mEq/g), medium (100 to200 mEq/g), and high (≥200 mEq/g) sodium intake. During a follow-up of4.25 years, 92 individuals (18.4%) developed ESRD. Among those with low, medium, and high sodium intakes, the incidence of ESRD was 6.1 (95% confidence interval [95% CI], 3.8-9.7), 7.9 (95% CI, 6.1-10.2), and 18.2 (95% CI, 11.3-29.3) per 100 patient-years, respectively (P0.001). Patients with high dietary sodium exhibited a blunted antiproteinuric effect of ACE inhibition despite similar BP among groups. Each 100-mEq/g increase in urinary sodium/creatinine excretion associated with a 1.61-fold (95% CI, 1.15-2.24) higher risk for ESRD; adjusting for baseline proteinuria attenuated this association to 1.38-fold (95% CI, 0.95-2.00). This association was independent from BP but was lost after adjusting for changes in proteinuria. In summary, among patients with CKD but without diabetes, high dietary salt (14 g daily) seems to blunt the antiproteinuric effect of ACE inhibitor therapy and increase the risk for ESRD, independent of BP control.

Activation of the renin–angiotensin system (RAS) is associated with atrial fibrillation (AF). The aim of this study was to investigate the relation between AF and polymorphisms in RAS. One hundred and fifty patients with AF, 100 patients with no documented episode of AF and 100 healthy subjects were consecutively recruited into the study. The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and the M235T, A-20C, and G-6A polymorphisms of the angiotensinogen gene were genotyped. Patients with AF had significantly lower frequency of II genotype of ACE I/D and higher frequency of angiotensinogen M235T polymorphism T allele and TT genotype and G-6A polymorphism G allele and GG genotype compared with the controls. AF patients had significantly larger left atrium, higher left ventricular mass index (LVMI) and higher frequency of significant valvular pathology. ACE I/D polymorphism II genotype, angiotensinogen M235T polymorphism TT genotype and G allele and GG genotype of angiotensinogen G-6A polymorphism were still independently associated with AF when adjusted for left atrium, LVMI and presence of significant valvular pathology. Genetic predisposition might be underlying the prevalence of acquired AF. Patients with a specific genetic variation in the RAS genes may be more liable to develop AF.

In chronic kidney disease simultaneous activation of the renin - angiotensin and sympathetic systems occurs. Kidney ischemia seems to play a key role in the pathogenesis. This review firstly summarizes experimental and clinical evidence in chronic kidney disease supporting this idea and addresses the possibility that this mechanism is also relevant in some other disease conditions. J Hypertens 27:1341-1349 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

The endothelium-derived vasoconstrictor molecule endothelin-1 (ET-1) has been suggested to play a role in the pathogenesis of Raynaud's phenomenon (RP) and systemic sclerosis (SSc). We studied the effect of bosentan on microvascular structure and function in patients with RP secondary to limited cutaneous SSc in a mechanistic pilot study. In this single center, open study, 15 patients with limited cutaneous SSc were treated with bosentan for 16 weeks with a follow-up period of 4 weeks. Changes in microvascular structure and function were studied with assessment of vasodilatory microvascular responses using laser Doppler fluxmetry combined with iontophoresis, capillary permeability using fluorescence videomicroscopy, nailfold capillary microscopy, and serological markers of endothelial activation. No significant changes were seen in vasodilator responses to acetylcholine and sodium nitroprusside following bosentan treatment. No effect was noted on capillary permeability during treatment. The number of nailfold capillaries remained unchanged. The endothelial activation marker vascular cell adhesion molecule did not change during treatment, but levels of thrombomodulin significantly decreased after 12 weeks of treatment. Bosentan did not induce significant changes in vasodilator responses, capillary permeability, and capillary density during treatment, so no evidence was obtained for structural improvement of microvascular structure and function in this short-time mechanistic pilot study in patients with lcSSc.

Patients with diabetes have an increased cardiovascular morbidity and mortality despite interventions to prevent these outcomes. Abnormalities in diurnal blood pressure patterns are also associated with excess cardiovascular mortality. The aim of this study was to determine the effects of diurnal blood pressure patterns on endothelial function and oxidative stress in patients with uncomplicated type 1 diabetes mellitus. Thirty-two normotensive and normoalbuminuric type 1 diabetic patients (21 dipper and 11 nondipper) and 37 healthy (27 dipper and 10 nondipper) volunteers underwent 24-h ambulatory blood pressure monitoring. Their endothelial functions were evaluated using flow mediated dilatation (FMD) and by measuring nitric oxide and thiobarbituric acid reactive substances (TBARS). Dippers were defined as subjects who exhibited an average reduction in both systolic and diastolic blood pressure of greater than 10% between day and night periods. Nondipper type 1 diabetic patients and controls had nighttime systolic and diastolic blood pressure values that were significantly higher than those of dipper diabetic patients (p

BACKGROUNDIn hypertension, sodium sensitivity (SS) of blood pressure is associated with renal hemodynamic abnormalities related to increased activity of the renal renin-angiotensin aldosterone system (RAAS). The renal mechanisms of SS in normotensives are unknown. Therefore, we studied whether SS is related to renal hemodynamics and renal responsiveness to angiotensin II (Angll) in young healthy adults.METHODSBlood pressure (mean arterial pressure (MAP)) and renal function were measured in 34 healthy men after 1-week low-sodium diet (LS; 50 mmol Na+/24 h), 1-week high-sodium diet (HS; 200 mmol Na+/24h), and 1-week HS-ACEi (enalapril 20 mg/day).The responses of effective renal plasma flow (ERPF; I-131-Hippuran clearance) to graded infusion of Angll were assessed during each condition.RESULTSThe sodium-induced change in MAP ranged from -7to+14mmHg. SS (a sodium-induced increase in MAP > 3 mm Hg) was present in 13 subjects. ERPF was lower in SS subjects during LS and during HS-ACEi. The Angll-induced decrease in ERPF was blunted in SS on LS (-25 +/- 6 vs. -29 +/- 7% in sodium-resistant (SR) subjects, P CONCLUSIONSS normotensive subjects have a blunted renal response to exogenous Angll. This is ameliorated by ACE, supporting a role for inappropriately high intrarenal RAAS activity. As these findings cannot be attributed to subclinical renal hypertensive damage, high intrarenal RAAS activity and altered renal hemodynamics may be primary phenomena underlying SS.

Nebivolol is a third generation beta-blocker. It is highly selective for the beta1-adrenoceptor, and has additional nitric oxide-mediated vasodilating and antioxidant properties, along with a favourable metabolic profile. Nebivolol is well tolerated by patients with hypertension and heart failure. Although several smaller studies were conducted with nebivolol in hypertensive patients, no large randomised clinical trials have been performed to prove efficacy on hard clinical end points. In patients with heart failure, a large mortality/morbidity trial was conducted, and nebivolol was shown to reduce the composite end point of mortality and hospitalisations. Nebivolol is registered, in Europe, for mild-to-moderate, uncomplicated hypertension and mild-to-moderate heart failure; and outside Europe, for hypertension. This review describes experimental and clinical data regarding this selective beta-blocker with vasodilating and antioxidant effects.

Obesity is a risk factor for renal graft loss. Higher body mass index (BMI) in native kidneys is associated with glomerular hyperfiltration. Whether higher BMI in renal transplants is associated with hyperfiltration is unknown. We investigated the impact of BMI on renal hemodynamics 1 year post-transplant. We analyzed glomerular filtration rate (GFR, I-125-iothalamate) and effective renal plasma flow (ERPF, I-131-hippurate) in 838 kidney transplants. Data were analyzed for all patients and for the subpopulation without diabetes. Long-term impact of BMI and renal hemodynamics were explored by Cox-regression. With higher BMI GFR and filtration fraction (FF) increased significantly. Multivariate analysis supported impact of BMI on GFR (adjusted r(2) of the model 0.275) and FF (adjusted r(2) of the model 0.158). This association was not explained by diabetes mellitus. On Cox-regression analysis, lower GFR and higher FF were independent determinants of overall graft loss and graft loss by patient mortality. Lower GFR and higher BMI were determinants of death-censored graft loss, with borderline contribution of higher FF. In renal transplants higher BMI is independently associated with higher GFR and FF one year posttransplant, suggesting glomerular hyperfiltration with altered afferent-efferent balance. Mechanisms underlying the long-term prognostic impact of hyperfiltration deserve further exploration.

A body mass index ( BMI) >= 25 kg/m(2) increases the risk for long-term renal damage, possibly by renal hemodynamic factors. As epidemiological studies suggest interaction of BMI and sodium intake, we studied the combined effects of sodium intake and BMI on renal hemodynamics. Glomerular filtration rate ( GFR) and effective renal plasma flow ( ERPF) were measured in 95 healthy men ( median age 23 years ( 95% confidence interval: 22-24), BMI: 23.0 +/- 2.5 kg/ m 2) on low ( 50 mmol Na+, LS) and high ( 200 mmol Na+, HS) sodium intake. Mean GFR and ERPF significantly increased by the change to HS ( both P = 25 versus = 25 versus

Background Offspring of patients with cardiovascular disease are at increased risk of developing cardiovascular events. We evaluated whether prevalence of risk factors in offspring of patients with increased cardiovascular risk is higher compared with the general population and whether the risk of cardiovascular events and prevalence of cardiovascular risk factors in offspring is dependent on parental vascular disease location. Methods Of 4270 patients enrolled in the SMART cohort we assessed after a follow-up of 7years (IQR 4-8) the presence of cardiovascular risk factors and disease in their 10,572 children by questionnaire. The SMART patients had symptomatic vascular disease (coronary artery disease (CAD) (n=1826), cerebrovascular disease (CVD) (n=637), peripheral artery disease (PAD) (n=275), abdominal aortic aneurysm (AAA) (n=98), polyvascular disease (≥2 vascular manifestations) (n=371)) or risk factors (hypercholesterolemia, diabetes, hypertension) (n=1063). The prevalence of risk factors in offspring was compared with the general population and stratified for parental vascular disease location. The relation between parental vascular disease location and cardiovascular events in offspring was determined by Poisson regression. Results The offspring had higher prevalence of in particular hypercholesterolemia and hypertension compared with the general population, irrespective of the parental vascular disease location. Higher risks of cardiovascular events compared with offspring of patients without manifest vascular disease were observed in offspring of patients with CAD (PR 1.8, 95%CI 0.9–3.4), CVD (PR 2.4, 95%CI 1.2–4.8), PAD (PR 2.8, 95%CI 1.3–6.4), polyvascular disease (PR 2.5, 95%CI 1.2–5.2), but not with AAA (PR 1.7, 95%CI 0.5–6.1). Conclusions In offspring from patients with cardiovascular disease or risk factors, the prevalence of traditional risk factors was higher compared with the general population, independent of the location of vascular disease of the parent. Offspring of patients with PAD had the highest risk of developing vascular disease.

Urinary albumin excretion is a predictor for cardiovascular mortality and morbidity. We investigated which parameters determine baseline urinary albumin excretion in nondiabetic subjects, without renal disease. In addition, we evaluated the parameters that predict the albuminuria-lowering efficacy of an angiotensin-converting enzyme inhibitor. In this substudy of the Prevention of Renal and Vascular Endstage Disease Intervention Trial, 384 microalbuminuric patients were included. Patient and biochemical characteristics were obtained at baseline and after 3 months of double-blinded, randomized treatment (fosinopril 20 mg or placebo). Mean age was 51.1±11.5 years, and 65.6% were male. Median urinary albumin excretion was 22.2 mg per 24 hours. At baseline, mean arterial pressure (β standardized =0.161; P =0.006), urinary sodium excretion (β standardized =0.154; P =0.011), and estimated renal function were independently associated with albumin excretion. In these predominantly normotensive to prehypertensive subjects, fosinopril reduced albumin excretion by 18.5% versus a 6.1% increase on placebo after 3 months ( P standardized =−0.303; P

Excretion of albumin in the urine is highly variable, ranging from nondetectable quantities to milligrams of albumin and even grams of albumin. Microalbuminuria is defined as low levels of urinary albumin excretion of 30 to 300 mg/d. Microalbuminuria is highly prevalent; in hypertensive and diabetic populations, its prevalence varies from 10 to 40%. It is interesting that microalbuminuria also is found frequently in seemingly healthy individuals (5 to 7%). The variable excretion of albumin in the urine is related to the risk for the individual to develop cardiovascular (CV) disease: Absence or very low levels of albuminuria is associated with low CV risk, whereas the CV risk increases markedly with increasing amount of albumin in the urine (even within the now considered normal range). The predictive power of urinary albumin levels for CV risk is independent of other CV risk factors and not only is present in individual with diabetes and/or hypertension but also in healthy individuals. Treatments that lower albuminuria are associated with CV protection, as demonstrated in randomized, controlled trials of patients with diabetes as well as in patients with hypertension. There is preliminary evidence that albuminuria lowering is CV protective in healthy individuals with an elevated albumin excretion rate. Differences between individuals in their level of albumin excretion are already observed at a very early age (just after birth). In fact, the interindividual variability seems to be relatively constant in the first 5 decades of life, indicating that microalbuminuria is not necessarily a consequence of vascular damage at later age. Higher levels of urinary albumin seem to reflect the ordinary interindividual variability in (renal and systemic) endothelial function. Experimental data show that between strains and even within strains, rats at young age show a remarkable difference in individual endothelial function, and this is strongly related to the susceptibility of that rat to organ damage. In conclusion, albuminuria seems to be a sensitive marker very early in life for the susceptibility of an individual to CV disease. It therefore may be an ideal target for early primary prevention using CV-protective therapy regimens.

Objective: To seek an association between total arterial compliance (TAC) and the extent of ischaemia at stress echocardiography. Design: Cohort study. Setting: Regional cardiac centre. Methods: 255 consecutive patients (147 men; mean (SD) age 58 (8)) presenting for stress echocardiography for clinical indications were studied. Wall motion score index (WMSI) was calculated and ischaemia was defined by an inducible or worsening wall motion abnormality. Peak WMSI was used to reflect the extent of dysfunction (ischaemia or scar), and ΔWMSI was indicative of extent of ischaemia. TAC was assessed at rest by simultaneous radial applanation tonometry and pulsed wave Doppler in all patients. Results: Ischaemia was identified by stress echocardiography in 65 patients (25%). TAC was similar in the groups with negative and positive echocardiograms (1.08 (0.41) v 1.17 (0.51) ml/mm Hg, not significant). However, the extent of dysfunction was associated with TAC independently of age, blood pressure, risk factors, and use of a β blocker. Moreover, the extent of ischaemia was determined by TAC, risk factors, and use of a β blocker. Conclusion: While traditional cardiovascular risk factors are strong predictors of ischaemia on stress echocardiography, TAC is an independent predictor of the extent of ischaemia.

Background— The effect of fish oil on heart rate (HR), a major risk factor for sudden death, is not well established. We calculated this effect in a meta-analysis of randomized, double-blind, placebo-controlled trials in humans. Methods and Results— Randomized trials of fish oil that evaluated HR were identified through MEDLINE (1966 through January 2005), hand-searching of references, and contact with investigators for unpublished results. Two investigators independently extracted trial data. A pooled estimate was calculated from random-effects meta-analysis. Predefined stratified meta-analyses and meta-regression were used to explore potential heterogeneity. Of 197 identified articles, 30 met inclusion criteria. Evidence for publication bias was not present. In the overall pooled estimate, fish oil decreased HR by 1.6 bpm (95% CI, 0.6 to 2.5; P =0.002) compared with placebo. Between-trial heterogeneity was evident (Q test, P P P =0.56) in trials with baseline HR P for interaction=0.03). Fish oil reduced HR by 2.5 bpm ( P P =0.27) in trials with duration P for interaction=0.07). HR reduction with fish oil intake did not significantly vary by fish oil dose (range, 0.81 to 15 g/d), type of HR measure, population age, population health, parallel versus crossover design, type of control oil, or study quality by Delphi criteria ( P for interaction >0.25 for each). Conclusions— In randomized controlled trials in humans, fish oil reduces HR, particularly in those with higher baseline HR or longer treatment duration. These findings provide firm evidence that fish oil consumption directly or indirectly affects cardiac electrophysiology in humans. Potential mechanisms such as effects on the sinus node, ventricular efficiency, or autonomic function deserve further investigation.

C-reactive protein (CRP) and microalbuminuria reflect intimately related components of the atherosclerotic disease process. Epidemiological studies found only modest associations between CRP and microalbuminuria. Blood pressure, one of the components of the metabolic syndrome in the general population, is the main determinant of microalbuminuria in diabetes and hypertension. We questioned whether CRP modifies the relationship of blood pressure and other cardiovascular risk factors with microalbuminuria in a cross-sectional study in 8592 inhabitants from Groningen, The Netherlands. The crude data showed an increase in the prevalence of microalbuminuria with increasing CRP quartiles (4.8, 9.6, 14.5, and 18.6%, P P =0.03). In subjects with a MAP P =0.11). This trend was much steeper and significant in subjects with an MAP >90 mm Hg (prevalence: 6.7%, 13.6%, 20.4%, 25.1%; P P =0.0004). No significant interactions between other risk factors and CRP with respect to the risk of microalbuminuria were encountered. Thus, CRP modifies the relation between blood pressure and microalbuminuria.

Objective: to examine the effect of angiotensin converting enzyme inhibition (ACEI) on soluble intercellular adhesion molecule 1 (sICAM-1) and C-reactive protein (CRP) in patients requiring coronary artery bypass grafting (CABG).Method: subgroup analysis of 42 patients randomised to Quinapril (40 mg daily determined) and 45 to placebo. sICAM-1 and CRP were greater than or equal to4 weeks before and 1 year after surgery.Results: there was no difference in sICAM-1 at baseline (142.2 mug/L vs 136.6 mug/L). There was significant reduction in sICAM-1 in patients receiving quinapril (142.2 +/- 10.8 mug/L vs 125.6 +/- 9.4 mug/L, p Conclusions: ACEI reduces sICAM-1 in patients undergoing CABG. The benefits of ACEI may partly be due to a reduction of the vascular inflammatory response.

The absence of nocturnal fall in blood pressure (BP) is named as nondipper status, which has been shown to be an additional risk factor for the development of left ventricular hypertrophy and cardiovascular events in several high-risk groups. The aim of this study was to determine the influences of the nondipper status and nocturnal blood pressure loads on left ventricular mass index (LVMI) in renal transplant recipients. A total of 35 nondiabetic renal transplant recipients were included into the study. A 24-h ambulatory blood pressure monitoring (ABPM) was performed for all recipients. The nondipper status was defined as either an increase in night-time mean arterial pressure (MAP) or a decrease of no more than 10% of daytime MAP. LVMI was measured by using two-dimensional guided M-mode echocardiography. The night-time systolic blood pressure (SBP) load was defined as the percentage of the time, during which SBP exceeded 125 mmHg during night time. The nondipping was common among renal transplant recipients, of whom 60% were nondipper in our study. LVMI was significantly higher in the nondipper group vs the dipper group (133 +/- 35 g/m(2) vs 109 +/- 26 g/m(2), P = 0.04). A fall in MAP at night time was 14.5 +/- 4.3% in the dipper group, while it was 1.4 +/- 6.1% in the nondipper group (P < 0.001). On stepwise multiple regression analysis, night-time SBP load and haemoglobin were independent predictors of LVMI (R(2) = 0.53). In conclusion, nondipping is common after renal transplantation. Night-time SBP load and low haemoglobin are closely related to the increase in LVMI in renal transplant recipients. ABPM may be a more useful tool in optimizing treatment strategies to reduce cardio-vascular events in renal transplant recipients.

Since the discovery of the polymorphism in the angiotensin converting enzyme (ACE) and the consequences of this polymorphism on the activity levels of the enzyme, numerous association studies have been performed. However, these investigations do not often adhere to the most stringent criteria for such studies. The initial study reporting a positive association of the ACE polymorphism and myocardial infarction showed an increased risk of the DD genotype. This initial association was eventually refuted by a large, well conducted association study, which found a risk ratio of 1.02 after combining their own data with all published data. Although such large, well conducted association studies have not been performed in left ventricular (LV) hypertrophy, the association between DD genotype and hypertrophy is more convincing with a 192% excess risk of LV hypertrophy in untreated hypertensives. The role of ACE genotype in LV growth is well established, especially in athletes. In heart failure, large studies or meta-analyses have not been performed, because most studies have selected different end-points. This hampers a proper meta-analysis of the results obtained in associations with heart failure. As most association studies do not fulfill the criteria for good association studies and use too small sample sizes, it remains important to perform a meta-analysis to add meaning to the results of such studies. Above all, it is important to obey the rules set for association studies, large sample size, small P values, report associations that make biological sense and alleles that affect the gene product in a physiologically meaningful way. (C) 2003 Elsevier Science Ltd. All rights reserved.

It has been proposed that insulin-mediated changes in muscle perfusion modulate insulin-mediated glucose uptake. However, the putative effects of insulin on the microcirculation that permit such modulation have not been studied in humans. We examined the effects of systemic hyperinsulinemia on skin microvascular function in eight healthy nondiabetic subjects. In addition, the effects of locally administered insulin on skin blood flow were assessed in 10 healthy subjects. During a hyperinsulinemic clamp, we measured leg blood flow with venous occlusion plethysmography, skin capillary density with capillaroscopy, endothelium-(in)dependent vasodilatation of skin microcirculation with iontophoresis of acetylcholine and sodium nitroprusside combined with laser Doppler fluxmetry, and skin vasomotion by Fourier analysis of microcirculatory blood flow. To exclude nonspecific changes in the hemodynamic variables, a time-volume control study was performed. Insulin iontophoresis was used to study the local effects of insulin on skin blood flow. Compared to the control study, systemic hyperinsulinemia caused an increase in leg blood flow (-0.54 ± 0.93 vs. 1.97 ± 1.1 ml · min-1 · dl-1; P < 0.01), an increase in the number of perfused capillaries in the resting state (-3.7 ± 3.0 vs. 3.4 ± 1.4 per mm2; P < 0.001) and during postocclusive reactive hyperemia (-0.8 ± 2.2 vs. 5.1 ± 3.7 per mm2; P < 0.001), an augmentation of the vasodilatation caused by acetylcholine (722 ± 206 vs. 989 ± 495%; P < 0.05) and sodium nitroprusside (618 ± 159 vs. 788 ± 276%; P < 0.05), and a change in vasomotion by increasing the relative contribution of the 0.01- to 0.02-Hz and 0.4- to 1.6-Hz spectral components (P < 0.05). Compared to the control substance, locally administered insulin caused a rapid increase (∼13.5 min) in skin microcirculatory blood flow (34.4 ± 42.5 vs. 82.8 ± 85.7%; P < 0.05). In conclusion, systemic hyperinsulinemia in skin 1) induces recruitment of capillaries, 2) augments nitric oxide-mediated vasodilatation, and 3) influences vasomotion. In addition, locally administered insulin 4) induces a rapid increase in total skin blood flow, independent of systemic effects.

Aims Osteopontin (OPN) is a multifunctional cytokine critically involved in cardiac fibrosis. However, the underlying mechanisms are unresolved. Non-coding RNAs are powerful regulators of gene expression and thus might mediate this process. Methods and results OPN and miR-21 were significantly increased in cardiac biopsies of patients with myocardial fibrosis. Ang II infusion via osmotic minipumps led to specific miRNA regulations with miR-21 being strongly induced in wild-type (WT) but not OPN knockout (KO) mice. This was associated with enhanced cardiac collagen content, myofibroblast activation, ERK-MAP kinase as well as AKT signalling pathway activation and a reduced expression of Phosphatase and Tensin Homologue (PTEN) as well as SMAD7 in WT but not OPN KO mice. In contrast, cardiotropic AAV9-mediated overexpression of OPN in vivo further enhanced cardiac fibrosis. In vitro, Ang II induced expression of miR-21 in WT cardiac fibroblasts, while miR-21 levels were unchanged in OPN KO fibroblasts. As pri-miR-21 was also increased by Ang II, we studied potential involved upstream regulators; Electrophoretic Mobility Shift and Chromatin Immunoprecipitation analyses confirmed activation of the miR-21 upstream-transcription factor AP-1 by Ang II. Recombinant OPN directly activated miR-21, enhanced fibrosis, and activated the phosphoinositide 3-kinase pathway. Locked nucleic acid-mediated miR-21 silencing ameliorated cardiac fibrosis development in vivo. Conclusion In cardiac fibrosis related to Ang II, miR-21 is transcriptionally activated and targets PTEN/SMAD7 resulting in increased fibroblast survival. OPN KO animals are protected from miR-21 increase and fibrosis development due to impaired AP-1 activation and fibroblast activation., Osteopontin (OPN) is a pleiotropic cytokine, which has been shown to be a pivotal factor in myofibroblast activation in cardiac fibrosis, thereby acting as a strong driver of heart failure development in humans. MicroRNAs (miRNAs) are under intense investigation as powerful regulators of various diseases. First phase I and II clinical trials using miRNA inhibitors have been initiated. We here show, that OPN is essential in the activation of AP-1 and subsequent transcription of miR-21 in cardiac fibrosis related to Ang II. OPN null mice are protected from miR-21 increase and fibrosis development due to impaired AP-1 activation and fibroblast activation. In the future, these findings may result in miRNA therapeutic approaches to treat patients with cardiac remodelling, in which levels of OPN and miR-21 are increased.

Background: Several non-sarcomeric genes have been postulated to act as modifiers in the phenotypic manifestations of hypertrophic cardiomyopathy (HCM). The development of atrial fibrillation (AF) in HCM has adverse prognostic implications with increased thromboembolism and functional class impairment. Aim: We tested the hypothesis that 2 non-sarcomeric genes [CYP11B2 (-344T > C) and COL1A1 (2046G > T)] are associated with the development of AF. Design: Prospective study. Methods: Two polymorphisms in non-sarcomeric genes [CYP11B2 (-344T > C) and COL1A1 (2046G > T)] were analysed in 159 HCM patients (49.3 +/- 14.9 years, 70.6% male) and 136 controls. All subjects were clinically stable and in sinus rhythm at entry in the study, without ischemic heart disease or other significant co-morbidities that could mask the effect of the analysed polymorphisms (i.e. previous AF). Thirty-nine patients (24.4%) developed AF during a median follow-up of 49.5 months. Results: Patients with the -344T > C polymorphism in CYP11B2 gene had a higher risk for AF development [HR: 3.31 (95% CI 1.29-8.50); P = 0.008]. In a multivariate analysis, the presence of the C allele in CYP11B2 gene [HR: 3.02 (1.01-8.99); P = 0.047], previous AF [HR: 2.81 (1.09-7.23); P = 0.033] and a left atrial diameter of a parts per thousand yen42 mm [HR: 2.69 (1.01-7.18); P = 0.048] were independent predictors of AF development. The presence of the polymorphic allele was associated with higher aldosterone serum levels. Conclusion: We have shown for the first time that the CYP11B2 polymorphism is an independent predictor for AF development in HCM patients. This highlights the importance of non-sarcomeric genes in the phenotypic heterogeneity of HCM. The association with higher aldosterone serum levels could relate to greater fibrosis and cardiac remodelling.

Objective and Design to assess if deletion of the angiotensin-converting enzyme (ACE) gene is a risk factor for abdominal aortic aneurysms (AAAs) in normotensive patients. Materials and Methods ACE gene polymorphism was examined by polymerase chain reaction in 124 subjects with AAA and in 112 control subjects. AAA normotensive patients (group A,n=56) were compared to normotensive control subjects (group B, n =112) and to AAA hypertensive patients (group C, n =68). All subjects enrolled in this study were Caucasian and from central and southern Italy.Results the distribution of ACE genotypes was: normotensive patients with AAAs (group A): 3 II, 14 ID, 39 DD; normotensive control subjects (group B): 36 II, 48 ID, 28 DD; hypertensive patients with AAAs (group C): 14 II, 32 ID, 22 DD. The DD genotype was more common in group A than in control groups (A vs B p

Genetic and environmental contributions to urinary excretion rates of norepinephrine (UNEV) and epinephrine (UEV) and their association with blood pressure (BP) were investigated in 91 African American (mean age, 17.3 +/- 2.6 years) and 101 European American (mean age, 18.7 +/- 3.4 years) mono- and di-zygotic twins. Genetic modeling was performed using Mx software. UNEV (1.9 +/- 1.3 mu g h(-1)) and UEV (0.2 +/- 0.2 mu g h(-1)) were highly correlated (r = 0.81, P

Objective: Increased levels of serum uric acid (SUA) are thought to be an independent risk marker for cardiovascular complications. Treatment with the angiotensin receptor blocker (ARB) losartan lowers SUA in contrast to other ARBs. Whether reductions in SUA during ARB therapy are associated with cardiovascular protection is unclear. We aimed to investigate this.Method: In a post-hoc analysis of the Reduction of Endpoints in Non insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy (IDNT) trials we determined whether the short-term effect of losartan and of irbesartan on SUA is related with long-term cardiovascular outcome by means of Cox regression.Results: Compared to placebo, losartan significantly changed SUA [-0.16 mg/dl; 95% confidence interval (CI) -0.01 to -0.30; P 0.031], whereas irbesartan did not (-0.09 mg/dl; (95% CI 0.09 to -0.28; P = 0.30). Each 0.5 mg/dl decrement in SUA during losartan treatment in the first 6 months resulted in a reduction in the risk of cardiovascular outcomes by 5.3% (95% CI 0.9 to 9.9; P = 0.017). Losartan reduced the risk of cardiovascular outcomes by 9.2% (95% CI -7.9 to 23.6). Adjustment for the 6-month change in SUA attenuated the treatment effect to 4.6% (95% CI -16.2 to 22.0), suggesting that part of the cardiovascular protective effect of losartan is attributable to its short-term effect on SUA.Conclusion: Losartan but not irbesartan significantly lowers SUA compared to placebo in patients with type 2 diabetes and nephropathy. The degree of reduction in SUA explains part of the cardiovascular effect of losartan. This supports the hypothesis that SUA is a modifiable risk factor for cardiovascular disease, at least in type 2 diabetics with nephropathy.

To the Editor: The meta-analysis by Fagard et al1 on the effects of various antihypertensive drug classes on left ventricular mass is based on the pairwise comparisons of the original studies and avoids the problems with previous meta-analyses, which considered each treatment arm of the different studies as a separate observation, without respect for the original pairwise design.2,3 The authors should be commended for choosing an approach that avoids indirect comparisons among drug classes. On the other hand, the method …

Background Blockade of the renin-angiotensin-aldosterone system (RAAS) at its rate-limiting step by means of renin inhibition has led to the development of direct renin inhibitors (DRIs). Given the renal and cardioprotective effects of RAAS blockade by angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, DRIs may increase the armamentarium for further organ protection. Over the last two decades the effects of DRIs on biomarkers for renal and cardiovascular disease have been investigated. This systematic review aims to delineate the effects of DRIs on surrogate markers of renal and cardiovascular function. Methods MEDLINE and previous systematic reviews were searched for articles reported between 1980 and 2008. A standardized dataset was extracted from articles describing the effects of DRIs on markers of renal and cardiac damage and hard outcomes. Results Fifty-two articles were included. Blood pressure reductions were generally insufficient using early generation DRIs. However, recent DRIs have greater blood pressure-lowering effects. Preclinical and clinical studies showed profound effects of DRIs on markers of renal function, including clear increases in renal plasma flow and reductions in albuminuria. These effects were observed either alone or in combination with other RAAS inhibitors and suggest potential large renal protective benefit. DRIs improved hemodynamic cardiovascular parameters, such as total peripheral resistance, arterial pressure and left ventricular mass index, to a similar extent as those observed with other RAAS inhibitors. Furthermore, addition of DRIs to optimal heart failure treatment resulted in further reductions in B-type natriuretic peptide. Conclusions Evidence from preclinical and clinical studies suggests that DRIs may have renal and cardiovascular effects beyond their ability to lower blood pressure. Results of ongoing hard outcome trials are awaited to definitively assess the renal and cardio-protective effects of these agents. J Hypertens 27:2321-2331 (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

This study evaluates the tracking stability of office blood pressure (BP), ambulatory BP (ABP), BP variability (BPV) and nocturnal BP drops (dipping) from childhood to early adulthood, and their dependence on ethnicity, gender and family history (FH) of essential hypertension (EH). Generalized estimating equations (GEEs) were used to estimate tracking coefficients for 295 European Americans and 252 African Americans, with a maximum of 12 measurements over a 15-year period. Office BP and ABP had moderate-to-relatively high tracking coefficients (r= 0.30-0.59; P

Introduction. Arrhythmogenic right ventricular dysplasia (ARVD) is a heritable disorder characterised by fibrofatty replacement of right ventricular myocytes and increased risk of ventricular arrhythmias and sudden cardiac death. Angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism affects myocardialACE levels. DD genotype favours myocardial fibrosis and is associated with malignant ventricular tachycardia.The aim of this study was to explore ACE gene polymorphism inARVD patients. Methods. Twenty-nine patients with ARVD and 24 controls were included.AllARVD patients had documented sustained ventricular tachycardia. Thirteen patients had syncopal episodes. Six patients were resuscitated from sudden cardiac death.ACE gene polymorphism was identified by polymerase chain reaction technique. Results. There was no significant difference in DD genotype frequency between ARVD patients and controls (44.8% vs. 45.8%, p=0.94). However, DD genotype frequency was significantly higher in ARVD patients with syncopal episodes compared to those without syncope (69.2% vs. 25.0%, p=0.017, odds ratio:6.750,95% confidence interval: 1.318—34.565). DD genotype was detected in higher frequency also in patients with a family history of sudden cardiac death (66.7% vs. 39.1%,p=0.36). Conclusion. High prevalence of DD genotype in ARVD patients with syncope suggests that ACE I/D polymorphism might be useful in identifying high-risk patients for syncope.

BACKGROUNDGenetic contribution to left ventricular (LV) structure is generally recognized, but whether and how this influence varies by ethnicity or with age is unknown.METHODSParticipants were 517 European-American (EA) and African-American (AA) twin pairs (mean age: 14.6 +/- 3.0) at visit 1 and 422 EA and AA twin pairs at follow-up 4.1 years later. Echocardiograms were obtained on both visits. Data were analyzed using the structural equation modeling software Mx.RESULTSBody mass index (BMI) was a strong predictor for all LV measures at both visits 1 and 2, accounting for 3.5-24.2% of the total variance. Hemodynamics explained up to 4.5% additional LV measures variance. After adjusting for BMI, LV measures showed substantial heritability (range: 21-71 %). Best-fitting longitudinal models revealed considerable novel genetic effects on the interventricular septum, posterior wall-, and relative wall thickness (RWT) (but not LV internal diameter), accounting for 32-41% of the phenotypic variance at visit 2, with no significant gender and ethnic effects. There was a gender difference for LV mass index in AAs (P CONCLUSIONSThe heritability of cardiac structure and geometry was equally substantial in both AAs and EAs. Significant novel genetic influences were detected for all measures but LV inner diameter and LV mass index in AA females. Further developmental genetic studies are warranted to elucidate the nature of the emerging gene effects during the transition from adolescence to adulthood.

Albuminuria has been proven to be associated with cardiovascular morbidity and mortality. Such an association has been found not only in subjects with diabetes and hypertension, but also in the general population. It could therefore be expected that especially subjects with higher albuminuria levels may benefit from blood pressure-lowering agents to improve their cardiovascular outcome.This study indicates that the efficacy of blood pressure-lowering agents to prevent cardiovascular events is dependent of the level of albuminuria before start of such treatment. The higher baseline albuminuria, the better the relative and absolute risk reduction for cardiovascular events with blood pressure-lowering drugs. The data also suggest a possible better cardiovascular protective effect of renin-angiotensin intervening agents compared with other blood pressure-lowering agents.Albuminuria has been proven to be associated with cardiovascular (CV) events in specific patient populations, but also in the general population. This study aimed to investigate whether the efficacy of blood pressure-lowering agents in preventing CV events depends on baseline urinary albumin excretion (UAE) and, if so, whether this holds true for blood pressure-lowering agents in general, or is limited to agents that interfere in the renin-angiotensin system.Data were used from a community-based cohort study and pharmacy dispensing records. Included were subjects with hypertension (systolic blood pressureor=140 and/or diastolic blood pressureor=90 mmHg), no cardiovascular disease history, and no previous use of blood pressure-lowering agents.During study follow-up (7.1 +/- 1.6 years), 122 CV events were observed in 1185 subjects included. Start of blood pressure-lowering agents vs. non-use was associated with a difference in absolute CV event risk of 0.7%, 6% and 12.6% for all subjects, those with UAEor= 15 mg day(-1) andor=30 mg day(-1), respectively. Cox regression analysis showed that the relative risk for CV events after start of blood pressure-lowering agents was significantly dependent (P0.05) on baseline UAE; with hazard ratios of 0.87 [95% confidence interval (CI) 0.48, 1.60, P = NS], 0.58 (95% CI 0.36, 0.94, P0.05) and 0.37 (95% CI 0.20, 0.68, P0.05), for subjects with UAE15,or=15 andor=30 mg day(-1), respectively. Results adjusted for covariates were essentially similar. The use of angiotensin converting enzyme inhibitor/angiotensin-II receptor blocker (ACEi/ARB) treatment tended to be associated with a more favourable CV prognosis when compared with non-ACEi/ARB treatment (difference P = 0.06).Our results suggest that the efficacy of blood pressure-lowering agents to prevent CV events is dependent on baseline albuminuria. The higher baseline albuminuria, the more absolute as well as relative risk reduction can be achieved. Our data suggest that this may especially be true for ACEi/ARBs. We caution that this is an observational study, and that these conclusions should therefore be regarded as hypothesis generating, rather than hypothesis testing.

Experimental and human studies demonstrate that long-term exposure to elevated aldosterone levels results in cardiac and vascular damage.We investigated long-term cardiovascular outcomes in patients with primary aldosteronism after surgical or medical treatment. Fifty-four patients with or without evidence of adrenal adenomas were prospectively followed up for a mean of 7.4 years after treatment with adrenalectomy or spironolactone. Patients with primary aldosteronism were compared with patients with essential hypertension and were treated to reach a blood pressure of less than 140/90 mm Hg. The main outcome measure was a combined cardiovascular end point comprising myocardial infarction, stroke, any type of revascularization procedure, and sustained arrhythmias.At baseline, the prevalence of cardiovascular events was greater in primary aldosteronism (35%) than in essential hypertension (11%) (odds ratio, 4.61; 95% confidence interval, 2.38-8.95; P.001), with odds ratios of 4.93, 4.36, and 2.80 for sustained arrhythmias, cerebrovascular events, and coronary heart disease, respectively. Blood pressure during follow-up was comparable in the primary aldosteronism and essential hypertension groups. Ten patients in the primary aldosteronism group and 19 in the essential hypertension group reached the primary end point (P= .85). Cox analysis indicated that older age and longer duration of hypertension were factors independently associated with the cardiovascular end point. Cardiovascular outcome was comparable in patients with aldosteronism treated with adrenalectomy vs aldosterone antagonists (P= .71).Primary aldosteronism is associated with a cardiovascular complication rate out of proportion to blood pressure levels that benefits substantially from surgical and medical treatment in the long term.

Objective— In patients with coronary artery disease, the concomitant presence of renal function impairment is associated with decreased survival. We aimed to assess whether in coronary artery diseased patients renal function impairment is associated with systemic vascular function, functional parameters of the renin-angiotensin system, or inflammation as potential mediators for cardiovascular risk. Methods and Results— We studied 125 patients, 87% male, with a mean age of 62.2±8.2 years; 72% had 3-vessel disease, and mean renal function was 74±13 mL/min per 1.73 m 2 . Internal thoracic artery rings were sampled during coronary bypass surgery and used for in vitro vascular measurements. We could not establish an association between endothelium-dependent vasorelaxation (response to methacholine) and renal function. In addition, vascular response to potassium chloride, phenylephrine, and angiotensin II were not associated with renal function. Finally, serum angiotensin-converting enzyme (ACE) activity, usage of ACE inhibitors, C-reactive protein, and soluble intercellular adhesion molecule 1 were not related to renal function. Conclusions— In coronary artery disease patients, mild renal function impairment is not associated with systemic vasomotor responsiveness, inflammation, or functional systemic parameters of the renin-angiotensin system. The relation between systemic endothelial dysfunction and mild renal insufficiency might be more complicated than previously thought.

Calcium plays a role in blood pressure (BP) regulation, but the importance of supplemental calcium intake for the prevention of hypertension is still debated. We conducted a meta-analysis of randomized controlled trials to determine the effect of calcium supplementation on BP. A systematic search for randomized trials of calcium supplementation and BP in non-pregnant subjects was performed in Medline from 1966 to June 2003. Seventy-one trials were identified, 40 of which met the criteria for meta-analysis (total of 2492 subjects). Two persons independently extracted data from original publications on changes in calcium intake and BP. In addition, data were collected on subjects' characteristics, that is, age, gender, initial BP and initial calcium intake. A random effects model was used to obtain the effect of calcium supplementation on BP, overall and in predefined population subgroups. Calcium supplementation (mean daily dose: 1200 mg) reduced systolic BP by -1.86 mm Hg (95% confidence interval: -2.91 to -0.81) and diastolic BP by -0.99 mm Hg (-1.61 to -0.37). In people with a relatively low calcium intake (< or =800 mg per day) somewhat larger BP estimates were obtained, that is, -2.63 (-4.03 to -1.24) for systolic BP and -1.30 (-2.13 to -0.47) for diastolic BP. Our study suggests that an adequate intake of calcium should be recommended for the prevention of hypertension. More research on BP in people with calcium-deficient diets is warranted.

Background— Microalbuminuria is associated with increased risk of cardiovascular events. We assessed whether therapeutic intervention aimed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects (15 to 300 mg/24 hours). Methods and Results— From the Prevention of Renal and Vascular Endstage Disease (PREVEND) cohort (n=8592), 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial (PREVEND IT). Of these subjects, 864 were randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo. The mean follow-up was 46 months, and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity. Mean age was 51±12 years; 65% of subjects were male, and 3.4% had a previous cardiovascular event. Mean cholesterol level was 5.8±1.0 mmol/L, mean systolic/diastolic blood pressure was 130±18/76±10 mm Hg, and median urinary albumin excretion was 22.8 (15.8 to 41.3) mg/24 hours. The primary end point occurred in 45 subjects (5.2%). Fosinopril reduced urinary albumin excretion by 26% ( P P =0.098, log-rank). Pravastatin did not reduce urinary albumin excretion, and subjects treated with pravastatin showed a 13% lower incidence of the primary end point than subjects in the placebo group (0.87 [0.49 to 1.57], P =0.649, log-rank). Conclusions— In microalbuminuric subjects, treatment with fosinopril had a significant effect on urinary albumin excretion. In addition, fosinopril treatment was associated with a trend in reducing cardiovascular events. Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events.

Background: Atherosclerotic complications are the main cause of death in adult patients with renal failure. Endothelial dysfunction is a hallmark of early atherosclerotic changes. The numerous risk factors for endothelial dysfunction present in adults are present in children with renal failure, as well. In addition to this, increased stiffness of the arterial tree conveys an increased risk for cardiovascular mortality. The aim of this study is to investigate whether pediatric kidney recipients already show endothelial dysfunction and have increased arterial stiffness. Methods: We investigated 20 pediatric kidney recipients with stable graft function and 20 healthy children. Endothelial function was studied noninvasively with ultrasound and digital signal analysis equipment as the percentage of post-ischemic flow-mediated dilatation (FMD) of the brachial artery. Parameters of arterial distensibility were calculated from distension of the brachial artery during the cardiac cycle, pulse pressure, and baseline diameter. Results: FMD was significantly less in patients (7.7% +/- 5.4%) than controls (15.0% +/- 7.1 %; P

Renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II (Ang II), AT1receptor blockers (ARB) is the cornerstone of renoprotective therapy. Still, the number of patients with end-stage renal disease is increasing worldwide, prompting the search for improved renoprotective strategies.In spite of proven efficacy at group level, the long-term renoprotective effect of RAAS blockade displays a marked between-patient heterogeneity, which is closely linked to between-patient differences in the intermediate parameters of blood pressure, proteinuria and renal haemodynamics. Of note, the between-patient differences by far exceed the between-regimen differences, and thus may provide a novel target for exploration and intervention.The responsiveness to RAAS blockade appears to be an individual characteristic — as demonstrated by studies applying a rotation-schedule design. The type and severity of renal disease, obesity, insulin-resistance, glycaemic control, and genetic factors may all be involved in individual differences in responsiveness, as well as dietary factors, such as dietary sodium and protein intake.Several strategies, such as dietary sodium restriction and diuretic therapy, dose-titration for proteinuria, and dual RAAS blockade with ACE-I and ARB, can improve the response to therapy at a group level. However, when analysed for their effect in individuals, it appears that these measures do not allow poor responders to catch up with the good responders, i.e. in spite of their efficacy at group level, the available measures are usually not sufficient to overcome individual resistance to RAAS blockade.We conclude that between-patient differences in responsiveness to renoprotective intervention should get specific attention as a target for intervention. Unravelling of the underlying mechanisms may allow development of specific intervention. Based on the currently available data, we propose that response-based treatment schedules, with a multidrug approach titrated and adapted at individual responses rather than fixed treatment schedules, may provide a fruitful strategy for more effective renoprotection.