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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.

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.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

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.

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.

The distal parts of the renal tubule play a critical role in maintaining homeostasis of extracellular fluids. In this review, we present an in-depth analysis of microarray-based gene expression profiles available for microdissected mouse distal nephron segments, i.e., the distal convoluted tubule (DCT) and the connecting tubule (CNT), and for the cortical portion of the collecting duct (CCD; Zuber et al., Proc Natl Acad Sci USA 106:16523-16528, 2009). Classification of expressed transcripts in 14 major functional gene categories demonstrated that all principal proteins involved in maintaining the salt and water balance are represented by highly abundant transcripts. However, a significant number of transcripts belonging, for instance, to categories of G-protein-coupled receptors or serine/threonine kinases exhibit high expression levels but remain unassigned to a specific renal function. We also established a list of genes differentially expressed between the DCT/CNT and the CCD. This list is enriched by genes related to segment-specific transport functions and by transcription factors directing the development of the distal nephron or collecting ducts. Collectively, this in silico analysis provides comprehensive information about relative abundance and tissue specificity of the DCT/CNT and the CCD expressed transcripts and identifies new candidate genes for renal homeostasis.

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

Purpose of the review: This review article synthesizes recent research findings on the psychological context of Type D personality and the mechanisms through which Type D affects disease progression and prognosis among patients with coronary heart disease (CHD).Recent findings: One in four patients with CHD has a Distressed (Type D) personality, which is characterized by two stable traits: social inhibition and negative affectivity. Type D personality predicts increased mortality and morbidity burden, and poorer health-related quality of life. Type D is part of a family of psychosocial risk factors that affect CHD prognosis. The pattern of co-occurrence of these psychosocial factors and intra-individual differences in psychosocial profiles may affect risk prediction accuracy. Multiple biological and behavioral processes have been associated with Type D personality. Summary:Identifying pathways explaining the observed associations between Type D personality and CHD is important to improve etiological and pathophysiological knowledge and to design personalized interventions, and targeting specific risk-associated pathways.

AIMS Sulodexide is a highly purified mixture of glycosaminoglycans that has been studied for its anti-albuminuric potential. Considering the effects of glycosaminoglycans on endothelial function and sodium homeostasis, we hypothesized that sulodexide may lower blood pressure (BP). In this meta-analysis, we therefore investigated the antihypertensive effects of sulodexide treatment. METHODS We selected randomized controlled trials that investigated sulodexide treatment of at least 4 weeks and measured BP at baseline and after treatment. Two reviewers independently extracted data on study design, risk of bias, population characteristics and outcome measures. In addition, we contacted authors and pharmaceutical companies to provide missing data. RESULTS Eight studies, totalling 3019 subjects (mean follow-up 4.4 months) were included. Mean age was 61 years and mean baseline BP was 135/75 mmHg. Compared with control treatment, sulodexide resulted in a significant systolic (2.2 mmHg [95% CI 0.3, 4.1], P = 0.02) and diastolic BP reduction (1.7 mmHg [95% CI 0.6, 2.9], P = 0.004). Hypertensive patients displayed the largest systolic BP and diastolic BP reductions (10.2/5.4 mmHg, P

BackgroundIncreases in serum creatinine with renin-angiotensin-aldosterone system (RAAS) inhibitors can lead to unnecessary discontinuation of these agents. The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection fraction, and pilot data suggest potential benefit in heart failure with preserved ejection fraction (HFpEF). The effects of LCZ696 on renal function have not been assessed.Methods and resultsA total of 301 HFpEF patients were randomly assigned to LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function [creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and urinary albumin to creatinine ratio (UACR)] at baseline, 12 weeks, and after 36 weeks of treatment. Worsening renal function (WRF) was determined as an serum creatinine increase of >0.3 mg/dL and/or >25% between two time-points. Mean eGFR at baseline was 65.4 20.4 mL/min per 1.73 m(2). The eGFR declined less in the LCZ696 group than in the valsartan group (-1.5 vs. -5.2 mL/min per 1.73 m(2); P = 0.002). The incidence of WRF was lower in the LCZ696 group (12%) than in the valsartan group (18%) at any time-point, but this difference was not statistically significant (P = 0.18). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group (2.4-2.9 mg/mmol), whereas it remained stable in the valsartan group (2.1-2.0 mg/mmol; P for difference between groups = 0.016).ConclusionIn patients with HFpEF, therapy with LCZ696 for 36 weeks was associated with preservation of eGFR compared with valsartan therapy, but an increase in UACR.

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.

Several studies reported sex differences in aldosterone. It is unknown whether these differences are associated with differences in volume regulation. Therefore we studied both aldosterone and extracellular volume in men and women on different sodium intakes. In healthy normotensive men ( n = 18) and premenopausal women ( n = 18) we investigated plasma aldosterone, blood pressure, and extracellular volume (125I-iothalamate), during both low (target intake 50 mmol Na+/day) and high sodium intake (target intake 200 mmol Na+/day) in a crossover setup. Furthermore, we studied the adrenal response to angiotensin II infusion (0.3, 1.0, and 3.0 ng·kg−1·min−1for 1 h) on both sodium intakes. Men had a significantly higher plasma aldosterone, extracellular volume, and systolic blood pressure than women during high sodium intake ( P < 0.05). During low sodium intake, extracellular volume and blood pressure were higher in men as well ( P < 0.05), whereas the difference in plasma aldosterone was no longer significant ( P = 0.252). The adrenal response to exogenous angiotensin II was significantly lower in men than in women on both sodium intakes. Constitutive sex differences in the regulation of aldosterone, characterized by a higher aldosterone and a lower adrenal response to exogenous angiotensin II infusion in men, are associated with a higher extracellular volume and blood pressure in men. These findings suggest that sex differences in the regulation of aldosterone contribute to differences in volume regulation between men and women.

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.

Background Increased activity of the three major physiological stress systems (immune-inflammatory system, hypothalamic-pituitary-adrenal-axis [HPA-axis], and autonomic nervous system [ANS]) is part of the pathophysiology of various somatic and psychiatric diseases. Oxidative damage is a key mechanism in both ageing and disease. Elucidating the relationship between these stress systems and oxidative damage would contribute to the understanding of the role of physiological stress in disease. This study therefore investigates associations between various measures of physiological stress and oxidative DNA (8-hydroxy-2′-deoxyguanosine, 8-OHdG) and lipid (F2-isoprostanes) damage. Methods Plasma 8-OHdG and F2-isoprostanes were measured using LC–MS/MS in 2858 subjects (aged 18–65). Plasma inflammation markers, salivary cortisol and ANS markers (three for each stress system) were determined. Linear regression analyses were adjusted for sociodemographics, sampling factors and medication. Results 8-OHdG was positively associated with all inflammation markers (β = 0.047–0.050, p

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.

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.

Background:We performed a genome-wide scan in a homogeneous Arab population to identify genomic regions linked to blood pressure (BP) and its intermediate phenotypes during mental and physical stress tests.Methods:The Oman Family Study subjects (N= 1277) were recruited from five extended families of ~10 generations. Hemodynamic phenotypes were computed from beat-to-beat BP, electrocardiography and impedance cardiography. Multi-point linkage was performed for resting, mental (word conflict test, WCT) and cold pressor (CPT) stress and their reactivity scores (s), using variance components decomposition-based methods implemented in SOLAR.Results:Genome-wide scans for BP phenotypes identified quantitative trait loci (QTLs) with significant evidence of linkage on chromosomes 1 and 12 for WCT-linked cardiac output (LOD = 3.1) and systolic BP (LOD = 3.5). Evidence for suggestive linkage for WCT was found on chromosomes 3, 17 and 1 for heart rate (LOD = 2.3), DBP (LOD = 2.4) and left ventricular ejection time (LVET), respectively. For △WCT, suggestive QTLs were detected for CO on chr11 (LOD = 2.5), LVET on chr3 (LOD = 2.0) and EDI on chr9 (LOD = 2.1). For CPT, suggestive QTLs for HR and LVET shared the same region on chr22 (LOD 2.3 and 2.8, respectively) and on chr9 (LOD = 2.3) for SBP, chr7 (LOD = 2.4) for SV and chr19 (LOD = 2.6) for CO. For △CPT, CO and TPR top signals were detected on chr15 and 10 (LOD; 2.40, 2.08) respectively. Conclusion: Mental stress revealed the largest number of significant and suggestive loci for normal BP reported to date. The study of BP and its intermediate phenotypes under mental and physical stress may help reveal the genes involved in the pathogenesis of essential hypertension.

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.

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.

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.

SUMMARY Background: Resistin could be the linkage between the adipose tissue and the insulin resistance. In humans, the role of resistin on metabolic and vascular homeostasis is not well defined. The aim of this study was to investigate the possible association between resistin expression and insulin resistance. Methods and results: We evaluated the relationship between monocyte expression of mRNA and anthropometric and metabolic parameters of insulin resistance. We focused on the potential role of resistin on endothelial function. Thirtynine patients with metabolic syndrome (MS) and clinically free from cardiovascular disease, and 15 healthy subjects were included in this study. All subjects underwent clinical examination, assessment of haematochemical parameters, bioimpedentiometry, measurement of monocyte resistin mRNA and of brachial-artery flow-mediated vasodilation (FMV). Patients with MS showed higher levels of interleukin-6 (IL; 2AE 1±1 AE 2v s. 1AE 2±0 AE9 pg/mL, P

Nebivolol is a third generation beta-blocker. It is highly selective for the beta 1-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 P-blocker with vasodilating and antioxidant effects.

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.

Background: Increases in serum creatinine with renin–angiotensin–aldosterone system ( RAAS ) inhibitors can lead to unnecessary discontinuation of these agents. The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection fraction, and pilot data suggest potential benefit in heart failure with preserved ejection fraction ( HFpEF ). The effects of LCZ696 on renal function have not been assessed. Methods and results: A total of 301 HFpEF patients were randomly assigned to LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function [creatinine, estimated glomerular filtration rate ( eGFR ), cystatin C, and urinary albumin to creatinine ratio ( UACR )] at baseline, 12 weeks, and after 36 weeks of treatment. Worsening renal function ( WRF ) was determined as an serum creatinine increase of > 0.3 mg/dL and/or > 25% between two time-points. Mean eGFR at baseline was 65.4 ± 20.4 mL/min per 1.73 m2. The eGFR declined less in the LCZ696 group than in the valsartan group ( –1.5 vs. –5.2 mL/min per 1.73 m2; P = 0.002 ). The incidence of WRF was lower in the LCZ696 group ( 12% ) than in the valsartan group ( 18% ) at any time-point, but this difference was not statistically significant ( P = 0.18 ). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group ( 2.4–2.9 mg/mmol ), whereas it remained stable in the valsartan group ( 2.1–2.0 mg/mmol; P for difference between groups = 0.016 ). Conclusion: In patients with HFpEF, therapy with LCZ696 for 36 weeks was associated with preservation of eGFR compared with valsartan therapy, but an increase in UACR.

AIMS Sulodexide is a highly purified mixture of glycosaminoglycans that has been studied for its anti-albuminuric potential. Considering the effects of glycosaminoglycans on endothelial function and sodium homeostasis, we hypothesized that sulodexide may lower blood pressure (BP). In this meta-analysis, we therefore investigated the antihypertensive effects of sulodexide treatment. METHODS We selected randomized controlled trials that investigated sulodexide treatment of at least 4 weeks and measured BP at baseline and after treatment. Two reviewers independently extracted data on study design, risk of bias, population characteristics and outcome measures. In addition, we contacted authors and pharmaceutical companies to provide missing data. RESULTS Eight studies, totalling 3019 subjects (mean follow-up 4.4 months) were included. Mean age was 61 years and mean baseline BP was 135/75 mmHg. Compared with control treatment, sulodexide resulted in a significant systolic (2.2 mmHg [95% CI 0.3, 4.1], P = 0.02) and diastolic BP reduction (1.7 mmHg [95% CI 0.6, 2.9], P = 0.004). Hypertensive patients displayed the largest systolic BP and diastolic BP reductions (10.2/5.4 mmHg, P

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.