Strategies to improve blood pressure control:a step forward to winning the battle

Objective: Hypertension represents a common risk factor for all major cardiovascular diseases. The issue of inappropriate blood pressure control in the hypertensive population is a worldwide still unsolved problem, with heavy consequences on the health care systems. A call to action is required to optimize blood pressure control and to reduce the cardiovascular risk. Methods and results: In this issue of the journal a new study presents the results of a multifaceted complex approach, in the context of a quality improvement program, through the involvement of a high functioning multidisciplinary team. A patient population largely underprivileged, urban and 75% African American, referring to an Internal Medicine Clinic, included a large majority of hypertensive patients with inappropriate blood pressure control. By addressing identified barriers to achieve optimal blood pressure control, the current improvement program pursued the education of physicians, nurses and patients as a key driver to optimize patients-provider communication and to achieve a satisfactory final result. Conclusions: The strategy described in the study by Sadeghi et al. allowed to maintain positive results for one year and thereafter. Despite some weaknesses, this multifaceted complex approach deserves particular attention since it describes relevant findings that represent a significant step forward to improving blood pressure control in the hypertensive population

Circulating leukocytes and oxidative Stress in cardiovascular diseases: a state of the art

Increased oxidative stress from both mitochondrial and cytosolic sources contributes to the development and the progression of cardiovascular diseases (CVDs), and it is a target of therapeutic interventions. The numerous efforts made over the last decades in order to develop tools able to monitor the oxidative stress level in patients affected by CVDs rely on the need to gain information on the disease state. However, this goal has not been satisfactorily accomplished until now. Among others, the isolation of circulating leukocytes to measure their oxidant level offers a valid, noninvasive challenge that has been tested in few pathological contexts, including hypertension, atherosclerosis and its clinical manifestations, and heart failure. Since leukocytes circulate in the blood stream, it is expected that they might reflect quite closely both systemic and cardiovascular oxidative stress and provide useful information on the pathological condition. The results of the studies discussed in the present review article are promising. They highlight the importance of measuring oxidative stress level in circulating mononuclear cells in different CVDs with a consistent correlation between degree of oxidative stress and severity of CVD and of its complications. Importantly, they also point to a double role of leukocytes, both as a marker of disease condition and as a direct contributor to disease progression. Finally, they show that the oxidative stress level of leukocytes reflects the impact of therapeutic interventions. It is likely that the isolation of leukocytes and the measurement of oxidative stress, once adequately developed, may represent an eligible tool for both research and clinical purposes to monitor the role of oxidative stress on the promotion and progression of CVDs, as well as the impact of therapies

Salt-regulating hormones in young normotensive obese subjects. Effects of saline load.

To investigate whether the response of salt-regulating hormones to volume expansion is impaired in obese subjects, we assessed the effects of saline load (0.25 mL/kg.min.120 min) in 9 young, healthy, normotensive obese subjects (body mass index, > 30 kg/m2) and in 10 lean control subjects (body mass index, < 25 kg/m2) matched for age, gender, height, and mean blood pressure. Hematocrit, plasma renin activity (PRA), plasma aldosterone (PA), atrial natriuretic factor (ANF), and urinary sodium excretion (UNaV) were evaluated. Saline load increased ANF levels significantly (P < .001) in lean subjects at both 60 and 120 minutes, whereas they decreased in obese subjects. Such decreases became significant (P < .01) at 120 minutes. Suppression of PRA and PA by saline load were more marked in lean than obese subjects. Hematocrit decreased in both groups, and UNaV increased more in lean than obese subjects during saline load. Comparisons of percent changes in ANF, PRA, and PA after saline load showed that the responses of lean and obese subjects were significantly different (P < .001 for ANF at both 60 and 120 minutes; P < .05 for PRA and PA at both 60 and 120 minutes). In conclusion, the lack of ANF response and the reduced suppression of PRA and PA to saline load indicate a dysfunction of these systems in obese subjects. This alteration may be involved in the higher susceptibility of obese subjects to developing hypertension

Occurrence of Fipronil in residential house dust in the presence and absence of pets: a hint for a comprehensive toxicological assessment

The presence of the insecticide Fipronil and its main products of toxicological relevance, namely Sulfone and Desulfinyl, was assessed in 161 residential house dust samples in the absence (N = 101) and presence (N = 60) of cats and dogs in Italy. High-resolution mass spectrometry analysis revealed a significant difference (p &lt; 0.001) in the dust contamination in the presence of pets (median: 467 vs. 24 ng/g dry weight), even if the highest value was found in the absence of pets (82,069 vs. 67,799 ng/g dry weight). Fipronil intake estimates from dust in toddlers, computed according to US-EPA and EU-ECHA guidelines, ranged from 333 to 556 and from 20 to 34 ng/kg per day for acute and chronic scenario, respectively. Dust seemed not able itself to lead to Fipronil overexposure with respect to acute and chronic toxicity health-based guidance values. Kittens were potentially overexposed to Fipronil under both acute (26,076 ng/kg per day) and chronic (1,633 ng/kg per day) scenarios. The mild symptomatology associated with acute intoxication could possibly determine case underreporting within pharmacosurveillance schemes. Its administration was estimated in 7.3\u20139.7 tons per year. Such a range suggests its prudent use under strict veterinary control to prevent pest resistance and ecotoxicological outcomes

Brain overexpression of uncoupling protein-2 (Ucp2) delays renal damage and stroke occurrence in stroke-prone spontaneously hypertensive rats

The downregulation of uncoupling protein-2 (UCP2) is associated with increased brain and kidney injury in stroke-prone spontaneously hypertensive rats (SHRSP) fed with a Japanese style hypersodic diet (JD). Systemic overexpression of UCP2 reduces organ damage in JD-fed SHRSP. We examined the effect of brain-specific UCP2 overexpression on blood pressure (BP), stroke occurrence and kidney damage in JD-fed SHRSP. Rats received a single i.c.v. injection of a lentiviral vector encoding UCP2 (LV-UCP2), or an empty vector. The brain delivery of LV-UCP2 significantly delayed the occurrence of stroke and kidney damage. The large reduction of proteinuria observed after LV-UCP2 injection was unexpected, because BP levels were unchanged. At the time of stroke, rats treated with LV-UCP2 still showed a large UCP2 upregulation in the striatum, associated with increases in OPA1 and FIS1 protein levels, and reductions in PGC1-α, SOD2, TNFα mRNA levels and NRF2 protein levels. This suggested UCP2 overexpression enhanced mitochondrial fusion and fission and reduced oxidative damage and inflammation in the striatum of JD-fed SHRSP rats. Our data suggest the existence of central mechanisms that may protect against hypertension-induced organ damage independently of BP, and strengthen the suitability of strategies aimed at enhancing UCP2 expression for the treatment of hypertensive damage

The direct renin inhibitor aliskiren improves vascular remodelling in transgenic rats harbouring human renin and angiotensinogen genes

In the present study, we tested the hypothesis that chronic treatment with the direct rennin inhibitor aliskiren improves the remodelling of resistance arteries in dTGR (double-transgenic rats). dTGR (5 weeks) were treated with aliskiren (3 mg/kg of body mass per day) or ramipril (1 mg/kg of body mass per day) for 14 days and compared with age-matched vehicle-treated dTGR. BP (blood pressure) was similarly reduced in both aliskiren-treated and ramipril-treated rats compared with control dTGR (167± 1 and 169± 2 mmHg compared with 197± 4 mmHg respectively; P<0.05). The M/L (media-to-lumen) ratio assessed on pressurized preparations was equally reduced in aliskiren-treated and ramipril-treated rats compared with controls (6.3± 0.5 and 6.4±0.2% compared with 9.8± 0.4% respectively; P<0.05). Endothelium-dependent and -independent relaxations were similar among the groups. L-NAME (NG-nitro-L-arginine methyl ester) significantly reduced acetylcholine-induced dilation in drug-treated dTGR. This effect was significantly more prominent in aliskiren-treated rats. eNOS (endothelial NO synthase) expression showed a 2-fold increase only in aliskiren-treated dTGR as compared with controls (P<0.01) and ramipril-treated dTGR (P<0.05). Plasma nitrite, as an index of NO production, was significantly increased in dTGR treated with either aliskiren or ramipril compared with controls. Only aliskiren induced a 2-fold increase in plasma nitrite, which was significantly greater than that induced by ramipril (P<0.05). gp91phox expression and ROS (reactive oxygen species) production in aorta were significantly and similarly reduced by both drugs. In conclusion, equieffective hypotensive doses of aliskiren or ramipril reduced the M/L ratio of mesenteric arteries and improved oxidative stress in dTGR. However, only aliskiren increased further NO production in the vasculature. Hence, in dTGR, direct renin inhibition induces favourable effects similar to that induced by ACE (angiotensin-converting enzyme) inhibition in improving vascular remodelling through different mechanisms. © The Authors Journal compilation. 2013 Biochemical Society

Natriuretic peptides and integrated risk assessment for cardiovascular disease. an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention

Reduced brain UCP2 expression mediated by microRNA-503 contributes to increased stroke susceptibility in the high-salt fed stroke-prone spontaneously hypertensive rat

UCP2 maps nearby the lod score peak of STR1-stroke QTL in the SHRSP rat strain. We explored the potential contribution of UCP2 to the high-salt diet (JD)-dependent increased stroke susceptibility of SHRSP. Male SHRSP, SHRSR, two reciprocal SHRSR/SHRSP-STR1/QTL stroke congenic lines received JD for 4 weeks to detect brain UCP2 gene/protein modulation as compared with regular diet (RD). Brains were also analyzed for NF-\u3baB protein expression, oxidative stress level and UCP2-targeted microRNAs expression level. Next, based on knowledge that fenofibrate and Brassica Oleracea (BO) stimulate UCP2 expression through PPAR\u3b1 activation, we monitored stroke occurrence in SHRSP receiving JD plus fenofibrate versus vehicle, JD plus BO juice versus BO juice plus PPAR\u3b1 inhibitor. Brain UCP2 expression was markedly reduced by JD in SHRSP and in the (SHRsr.SHRsp-(D1Rat134-Mt1pa)) congenic line, whereas NF-\u3baB expression and oxidative stress level increased. The opposite phenomenon was observed in the SHRSR and in the (SHRsp.SHRsr-(D1Rat134-Mt1pa)) reciprocal congenic line. Interestingly, the UCP2-targeted rno-microRNA-503 was significantly upregulated in SHRSP and decreased in SHRSR upon JD, with consistent changes in the two reciprocal congenic lines. Both fenofibrate and BO significantly decreased brain microRNA-503 level, upregulated UCP2 expression and protected SHRSP from stroke occurrence. In vitro overexpression of microRNA-503 in endothelial cells suppressed UCP2 expression and led to a significant increase of cell mortality with decreased cell viability. Brain UCP2 downregulation is a determinant of increased stroke predisposition in high-salt-fed SHRSP. In this context, UCP2 can be modulated by both pharmacological and nutraceutical agents. The microRNA-503 significantly contributes to mediate brain UCP2 downregulation in JD-fed SHRSP

Potential Prognostic Significance of Decreased Serum Levels of TRAIL after Acute Myocardial Infarction

BACKGROUND: Since soluble TRAIL exhibits anti-inflammatory and anti-atherosclerotic activities both in vitro and in animal models, this study was designed to assess the relationship between the serum levels of TRAIL and clinical outcomes in patients with acute myocardial infarction (AMI). METHODOLOGY/PRINCIPAL FINDINGS: Levels of TRAIL were measured by ELISA in serial serum samples obtained from 60 patients admitted for AMI, both during hospitalization and in a follow-up of 12 months, as well as in 60 healthy control subjects. Serum levels of TRAIL were significantly decreased in patients with AMI at baseline (within 24 hours from admission), compared with healthy controls, and showed a significant inverse correlation with a series of negative prognostic markers, such as CK, CK-MB and BNP. TRAIL serum levels progressively increased at discharge, but normalized only at 6-12 months after AMI. Of note, low TRAIL levels at the patient discharge were associated with increased incidence of cardiac death and heart failure in the 12-month follow-up, even after adjustment for demographic and clinical risk parameters (hazard ratio [HR] of 0.93 [95% CI, 0.89 to 0.97]; p = 0.001). CONCLUSIONS/SIGNIFICANCE: Although the number of patients studied was limited, our findings indicate for the first time that circulating TRAIL might represent an important predictor of cardiovascular events, independent of conventional risk markers