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Find video protocols related to scientific articles indexed in Pubmed.
Catheter-based renal sympathetic denervation: limitations to and gaps in the evidence.
Curr. Opin. Cardiol.
PUBLISHED: 05-27-2014
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Renal sympathetic nerves play a significant role in the development and maintenance of hypertension. Percutaneous catheter-based radioablation of the sympathetic nerves around the renal arteries is a true innovation in follow up to prior animal studies. In this opinion article, we will review the role of the renal sympathetic network in hypertension, and the evidence (or the lack of it) for renal sympathetic denervation as a treatment modality for human hypertension.
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The effects of lysine analogs during pelvic surgery: a systematic review and meta-analysis.
Transfus Med Rev
PUBLISHED: 04-29-2014
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Pelvic vasculature is complex and inconsistent while pelvic bones impede access to pelvic organs. These anatomical characteristics render pelvic surgery inherently difficult, and some of these procedures are frequently associated with blood loss that necessitates blood transfusion. The aim of this study was to review the literature on the use of lysine analogs to prevent bleeding and blood transfusion during pelvic surgery. The objective of this study was to assess the safety and efficacy of lysine analogs during pelvic surgery. A systematic literature search was performed using Medline, Cochrane Register of Clinical Trials, Embase, and the reference lists of relevant articles. Randomized controlled trials or observational cohort studies comparing a lysine analog to placebo or standard care were included. Outcomes collected were blood transfusion, blood loss, thromboembolic adverse events (myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism), nonthromboembolic adverse events, and death. There were no language limitations. Fifty-six articles reported on 68 comparisons between a lysine analog and an inactive comparator, involving a total of 7244 patients published between 1961 and 2013. Thirty-nine studies evaluated urologic procedures, and 21 evaluated gynecologic procedures. Thirty-six studies (60%) were published before 1980. Of the 43 randomized comparisons, only 30 (44%) had a score of 3 or higher on Jadad's 5-point scale of methodological quality. Among randomized trials, lysine analogs reduced the risk of blood transfusion (pooled odds ratio [OR], 0.47; 95% confidence interval [CI], 0.35-0.64) and blood loss (pooled OR, 0.22; 95% CI, 0.18-0.27). There was a small statistically insignificant increased risk of thromboembolic events (pooled OR, 1.07; 95% CI, 0.72-1.59) and no-thrombotic serious adverse events (pooled OR, 1.11; 95% CI, 0.67-1.83). In the 17 randomized trials published since the year 2000, only 6 thrombotic events were reported, 4 of which occurred in the placebo arm. Lysine analogs did not increase risk of death (pooled OR, 0.91; 95% CI, 0.34-2.48). These results are significant as they indicate that lysine analogs significantly reduce blood loss and blood transfusion during pelvic surgery. Although there does not appear to be a large increase in the risk of thromboembolic and nonthrombotic adverse events, more data are required to definitively assess these outcomes. Based on this review, lysine analogs during pelvic surgery seem to reduce bleeding and blood transfusion requirements. Although there does not seem to be a significant risk of adverse effects, larger studies would help clarify risks, if any, associated with lysine analog use.
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What is the feasibility of implementing effective sodium reduction strategies to treat hypertension in primary care settings? A systematic review.
J. Hypertens.
PUBLISHED: 04-04-2014
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To evaluate whether efficacious counseling methods on sodium restriction can be successfully incorporated into primary care models for the management of hypertension.
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Autonomic nervous system dysregulation in pediatric hypertension.
Curr. Hypertens. Rep.
PUBLISHED: 03-18-2014
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Historically, primary hypertension (HTN) has been prevalent typically in adults. Recent data however, suggests an increasing number of children diagnosed with primary HTN, mainly in the setting of obesity. One of the factors considered in the etiology of HTN is the autonomous nervous system, namely its dysregulation. In the past, the sympathetic nervous system (SNS) was regarded as a system engaged mostly in buffering major acute changes in blood pressure (BP), in response to physical and emotional stressors. Recent evidence suggests that the SNS plays a much broader role in the regulation of BP, including the development and maintenance of sustained HTN by a chronically elevated central sympathetic tone in adults and children with central/visceral obesity. Consequently, attempts have been made to reduce the SNS hyperactivity, in order to intervene early in the course of the disease and prevent HTN-related complications later in life.
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Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for the management of blood pressure in CKD.
Am. J. Kidney Dis.
PUBLISHED: 03-06-2014
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The KDIGO (Kidney Disease: Improving Global Outcomes) 2012 clinical practice guideline for the management of blood pressure (BP) in chronic kidney disease (CKD) provides the structural and evidence base for the Canadian Society of Nephrology (CSN) commentary on this guideline's relevancy and application to the Canadian health care system. While in general agreement, we provide commentary on 13 of the 21 KDIGO guideline statements. Specifically, we agreed that nonpharmacological interventions should play a significant role in the management of hypertension in patients with CKD. We also agreed that the approach to the management of hypertension in elderly patients with CKD should be individualized and take into account comorbid conditions to avoid adverse outcomes from excessive BP lowering. In contrast to KDIGO, the CSN Work Group believes there is insufficient evidence to target a lower BP for nondiabetic CKD patients based on the presence and severity of albuminuria. The CSN Work Group concurs with the Canadian Hypertension Education Program (CHEP) recommendation of a target BP for all non-dialysis-dependent CKD patients without diabetes of ?140 mm Hg systolic and ?90 mm Hg diastolic. Similarly, it is our position that in diabetic patients with CKD and normal urinary albumin excretion, raising the threshold for treatment from <130 mm?Hg systolic BP to <140 mm Hg systolic BP could increase stroke risk and the risk of worsening kidney disease. The CSN Work Group concurs with the CHEP and the Canadian Diabetic Association recommendation for diabetic patients with CKD with or without albuminuria to continue to be treated to a BP target similar to that of the overall diabetes population, aiming for BP levels < 130/80 mm Hg. Consistent with this, the CSN Work Group endorses a BP target of <130/80 mm Hg for diabetic patients with a kidney transplant. Finally, in the absence of evidence for a lower BP target, the CSN Work Group concurs with the CHEP recommendation to target BP<140/90 mm Hg for nondiabetic patients with a kidney transplant.
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Spot urine protein measurements in kidney transplantation: a systematic review of diagnostic accuracy.
Nephrol. Dial. Transplant.
PUBLISHED: 01-26-2014
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Quantification of proteinuria (albuminuria) in renal transplant recipients is important for diagnostic and prognostic purposes. Recent guidelines have recommended quantification of proteinuria by spot protein-to-creatinine ratio (PCR) or spot albumin-to-creatinine ratio (ACR). Validity of spot measurements remains unclear in renal transplant recipients.
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The 2014 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.
Can J Cardiol
PUBLISHED: 01-23-2014
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Herein, updated evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in Canadian adults are detailed. For 2014, 3 existing recommendations were modified and 2 new recommendations were added. The following recommendations were modified: (1) the recommended sodium intake threshold was changed from ? 1500 mg (3.75 g of salt) to approximately 2000 mg (5 g of salt) per day; (2) a pharmacotherapy treatment initiation systolic blood pressure threshold of ? 160 mm Hg was added in very elderly (age ? 80 years) patients who do not have diabetes or target organ damage (systolic blood pressure target in this population remains at < 150 mm Hg); and (3) the target population recommended to receive low-dose acetylsalicylic acid therapy for primary prevention was narrowed from all patients with controlled hypertension to only those ? 50 years of age. The 2 new recommendations are: (1) advice to be cautious when lowering systolic blood pressure to target levels in patients with established coronary artery disease if diastolic blood pressure is ? 60 mm Hg because of concerns that myocardial ischemia might be exacerbated; and (2) the addition of glycated hemoglobin (A1c) in the diagnostic work-up of patients with newly diagnosed hypertension. The rationale for these recommendation changes is discussed. In addition, emerging data on blood pressure targets in stroke patients are discussed; these data did not lead to recommendation changes at this time. The Canadian Hypertension Education Program recommendations will continue to be updated annually.
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Short daily versus conventional hemodialysis for hypertensive patients: a randomized cross-over study.
PLoS ONE
PUBLISHED: 01-01-2014
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Treatment of end stage renal disease patients with short daily hemodialysis has been associated with an improvement in blood pressure. It is unclear from these studies if anti-hypertensive management had been optimized prior to starting short daily hemodialysis. Also, the potential mechanism(s) of blood pressure improvement remain to be fully elucidated.
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Clinical hypotension with co-prescription of macrolide antibiotics and calcium-channel blockers in haemodialysis patients: a retrospective chart review.
Drug Saf
PUBLISHED: 07-23-2013
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Macrolide antibiotics inhibit the cytochrome p450 enzyme system, which metabolizes calcium-channel blockers. This may result in a clinically significant interaction, causing hypotension in patients co-prescribed these two drugs. Since these drugs are frequently used in the haemodialysis population, we studied the effect of their co-prescription on actual blood pressure.
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Percutaneous Renal Sympathetic Denervation: 2013 and Beyond.
Can J Cardiol
PUBLISHED: 07-02-2013
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Systemic hypertension affects almost a quarter of Canadian adults. Although most can achieve adequate blood pressure control using a combination of medical and lifestyle interventions, many have resistant hypertension and are unable to reach their target. Percutaneous renal sympathetic denervation has been developed to address a crucial mechanism in the pathophysiology of hypertension: renal sympathetic overactivity. In 2009, the first-in-man experience with renal denervation was published. Several studies followed, including the randomized Symplicity HTN-2 trial of 106 patients: 6-month mean blood pressure reduction was 32/12 mm Hg in those who underwent renal denervation, vs a change of +1/0 Hg in those who did not. However, all the evidence to date suffers from the same drawbacks: studies are small, and follow-up is short and largely incomplete. The future of renal denervation will be determined by 3 factors. First, there will be more and better evidence. Symplicity HTN-3 has randomized 530 patients to renal denervation vs a sham procedure; 24-hour ambulatory blood pressure monitoring will be assessed in all participants. Other quality trials will follow, including ones that will assess clinical end points. Second, other indications for this treatment will be investigated. Sympathetic overactivity is implicated in many other conditions, including heart failure and arrhythmia; sympathetic denervation might benefit these patients as well. Third, myriad devices, using different methods to achieve renal denervation, are being developed. The first renal denervation system was approved for clinical use in Canada in March 2012. Until more data are available, patients undergoing this procedure should be carefully screened and, ideally, enrolled in research protocols.
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Adherence to blood pressure-lowering drugs and resistant hypertension: should trial of direct observation therapy be part of preassessment for renal denervation?
Can J Cardiol
PUBLISHED: 05-27-2013
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Renal denervation (RDN) is increasingly used for resistant hypertension. We report here a case of pseudoresistance of hypertension caused by nonadherence to prescribed drug therapy (6 medications), which evaded detection by verification of prescription filling. Direct observation therapy (DOT), in which usual antihypertensive medications are given under supervision, produced substantial reductions in blood pressure, which was subsequently controlled chronically with 3 antihypertensive agents, confirming pseudoresistant hypertension. The novel teaching points are that evaluation of nonadherence to drug therapy is a crucial component in diagnosing resistant hypertension before RDN and that DOT may be extremely useful in avoiding an unnecessary and costly procedure.
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BpTRUth: Do automated blood pressure monitors outperform mercury?
J Am Soc Hypertens
PUBLISHED: 04-12-2013
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Manual measurement of blood pressure (BP) in the office (MOBP) is inferior in accuracy when compared with ambulatory BP measurements (ABPM) since it misses white coat and masked effects on BP. BpTRU, an automated office BP device (AOBP), has been reported to reduce white coat effect. We performed a retrospective review of the diagnostic accuracy of MOBP (taken by a trained nurse in clinical hypertension) and AOBP using the Bland-Altman method in hypertensive patients referred to a Renal Hypertension Clinic. In 329 hypertensive patients, the 95% limits of agreement between systolic AOBP and ABPM were -31 mm Hg to 33 mm Hg and for MOBP and ABPM were -27.8 mm Hg to 37.4 mm Hg. The bias between systolic MOBP and systolic ABPM was 4.9 mm Hg (95% confidence interval, 3.0-6.6 mm Hg) whereas the bias between the systolic AOBP and the systolic ABPM was -3.2 (95% confidence interval, -1.3 to -5.0). AOBP did not improve treatment relevant classification errors compared with MOBP (28% vs. 23%; P = .052). Our data support findings by others showing that AOBP improves, but does not eliminate, white coat effect. The increased detection of white coat effect appears related to systematic downward bias by BpTRU. As a result, detection of masked effect is undermined by BpTRU.
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Pharmacologic treatment of hypertension in patients with chronic kidney disease.
Am J Cardiovasc Drugs
PUBLISHED: 04-05-2013
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Hypertension remains an important cause of morbidity and mortality in patients with chronic kidney disease. It both contributes to and is a consequence of chronic renal dysfunction. There is a high prevalence of hypertension in chronic kidney disease, and rates of control remain sub-optimal. Numerous studies have highlighted the benefit of treating hypertension in reducing the overall mortality as well as progression of renal disease in this population. Non-pharmacologic treatment strategies remain the primary intervention in all patients but are insufficient on their own to control hypertension in most cases. Pharmacologic treatment recommendations, however, vary depending on the specific etiology of disease as well as patient characteristics. Though most classes of anti-hypertensive drugs can be used to lower blood pressure in chronic kidney disease, therapy needs to be selected based on the presence of specific co-morbidities as well as the etiology of the kidney disease. Most patients will require multi-drug therapy for achieving target blood pressure goals. This review discusses the pharmacologic options in management of hypertension in various forms of chronic kidney disease.
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Do high doses of AT(1)-receptor blockers attenuate central sympathetic outflow in humans with chronic heart failure?
Clin. Sci.
PUBLISHED: 03-19-2013
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In patients with CHF (chronic heart failure) sympathetic activity increases as cardiac performance decreases and filling pressures increase. We hypothesized that in patients with mild-to-moderate CHF, higher than conventional doses of an AT1-receptor [AngII (angiotensin II) type 1 receptor] antagonist would achieve greater central AT1-receptor blockade, resulting in diminished MSNA (muscle sympathetic nerve activity) and augmented MSNA variability, two indices of central effects on sympathetic outflow. In total, 13 patients with ischaemic cardiomyopathy [NYHA (New York Heart Association) class II-III] were weaned off all pharmacological RAS (renin-angiotensin system) modifiers, and then randomized to receive a low (50 mg/day) or high (200 mg/day) dose of losartan. Central haemodynamics, MSNA and its variability, plasma catecholamines, AngI (angiotensin I) and AngII and aldosterone were assessed both before and 3 months after randomization. Neither dose altered BP (blood pressure), PCWP (pulmonary capillary wedge pressure) or CI (cardiac index) significantly. Compared with 50 mg daily, losartan 200 mg/day decreased MSNA significantly (P<0.05), by approximately 15 bursts/min, and increased MSNA variability within the 0.27-0.33 Hz high-frequency range by 0.11 units(2)/Hz (P=0.06). PNE [plasma noradrenaline (norepinephrine)] fell in parallel with changes in MSNA (r=0.62; P<0.05). These findings support the hypothesis that higher than conventional doses of lipophilic ARBs (AT1-receptor blockers) can modulate the intensity and variability of central sympathetic outflow in patients with CHF. The efficacy and safety of this conceptual change in the therapeutic approach to heart failure merits prospective testing in clinical trials.
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Renal sympathetic denervation for resistant hypertension.
Can J Cardiol
PUBLISHED: 02-11-2013
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Resistant hypertension is an increasingly prevalent health problem associated with important adverse cardiovascular outcomes. The pathophysiology that underlies this condition involves increased function of both the sympathetic nervous system and the renin-angiotensin II-aldosterone system. A crucial link between these 2 systems is the web of sympathetic fibres that course within the adventitia of the renal arteries. These nerves can be targeted by applying radiofrequency energy from the lumen of the renal arteries to renal artery walls (percutaneous renal sympathetic denervation [RSD]), an approach that has attracted great interest. This paper critically reviews the evidence supporting the use of RSD. Small studies suggest that RSD can produce dramatic blood pressure reductions: In the randomized Symplicity HTN-2 trial of 106 patients, the mean fall in blood pressure at 6 months in patients who received the treatment was 32/12 mm Hg. However, there are limitations to the evidence for RSD in the treatment of resistant hypertension. These include the small number of patients studied; the lack of any placebo-controlled evidence; the fact that blood pressure outcomes were based on office assessments, as opposed to 24-hour ambulatory monitoring; the lack of longer-term efficacy data; and the lack of long-term safety data. Some of these concerns are being addressed in the ongoing Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-3) trial. The first percutaneous RSD system was approved by Health Canada in the spring of 2012. But until more and better-quality data are available, this procedure should generally be reserved for those patients whose resistant hypertension is truly uncontrolled.
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The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.
Can J Cardiol
PUBLISHED: 01-12-2013
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We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2013. This years update includes 2 new recommendations. First, among nonhypertensive or stage 1 hypertensive individuals, the use of resistance or weight training exercise does not adversely influence blood pressure (BP) (Grade D). Thus, such patients need not avoid this type of exercise for fear of increasing BP. Second, and separately, for very elderly patients with isolated systolic hypertension (age 80 years or older), the target for systolic BP should be < 150 mm Hg (Grade C) rather than < 140 mm Hg as recommended for younger patients. We also discuss 2 additional topics at length (the pharmacological treatment of mild hypertension and the possibility of a diastolic J curve in hypertensive patients with coronary artery disease). In light of several methodological limitations, a recent systematic review of 4 trials in patients with stage 1 uncomplicated hypertension did not lead to changes in management recommendations. In addition, because of a lack of prospective randomized data assessing diastolic BP thresholds in patients with coronary artery disease and hypertension, no recommendation to set a selective diastolic cut point for such patients could be affirmed. However, both of these issues will be examined on an ongoing basis, in particular as new evidence emerges.
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The 2011 Canadian Hypertension Education Program recommendations for the management of hypertension: blood pressure measurement, diagnosis, assessment of risk, and therapy.
Can J Cardiol
PUBLISHED: 03-02-2011
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We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2011. The major guideline changes this year are: (1) a recommendation was made for using comparative risk analogies when communicating a patients cardiovascular risk; (2) diagnostic testing issues for renal artery stenosis were discussed; (3) recommendations were added for the management of hypertension during the acute phase of stroke; (4) people with hypertension and diabetes are now considered high risk for cardiovascular events if they have elevated urinary albumin excretion, overt kidney disease, cardiovascular disease, or the presence of other cardiovascular risk factors; (5) the combination of an angiotensin-converting enzyme (ACE) inhibitor and a dihydropyridine calcium channel blocker (CCB) is preferred over the combination of an ACE inhibitor and a thiazide diuretic in persons with diabetes and hypertension; and (6) a recommendation was made to coordinate with pharmacists to improve antihypertensive medication adherence. We also discussed the recent analyses that examined the association between angiotensin II receptor blockers (ARBs) and cancer.
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Effects of ACE inhibitors on cardiac angiotensin II and aldosterone in humans: "Relevance of lipophilicity and affinity for ACE".
Am. J. Hypertens.
PUBLISHED: 07-15-2010
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Angiotensin-converting enzyme (ACE) inhibitors differ in their lipophilic/hydrophilic index that determines their tissue bioavailability and affinity to ACE, which may result in major differences in the degree of blockade of cardiac ACE. We evaluated the hypothesis that in patients with chronic heart failure (CHF) and activated cardiac renin-angiotensin-aldosterone system (RAAS), lipophilic ACE inhibitors with high affinity for ACE (perindopril and quinapril) will cause marked blockade of cardiac angiotensin (Ang) II and aldosterone generation, but not a hydrophilic ACE inhibitor with low affinity for ACE (lisinopril).
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Spironolactone for difficult to control hypertension in chronic kidney disease: an analysis of safety and efficacy.
J Am Soc Hypertens
PUBLISHED: 07-13-2010
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Spironolactone is effective at treating difficult to control hypertension in the general population, and it is unknown if it is safe or effective for those with chronic kidney disease (CKD) and difficult-to-control hypertension. In a retrospective cohort design, 88 patients with difficult-to-control hypertension study were assessed for blood pressure (BP) response to spironolactone as well as for biochemical changes. In the CKD group (34 patients), the average systolic BP (SBP) fell from 153 ± 18 to 143 ± 20 mm Hg (P = .006) compared with a fall in SBP from 150 ± 17 to 135 ± 17 mm Hg (P < .0001) in the non-CKD group (P < .0001). In 44% of those with CKD and 59% of those without CKD, SBP decreased by >10 mm Hg (defined as responders; P = .22). Potassium rose by 0.5 ± 0.6 mmol/L in the CKD group and 0.3 ± 0.5 mmol/L in the non-CKD group (P = .12). The overall incidence of hyperkalemia was 5.7% in the CKD group and 0% in the non-CKD group (P = .07). Spironolactone is associated with a significant fall in BP among those with CKD and difficult-to-control BP. It is associated with a modest rise in serum potassium, which is more pronounced among those with glomerular filtration rate below 45 mL/minute.
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White coat hypertension in children: not rare and not benign?
J Am Soc Hypertens
PUBLISHED: 08-13-2009
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The clinical significance of white coat hypertension (WCH) remains uncertain. We aimed to evaluate the target organ damage (TOD) in children with essential hypertension (HTN) and WCH. We retrospectively analyzed the body mass index (BMI) and ambulatory blood pressure monitoring (ABPM) in 183 untreated children aged 5 to 19 years who were referred for assessment of hypertension and had secondary hypertension ruled out. Left ventricular mass index (LVMi) and carotid intima media thickness (CIMT) were analyzed in a subset of 106 children. WCH was found in 54/183 children (29.5%) who had normal mean arterial pressure (MAP), MAP load, and MAP day/night ratio. However, the mean+/-SD LVMi (g/m(2.7)) was identical in HTN and WCH patients (38.2+/-10.9 vs. 37.0+/-11.3, P=.59); it exceeded the 95th percentile in 40% HTN and 36% WCH patients (NS). The mean CIMT was significantly higher compared with normal, but not different between HTN and WCH; it exceeded the 95th percentile in 26% HTN and 29% WCH patients. WCH was found in up to 30% of children referred for HTN. Patients with WCH have TOD comparable to that found in HTN patients despite similar BMI, significantly lower average BP and BP load and a well-preserved BP dipping pattern.
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Hypertension in dialysis and kidney transplant patients.
Can J Cardiol
PUBLISHED: 05-07-2009
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For the first time, the Canadian Hypertension Education Program has studied the evidence supporting blood pressure control in people requiring renal replacement therapy for end-stage kidney disease, including those on dialysis and with renal transplants. According to the Canadian Organ Replacement Registrys 2008 annual report, there were an estimated 33,832 people with end-stage renal disease in Canada at the end of 2006, an increase of 69.7% since 1997. Of these, 20,465 were on dialysis and 13,367 were living with a functioning kidney transplant. Thus, it is becoming more likely that primary care practitioners will be helping to care for these complex patients. With the lack of large controlled clinical trials, the consensus recommendation based on interpretation of the existing literature is that blood pressure should be lowered to below 140/90 mmHg in hypertensive patients on renal replacement therapy and to below 130/80 mmHg for renal transplant patients with diabetes or chronic kidney disease.
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The 2012 Canadian hypertension education program recommendations for the management of hypertension: blood pressure measurement, diagnosis, assessment of risk, and therapy.
Can J Cardiol
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We updated the evidence-based recommendations for the diagnosis, assessment, prevention, and treatment of hypertension in adults for 2012. The new recommendations are: (1) use of home blood pressure monitoring to confirm a diagnosis of white coat syndrome; (2) mineralocorticoid receptor antagonists may be used in selected patients with hypertension and systolic heart failure; (3) a history of atrial fibrillation in patients with hypertension should not be a factor in deciding to prescribe an angiotensin-receptor blocker for the treatment of hypertension; and (4) the blood pressure target for patients with nondiabetic chronic kidney disease has now been changed to < 140/90 mm Hg from < 130/80 mm Hg. We also reviewed the recent evidence on blood pressure targets for patients with hypertension and diabetes and continue to recommend a blood pressure target of less than 130/80 mm Hg.
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Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction.
Hypertension
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We reported aldosterone as a novel adipocyte-derived factor that regulates vascular function. We aimed to investigate molecular mechanisms, signaling pathways, and functional significance of adipocyte-derived aldosterone and to test whether adipocyte-derived aldosterone is increased in diabetes mellitus-associated obesity, which contributes to vascular dysfunction. Studies were performed in the 3T3-L1 adipocyte cell line and mature adipocytes isolated from human and mouse (C57BL/6J) adipose tissue. Mesenteric arteries with and without perivascular fat and mature adipocytes were obtained from obese diabetic db/db and control db/+ mice. Aldosterone synthase (CYP11B2; mRNA and protein) was detected in 3T3-L1 and mature adipocytes, which secrete aldosterone basally and in response to angiotensin II (Ang II). In 3T3-L1 adipocytes, Ang II stimulation increased aldosterone secretion and CYP11B2 expression. Ang II effects were blunted by an Ang II type 1 receptor antagonist (candesartan) and inhibitors of calcineurin (cyclosporine A and FK506) and nuclear factor of activated T-cells (VIVIT). FAD286 (aldosterone synthase inhibitor) blunted adipocyte differentiation. In candesartan-treated db/db mice (1 mg/kg per day, 4 weeks) increased plasma aldosterone, CYP11B2 expression, and aldosterone secretion were reduced. Acetylcholine-induced relaxation in db/db mesenteric arteries containing perivascular fat was improved by eplerenone (mineralocorticoid receptor antagonist) without effect in db/+ mice. Adipocytes possess aldosterone synthase and produce aldosterone in an Ang II/Ang II type 1 receptor/calcineurin/nuclear factor of activated T-cells-dependent manner. Functionally adipocyte-derived aldosterone regulates adipocyte differentiation and vascular function in an autocrine and paracrine manner, respectively. These novel findings identify adipocytes as a putative link between aldosterone and vascular dysfunction in diabetes mellitus-associated obesity.
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