Ross D. Feldman

The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy

OBJECTIVE To update the evidence-based recommendations for the prevention and management of hypertension in adults for 2009. OPTIONS AND OUTCOMES For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease. EVIDENCE A Cochrane collaboration librarian conducted an independent MEDLINE search from 2007 to August 2008 to update the 2008 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to less than 2300 mg (100 mmol)/day (and 1500 mg to 2300 mg [65 mmol to 100 mmol]/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m(2) to 24.9 kg/m(2)) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patients global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin- converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as the initial treatment of hypertension if the systolic blood pressure is 20 mmHg above the target or if the diastolic blood pressure is 10 mmHg above the target. The combination of ACE inhibitors and ARBs should not be used. Other agents appropriate for first-line therapy for isolated systolic hypertension include long- acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered. VALIDATION All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.

The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.

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.

The 2011 Canadian Hypertension Education Program Recommendations for the Management of Hypertension: Blood Pressure Measurement, Diagnosis, Assessment of Risk, and Therapy

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.

Regulation of tyrosine kinase activation and granule release through β-arrestin by CXCR1

Chemoattractant-stimulated granule release from neutrophils, basophils and eosinophils is critical for the innate immune response against infectious bacteria. Interleukin 8 (IL-8) activation of the chemokine receptor CXCR1 was found to stimulate rapid formation of β-arrestin complexes with Hck or c-Fgr. Formation of β-arrestin–Hck complexes led to Hck activation and trafficking of the complexes to granule-rich regions. Granulocytes expressing a dominant-negative β-arrestin–mutant did not release granules or activate tyrosine kinases after IL-8 stimulation. Thus, β-arrestins regulate chemokine-induced granule exocytosis, indicating a broader role for β-arrestins in the regulation of cellular functions than was previously suspected.

A Simplified Approach to the Treatment of Uncomplicated Hypertension: A Cluster Randomized, Controlled Trial

Notwithstanding the availability of antihypertensive drugs and practice guidelines, blood pressure control remains suboptimal. The complexity of current treatment guidelines may contribute to this problem. To determine whether a simplified treatment algorithm is more effective than guideline-based management, we studied 45 family practices in southwestern Ontario, Canada, using a cluster randomization trial comparing the simplified treatment algorithm with the Canadian Hypertension Education Program guidelines. The simplified treatment algorithm consisted of the following: (1) initial therapy with a low-dose angiotensin-converting enzyme inhibitor/diuretic or angiotensin receptor blocker/diuretic combination; (2) up-titration of combination therapy to the highest dose; (3) addition of a calcium channel blocker and up-titration; and (4) addition of a non—first-line antihypertensive agent. The proportion of patients treated to target blood pressure (systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg for patients without diabetes mellitus or systolic blood pressure <130 mm Hg and diastolic blood pressure <80 mm Hg for diabetic patients) at 6 months was analyzed at the practice level. The proportion of patients achieving target was significantly higher in the intervention group (64.7% versus 52.7%; absolute difference: 12.0%; 95% CI: 1.5% to 22.4%; P=0.026). Multivariate analysis of patient-level data showed that assignment to the intervention arm increased the chance of reaching the target by 20% (P=0.028), when adjusted for other covariates. In conclusion, the Simplified Treatment Intervention to Control Hypertension Study indicates that a simplified antihypertensive algorithm using initial low-dose fixed-dose combination therapy is superior to guideline-based practice for the management of hypertension.

GPR30 Expression Is Required for the Mineralocorticoid Receptor–Independent Rapid Vascular Effects of Aldosterone

It has been increasingly appreciated that steroids elicit acute vascular effects through rapid, so-called nongenomic signaling pathways. Though aldosterone, for example, has been demonstrated to mediate rapid vascular effects via both mineralocorticoid receptor–dependent and –independent pathways, the mechanism(s) of this mineralocorticoid receptor–independent effect of aldosterone is yet to be determined. For estrogen, its rapid effects have been reported to be, at least in part, mediated via the 7-transmembrane–spanning, G protein–coupled receptor GPR30. Previous studies have demonstrated common response outcomes in response to both aldosterone and estrogen on GPR30 expression, ie, activation of phosphatidylinositol 3-kinase–dependent contraction and extracellular signal-regulated kinase activation in vascular smooth muscle cells. The present studies were undertaken to test the hypothesis that the rapid response to aldosterone in smooth muscle is dependent on the availability of a GPR30-dependent signaling pathway. These findings not only reconcile differences in the literature for aldosterone response in freshly isolated versus cultured aortic smooth muscle cells but also suggest alternative therapeutic strategies for modulating aldosterone actions on the vasculature in vivo.

Aldosterone Regulates Vascular Reactivity Short-Term Effects Mediated by Phosphatidylinositol 3-Kinase–Dependent Nitric Oxide Synthase Activation

Background—There is increasing evidence for rapid nongenomic effects of aldosterone. Therefore, we studied the immediate effects of aldosterone on vascular reactivity in rat aortic ring segments and on endothelial and vascular smooth muscle cellular responses. Methods and Results—In endothelium-intact ring segments, aldosterone attenuated phenylephrine-mediated constriction (maximal reduction, 25±4% below control phenylephrine-mediated constriction). In contrast, in endothelium-denuded vessels, aldosterone mediated a monophasic dose-dependent enhancement of vasoconstrictor response. In endothelial cells, aldosterone caused a phosphatidylinositol 3-kinase (PI3K)–dependent increase in nitric oxide synthase activity as well as PI3K-dependent activation of extracellular signal–regulated kinase 1/2 and p70 S6 kinase. Conclusions—Overall, these data support a novel effect of aldosterone on vascular endothelial and smooth muscle cell function. These rapid effects of aldosterone might be important in both the short- and long-term regulation of peripheral vascular resistance. Furthermore, in the setting of endothelial dysfunction, alterations in aldosterone’s short-term vascular responses might contribute to its pathophysiological effects in cardiovascular disease.

Insulin-mediated vasodilation: impairment with increased blood pressure and body mass

Insulin resistance is associated with hypertension although it is not known if this relationship is casual. Studies have shown that insulin increases skeletal-muscle blood flow despite also increasing sympathetic activity. To determine whether insulin may act as a direct vasodilator and whether insulin-mediated vascular effects are altered in hypertension, we studied insulin-mediated alterations in dorsal-hand-vein compliance in normotensive and mild and borderline hypertensive subjects. In phenylephrine pre-constricted vessels, insulin caused a dose-dependent increase in venous distensibility. Insulin-mediated venodilation was significantly impaired in hypertensive subjects. The vasodilator potency of insulin was significantly correlated with both blood pressure and body mass index. Insulin may be an endogenous vasodilator. Further, in hypertensive and obese subjects, impairment of insulin-mediated vasodilation may contribute to the increase in peripheral resistance characteristic of hypertension.

A Randomized Study Comparing a Patient-Directed Hypertension Management Strategy With Usual Office-Based Care

This study aimed to compare the efficacy of a patient-directed management strategy with office-based management in maintaining blood pressure control in patients with chronic stable hypertension using a randomized trial of two months duration. The subjects had chronic stable essential hypertension without secondary causes or unstable cardiovascular disease and were selected through the offices of 11 family physicians and a tertiary care hypertension research unit. Patients were randomly assigned (2:1 ratio) to either a patient-directed management strategy using home blood pressure monitoring to adjust drug therapy if readings consistently exceeded defined limits, or office-based management through physician visits. The primary endpoint was the change from baseline in mean arterial pressure as determined by automatic ambulatory blood pressure monitoring. Secondary endpoints were changes in compliance, quality of life, and health care resource use. Ninety-one potential subjects were screened and 31 were randomized. Subjects in the patient-directed management group employed the drug adjustment protocols appropriately without complications. A significant difference in change in mean blood pressure was observed, favoring the patient-directed management (-0.95 mm Hg and +1.90 mm Hg, respectively, for patient-directed management and office-based management, P = .039). Compliance rates and quality of life scores were not significantly different between groups. Physician visits were more frequent in the patient-directed management group (1.05 v 0.20 visits/8 weeks, respectively, for patient-directed management and office-based management groups, P = .045). A patient-directed hypertensive management strategy may be feasible for patients with chronic stable hypertension. Such a strategy may improve blood pressure control compared with usual office-based care. However, physician visits may be increased using this strategy, at least in the short term.

β-Arrestins regulate a Ral-GDS–Ral effector pathway that mediates cytoskeletal reorganization

β-Arrestins are important in chemoattractant receptor-induced granule release, a process that may involve Ral-dependent regulation of the actin cytoskeleton. We have identified the Ral GDP dissociation stimulator (Ral-GDS) as a β-arrestin-binding protein by yeast two-hybrid screening and co-immunoprecipitation from human polymorphonuclear neutrophilic leukocytes (PMNs). Under basal conditions, Ral-GDS is localized to the cytosol and remains inactive in a complex formed with β-arrestins. In response to formyl-Met-Leu-Phe (fMLP) receptor stimulation, β-arrestin–Ral-GDS protein complexes dissociate and Ral-GDS translocates with β-arrestin from the cytosol to the plasma membrane, resulting in the Ras-independent activation of the Ral effector pathway required for cytoskeletal rearrangement. The subsequent re-association of β-arrestin–Ral-GDS complexes is associated with the inactivation of Ral signalling. Thus, β-arrestins regulate multiple steps in the Ral-dependent processes that result in chemoattractant-induced cytoskeletal reorganization.