Marcel Ruzicka

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.

Guidelines for the management of chronic kidney disease

New guidelines for the management of chronic kidney disease have been developed by the Canadian Society of Nephrology (Appendix 1 contains the full-text guidelines; available at [www.cmaj.ca/cgi/content/full/179/11/1154/DC1][1]). These guidelines describe key aspects of the management of chronic

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.

The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events.

Adipocytes Produce Aldosterone Through Calcineurin-Dependent Signaling Pathways: Implications in Diabetes Mellitus–Associated Obesity and Vascular Dysfunction

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.

Pathophysiologic and Therapeutic Importance of Tissue ACE: A Consensus Report

Angiotensin-converting enzyme (ACE) activation and the de novo production of angiotensin II contribute to cardiovascular disease through direct pathological tissue effects, including vascular remodeling and inflammation, as well as indirect action on nitric oxide bioavailability and its consequences. The endothelium plays a pivotal role in both vascular function and structure; thus, the predominant localization of ACE to the endothelium has implications for the pathobiology of vascular disease, such as coronary artery disease. Numerous experimental studies and clinical trials support the emerging realization that tissue ACE is a vital therapeutic target, and that its inhibition may restore endothelial function or prevent endothelial dysfunction. These effects exceed those attributable to blood pressure reduction alone; hence, ACE inhibitors may exert an important part of their effects through direct tissue action. Pharmacologic studies show that while ACE inhibitors may differ according to their binding affinity for tissue ACE the clinical significance remains to be determined.

The renin-angiotensin system and volume overload-induced cardiac hypertrophy in rats. Effects of angiotensin converting enzyme inhibitor versus angiotensin II receptor blocker.

BackgroundThe degree of cardiac hypertrophy is not only load dependent: Among other factors, the renin-angiotensin system may play a role in the regulation of cardiac myocyte growth. Methods and ResultsTo evaluate the role of the renin-angiotensin system in volume overload-induced cardiac hypertrophy, we assessed 1) the time course of changes in cardiac hemodynamics, cardiac anatomy, and plasma and cardiac renin activity in response to volume overload induced by two sizes abdominal aortocaval shunt and 2) the effects of chronic treatment with an angiotensin converting enzyme inhibitor (ACEI) versus an angiotensin H receptor blocker on hemodynamics and cardiac hypertrophy. Drug treatment started 3 days before shunt surgery. An increase in left ventricular end-diastolic pressure (LVEDP) and the development of right ventricular (RV) and left ventricular (LV) eccentric hypertrophy in response to volume overload occurred within the first week after induction of the shunt. Plasma renin activity (PRA) and cardiac renin activity peaked shortly after induction of the shunt. During the chronic phase, LVEDP and PRA decreased somewhat but remained significantly elevated up to 7 weeks after shunt surgery. Cardiac renin activity returned toward normal within 4 weeks after surgery. Treatment with the ACEI enalapril caused only a modest decrease in LV internal diameter but did not affect increases in LV and RV weights in response to volume overload despite a major decrease in LVEDP after chronic treatment. In contrast, treatment with the angiotensin II receptor blocker losartan, which had similar effects on cardiac and peripheral hemodynamics, prevented dilation of the LV after 7 days and attenuated the dilation of the LV after 28 days. Moreover, increases in LV and RV weights were significantly attenuated by losartan. ConclusionsThe development of volume overload-induced cardiac hypertrophy is associated with significant increases in PRA and cardiac renin activity shortly after induction of an aortocaval shunt. Whereas the two blockers of the renin-angiotensin system decreased LVEDP to a similar extent, only the angiotensin II receptor blocker blunted the hypertrophic response of the heart to volume overload, which is indicative for other than hemodynamic determinants of the cardiac hypertrophic response. One trophic factor may be cardiac angiotensin H generated via an angiotensin lI-forming enzyme resistant to ACEI and possibly activated by cardiac volume overload.

Effects of ACE Inhibitors on Circulating Versus Cardiac Angiotensin II in Volume OverloadInduced Cardiac Hypertrophy in Rats

BACKGROUND Cardiac volume overload by an aortocaval shunt increases left ventricular end-diastolic pressure (LVEDP) and plasma and cardiac renin activity and results in LV hypertrophy. To a similar extent, the angiotensin-converting enzyme (ACE) inhibitors enalapril and quinapril prevent the increase in LVEDP. However, only quinapril attenuates the development of LV hypertrophy. We hypothesize that a low affinity of enalapril for cardiac ACE results in continuing generation of cardiac angiotensin II and thus hypertrophic growth of cardiomyocytes. METHODS AND RESULTS In the present study, we assessed plasma and cardiac angiotensins I and II 1 and 7 days after aortocaval shunt and the effects of enalapril and quinapril started 3 days before surgery on plasma and cardiac angiotensin I and II at the same time points. Aortocaval shunt increased plasma angiotensin II at 1 day by 180%, but only a small increase (by 40%) persisted at 7 days. Aortocaval shunt increased LV angiotensin II by 100% and 65% at 1 and 7 days, respectively. Both blockers similarly prevented the increase in plasma angiotensin II by aortocaval shunt at both time points. In contrast, only quinapril prevented the rise in LV angiotensin II induced by shunt at 1 and 7 days. CONCLUSIONS Aortocaval shunt increases LVEDP and plasma and cardiac angiotensin II and results in LV hypertrophy. Only prevention of the increase in LVEDP and in plasma and cardiac angiotensin II attenuates the development of LV hypertrophy, consistent with the concept that angiotensin II is involved in the development of cardiac hypertrophy by aortocaval shunt by both hemodynamic and cardiac trophic effects. This study is the first to show that differences in affinity for cardiac ACE may determine the effect of ACE inhibitors on cardiac angiotensin II and therefore cardiac hypertrophy.

Relevance of Blockade of Cardiac and Circulatory Angiotensin-Converting Enzyme for the Prevention of Volume Overload–Induced Cardiac Hypertrophy

BACKGROUND Angiotensin-converting enzyme (ACE) inhibitors show major differences in their affinity for cardiac and other tissue ACEs, and their effects on tissue ACE range from minimal to nearly complete blockade. Angiotensin II taken up from the circulation or generated in the heart may mediate the cardiac hypertrophic response to increased cardiac load. Thus, differences between the ACE inhibitors regarding their effects on cardiac ACE may determine their effects on prevention or regression of cardiac hypertrophy. METHODS AND RESULTS In the present study, we assessed the effects of ACE inhibitors with low (enalapril) and high (quinapril) affinity for cardiac tissue ACE on prevention of volume overload-induced cardiac hypertrophy in relation to their hemodynamic effects. Both blockers were equipotent for circulatory ACE as assessed from the pressure response curve to angiotensin I. Both blockers partially (and similarly) prevented the increase in left ventricular end-diastolic pressure by aortocaval shunt. However, only quinapril prevented or attenuated the development of right ventricular hypertrophy and left ventricular hypertrophy and dilation. CONCLUSIONS The present findings further stress the involvement of the renin-angiotensin system as a trophic stimulus in the development of cardiac hypertrophy in this model. Moreover, the low affinity of enalapril for cardiac ACE appears to lead to continuous angiotensin II generation in the heart and can thus explain the failure of enalapril to attenuate hypertrophic response of the heart induced by shunt despite decreasing cardiac volume overload.