Hypertension: Ruzicka M

Khan NA, Hemmelgarn B, Herman RJ, Bell CM, Mahon JL, Leiter LA, Rabkin SW, Hill MD, Padwal R, Touyz RM, Larochelle P, Feldman RD, Schiffrin EL, Campbell NR, Moe G, Prasad R, Arnold MO, Campbell TS, Milot A, Stone JA, Jones C, Ogilvie RI, Hamet P, Fodor G, Carruthers G, Burns KD, Ruzicka M, DeChamplain J, Pylypchuk G, Petrella R, Boulanger JM, Trudeau L, Hegele RA, Woo V, McFarlane P, Vallée M, Howlett J, Bacon SL, Lindsay P, Gilbert RE, Lewanczuk RZ, Tobe S, Anonymous00150. · Division of General Internal Medicine, University of British Columbia, Vancouver, Canada. · Can J Cardiol. · Pubmed #19417859 No free full text.

Abstract: 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 patient's 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.

Padwal RS, Hemmelgarn BR, Khan NA, Grover S, McKay DW, Wilson T, Penner B, Burgess E, McAlister FA, Bolli P, Hill MD, Mahon J, Myers MG, Abbott C, Schiffrin EL, Honos G, Mann K, Tremblay G, Milot A, Cloutier L, Chockalingam A, Rabkin SW, Dawes M, Touyz RM, Bell C, Burns KD, Ruzicka M, Campbell NR, Vallée M, Prasad R, Lebel M, Tobe SW, Anonymous00149. · Division of General Internal Medicine, University of Alberta, Edmonton, Canada. · Can J Cardiol. · Pubmed #19417858 No free full text.

Abstract: OBJECTIVE: To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with hypertension. OPTIONS AND OUTCOMES: The diagnosis of hypertension is dependent on appropriate blood pressure measurement, the timely assessment of serially elevated readings, the degree of blood pressure elevation, the method of measurement (office, ambulatory, home) and associated comorbidities. The presence of cardiovascular risk factors and target organ damage should be ascertained to assess global cardiovascular risk and determine the urgency, intensity and type of treatment required. EVIDENCE: MEDLINE searches were conducted from November 2007 to October 2008 with the aid of a medical librarian. Reference lists were scanned, experts were contacted, and the personal files of authors and subgroup members were used to identify additional studies. Content and methodological experts assessed studies using prespecified, standardized evidence-based algorithms. Recommendations were based on evidence from peer-reviewed full-text articles only. RECOMMENDATIONS: Recommendations for blood pressure measurement, criteria for hypertension diagnosis and follow-up, assessment of global cardiovascular risk, diagnostic testing, diagnosis of renovascular and endocrine causes of hypertension, home and ambulatory monitoring, and the use of echocardiography in hypertensive individuals are outlined. Key messages include continued emphasis on the expedited, accurate diagnosis of hypertension, the importance of global risk assessment and the need for ongoing monitoring of hypertensive patients to identify incident type 2 diabetes. 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 were required to be supported by at least 70% of task force members. These guidelines will continue to be updated annually.

Khan NA, Hemmelgarn B, Padwal R, Larochelle P, Mahon JL, Lewanczuk RZ, McAlister FA, Rabkin SW, Hill MD, Feldman RD, Schiffrin EL, Campbell NR, Logan AG, Arnold M, Moe G, Campbell TS, Milot A, Stone JA, Jones C, Leiter LA, Ogilvie RI, Herman RJ, Hamet P, Fodor G, Carruthers G, Culleton B, Burns KD, Ruzicka M, deChamplain J, Pylypchuk G, Gledhill N, Petrella R, Boulanger JM, Trudeau L, Hegele RA, Woo V, McFarlane P, Touyz RM, Tobe SW, Anonymous00039. · Division of General Internal Medicine, University of British Columbia, Vancouver, British Columbia. · Can J Cardiol. · Pubmed #17534460 links to  free full text

Abstract: OBJECTIVE: To provide updated, evidence-based recommendations for the prevention and management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence was reviewed from randomized controlled trials and systematic reviews of trials. 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. For treatment of patients with kidney disease, the progression of kidney dysfunction was also accepted as a clinically relevant primary outcome. EVIDENCE: A Cochrane collaboration librarian conducted an independent MEDLINE search from 2005 to August 2006 to update the 2006 Canadian Hypertension Education Program recommendations. In addition, reference lists were scanned and experts were contacted to identify additional published studies. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: Dietary lifestyle modifications for prevention of hypertension, in addition to a well-balanced diet, include a dietary sodium intake of less than 100 mmol/day. In hypertensive patients, the dietary sodium intake should be limited to 65 mmol/day to 100 mmol/day. Other lifestyle modifications for both normotensive and hypertensive patients include: performing 30 min to 60 min of aerobic exercise four to seven days per week; maintaining a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm in men and less than 88 cm in women); limiting alcohol consumption to no more than 14 units per week in men or nine units per week in women; following a diet reduced in saturated fat and cholesterol, and one that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and considering stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should take into account each individual's global atherosclerotic risk, target organ damage and any comorbid conditions: blood pressure should be lowered to lower than 140/90 mmHg in all patients and lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients require more than one agent to achieve these blood pressure targets. In 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 (except in black patients), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). First-line therapy for isolated systolic hypertension includes long-acting dihydropyridine CCBs or ARBs. Certain comorbid conditions provide compelling indications for first-line use of other agents: 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 plus diuretic combination is preferred; in patients with nondiabetic chronic kidney disease, 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.

Prasad GV, Ruzicka M, Burns KD, Tobe SW, Lebel M. · Division of Nephrology, St Michael's Hospital, University of Toronto, Toronto, Canada. · Can J Cardiol. · Pubmed #19417862 No free full text.

Abstract: 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 Registry's 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.

Khan NA, Hemmelgarn B, Herman RJ, Rabkin SW, McAlister FA, Bell CM, Touyz RM, Padwal R, Leiter LA, Mahon JL, Hill MD, Larochelle P, Feldman RD, Schiffrin EL, Campbell NR, Arnold MO, Moe G, Campbell TS, Milot A, Stone JA, Jones C, Ogilvie RI, Hamet P, Fodor G, Carruthers G, Burns KD, Ruzicka M, dechamplain J, Pylypchuk G, Petrella R, Boulanger JM, Trudeau L, Hegele RA, Woo V, McFarlane P, Vallée M, Howlett J, Katzmarzyk P, Tobe S, Lewanczuk RZ, Anonymous00046. · Division of General Internal Medicine, University of British Columbia, Vancouver, Canada. · Can J Cardiol. · Pubmed #18548143 links to  free full text

Abstract: OBJECTIVE: To update the evidence-based recommendations for the prevention and management of hypertension in adults. OPTIONS AND OUTCOMES: For lifestyle and pharmacological interventions, evidence was preferentially reviewed from randomized controlled trials and systematic reviews of trials. 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 2006 to August 2007 to update the 2007 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by content and methodological experts using prespecified levels of evidence. RECOMMENDATIONS: For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium intake to less than 100 mmol/day (and 65 mmol/day 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 one 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 patient's 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. 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 nonblack patients), 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 for initial treatment of hypertension if systolic blood pressure is 20 mmHg above target or if diastolic blood pressure is 10 mmHg above target. 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 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 but 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.

Padwal RJ, Hemmelgarn BR, Khan NA, Grover S, McAlister FA, McKay DW, Wilson T, Penner B, Burgess E, Bolli P, Hill MD, Mahon J, Myers MG, Abbott C, Schiffrin EL, Honos G, Mann K, Tremblay G, Milot A, Cloutier L, Chockalingam A, Rabkin SW, Dawes MD, Touyz RM, Bell C, Burns KD, Ruzicka M, Campbell NR, Lebel M, Tobe SW, Anonymous00045. · Division of General Internal Medicine, University of Alberta, Edmonton, Canada. · Can J Cardiol. · Pubmed #18548142 links to  free full text

Abstract: OBJECTIVE: To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with hypertension. OPTIONS AND OUTCOMES: The diagnosis of hypertension is dependent on appropriate blood pressure measurement, the timely assessment of serially elevated readings, degree of blood pressure elevation, method of measurement (office, ambulatory, home) and associated comorbidities. The presence of cardiovascular risk factors and target organ damage should be ascertained to assess global cardiovascular risk and determine the urgency, intensity and type of treatment required. EVIDENCE: MEDLINE searches were conducted from November 2006 to October 2007 with the aid of a medical librarian. Reference lists were scanned, experts were contacted, and the personal files of authors and subgroup members were used to identify additional studies. Content and methodological experts assessed studies using prespecified, standardized evidence-based algorithms. Recommendations were based on evidence from peer-reviewed, full-text articles only. RECOMMENDATIONS: Recommendations for blood pressure measurement, criteria for hypertension diagnosis and follow-up, assessment of global cardiovascular risk, diagnostic testing, diagnosis of renovascular and endocrine causes of hypertension, home and ambulatory monitoring, and the use of echocardiography in hypertensive individuals are outlined. Key messages in 2008 include continued emphasis on the expedited, accurate diagnosis of hypertension, the importance of global risk assessment and the need for ongoing monitoring of hypertensive patients to identify incident type 2 diabetes. 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 received at least 70% consensus. These guidelines will continue to be updated annually.

Ruzicka M, Burns KD, Culleton B, Tobe SW, Anonymous00042. · Division of Nephrology, University of Ottawa, Ottawa, Ontario. · Can J Cardiol. · Pubmed #17534470 links to  free full text

Abstract: Hypertension is highly prevalent in patients with chronic kidney disease (CKD). As either the cause or the consequence of CKD, hypertension is an important independent factor determining the rate of loss of renal function. Hypertension is also a significant independent risk factor for cardiovascular events in patients with CKD, the leading cause of their morbidity and mortality. Based on evidence from observational cohort studies and randomized clinical trials, the Canadian Hypertension Education Program (CHEP) recommends a target blood pressure (BP) of lower than 130/80 mmHg in hypertensive patients with nondiabetic CKD. The CHEP also endorses the use of renin-angiotensin system blockers for the BP-lowering regimen in nondiabetic patients with CKD and significant proteinuria. It is recognized that the majority of nondiabetic patients with CKD will require two or more BP-lowering drugs to attain target BP. Furthermore, extracellular fluid volume expansion is a major contributor to hypertension in patients with CKD, and diuretics should be part of the BP-lowering regimen in the majority of patients. Patients with CKD are recognized to be at high risk for cardiovascular events, and studies testing new emerging treatments of hypertension to reduce the burden of CKD on renal and cardiovascular outcomes are underway. In this regard, the CHEP will continue to review and update all its recommendations annually.

Ruzicka M, Leenen FH. · Hypertension Unit, University of Ottawa Heart Institute, 40 Ruskin Street, Room H360, Ottawa, Ontario, Canada K1Y 4W7. · Curr Hypertens Rep. · Pubmed #16884664 No free full text.

Abstract: Hypertension control rates remain alarmingly low worldwide despite the extensive evidence for decreased rates of cardiovascular, cerebrovascular, and renal events in response to blood pressure (BP) lowering to recommended targets. Several classes of antihypertensive drugs are available, which in combination can produce major decreases in BP, with minimal side effects. Moreover, most patients only have mild hypertension and, in general, can be controlled to < 140/90 mm Hg by proper combinations of two antihypertensive drugs. Although patient-related factors clearly contribute to poor control of hypertension, physician-related factors, particularly "passive" therapeutic inertia, are as responsible if not more so. Recent studies clearly indicate that monitoring performance of individual physicians and providing feedback on the care delivered by them can move treatment of hypertension to BP control rates in the 60% to 70% range. If health care organizations would implement this approach, enormous benefits could be expected for the prevention of cardiovascular and cerebrovascular disease.

MacKinnon M, Leenen FH, Ruzicka M. · Division of Nephrology and Kidney Research Centre, The Ottawa Hospital-Riverside Campus, Room 5-21, 1967 Riverside Drive, Ottawa, Ontario, Canada, K1H 7W9. · Curr Hypertens Rep. · Pubmed #16386205 No free full text.

Abstract: ALLHAT was designed to test the hypothesis that "newer" antihypertensive agents are superior to a thiazide diuretic for cardiovascular outcomes. Pre-specified secondary outcomes included the development of end-stage renal disease (ESRD) (dialysis, renal transplantation, or death from renal cause) and estimated glomerular filtration rate (GFR). ALLHAT showed no differences in the overall rates of ESRD between those randomized to chlorthalidone, amlodipine, or lisinopril. It showed a slower rate of decline of GFR among those randomized to amlodipine in both diabetics and nondiabetics, and in the composite end point (ESRD or > or = 50% decline in GFR) in nondiabetics. The results of ALLHAT are consistent with other studies that, for the patient population studied (presumably largely nonalbuminuric patients with and without diabetes), at systolic BP > 130 mm Hg, there is no difference for renal outcomes between a thiazide diuretic, dihydropyridine calcium channel blocker, and ACEI-initiated treatment for 5 to 6 years of follow-up. These results suggest that BP control per se remains the most important objective for this patient population.

Ruzicka M, Leenen FH. · University of Ottawa Centre for Kidney Diseases, Canada. · Can J Cardiol. · Pubmed #12518184 links to  free full text

Abstract: Mild to moderate hypertension still remains poorly controlled. This relates to multiple factors including low antihypertensive efficacy of single drug therapies, reluctance of primary care physicians to modify or titrate initially chosen therapy to obtain target blood pressure and poor compliance with medication. Evidence discussed in the present paper points to superior control of blood pressure by combinations of low doses of two drugs compared with monotherapy in regular doses. This superior effectiveness of combined therapy relates to a better antihypertensive efficacy and higher response rates in the low range of doses as the result of complementary mechanisms of antihypertensive effects. It is associated with better tolerance as the result of a lower rate of side effects in the low range of dosing, improved compliance from better tolerance and simple drug regimen, and lower cost. Increased use of fixed, low dose combination therapies can be expected to result in better control of arterial hypertension in the population. Given the evidence for superior antihypertensive efficacy and better tolerability, and the absence of harm from fixed, low dose drug combinations per se, this alternative deserves more consideration in the guidelines of major hypertension organizations.

Leenen FH, Ruzicka M, Huang BS. · Hypertension Unit, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada. · Curr Hypertens Rep. · Pubmed #11884268 No free full text.

Abstract: Genetically salt-sensitive rats, such as Dahl S and spontaneously hypertensive rats, show clear hypertensive responses to a high salt diet. Neural mechanisms play an essential role in salt-induced hypertension, and recent studies indicate that centrally induced sympathetic hyperactivity actually causes the hypertension. This review discusses the view that the renal genotype is not the only determinant of salt-induced sympathetic hyperactivity and hypertension, and that changes in genetic control of neuronal responses to cerebrospinal fluid Na(+) may play a primary role.

Dzau VJ, Bernstein K, Celermajer D, Cohen J, Dahlöf B, Deanfield J, Diez J, Drexler H, Ferrari R, van Gilst W, Hansson L, Hornig B, Husain A, Johnston C, Lazar H, Lonn E, Lüscher T, Mancini J, Mimran A, Pepine C, Rabelink T, Remme W, Ruilope L, Ruzicka M, Schunkert H, Swedberg K, Unger T, Vaughan D, Weber M, Anonymous00247. · Department of Medicine, Brigham Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. · Am J Cardiol. · Pubmed #11694220 No free full text.

Abstract: 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.

Leenen FH, Ruzicka M, Huang BS. · Hypertension Unit, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, K1Y 4W7, Canada. · Curr Hypertens Rep. · Pubmed #11470014 No free full text.

Abstract: It is generally assumed that the arterial vasodilation induced by inhibition of Ca(2+) influx into vascular smooth muscle cells represents the main mechanism for the hypotensive effect of dihydropyridine calcium channel blockers. Increases in sympathetic tone have been related to activation of the arterial baroreflex by rapid lowering of blood pressure. This review highlights new findings in two areas. First, in animal studies, direct central administration of dihydropyridines such as nifedipine or amlodipine lowers sympathetic nerve activity and thereby blood pressure. Peripheral administration of nifedipine or amlodipine at low rates appears to result in gradual accumulation of drug in the central nervous system, and also causes lowering of sympathetic nerve activity and thereby lowering of blood pressure (rather than by arterial vasodilation). Second, in hypertensive humans treated with long-acting dihydropyridines and presumably little activation of the arterial baroreflex, some studies have demonstrated lowering of sympathetic activity (as assessed by plasma norepinephrine), but others reported increases (as assessed by plasma norepinephrine or microneurography). This sympathoexcitatory response may be due to activation of the renin-angiotensin system, particularly at higher doses.

Ruzicka M, Leenen FH. · Department of Internal Medicine, University of Ottawa, Ontario, Canada. · Drugs. · Pubmed #11434450 No free full text.

Abstract: Mild to moderate hypertension still remains poorly controlled. This relates to multiple factors including low antihypertensive efficacy of single drug therapies reluctance of primary care physicians to modify/titrate initially chosen therapy to obtain target blood pressure, and poor compliance with medication. Several guidelines for the treatment of high blood pressure now include combination therapy with low doses of 2 drugs as one of the strategies for the initial management of mild/moderate arterial hypertension. Evidence discussed in this article points to superior control of blood pressure by combinations of low doses of 2 drugs as compared with monotherapy in regular doses. This superior effectiveness of combined therapy relates to a better antihypertensive efficacy and higher response rates in the low range of doses as the result of complementary mechanisms of antihypertensive effects, better tolerance as a result of a lower rate of adverse effects in the low dose range, improved compliance from better tolerance and simple drug regimen, and lower cost. Whether increased use of fixed low dose combination therapies would translate to better control of arterial hypertension in the population and thereby further reduction of cardiovascular/cerebrovascular morbidity and mortality caused by hypertension remains to be assessed.

Ruzicka M, Coletta E, Floras J, Leenen FH. · Hypertension Unit H360, University of Ottawa Heart Institute, University of Ottawa, 40 Ruskin Street, Ottawa, Ontario, Canada K1Y 4W7. · J Hypertens. · Pubmed #15097246 No free full text.

Abstract: BACKGROUND: Dihydropyridines have both sympathoexcitatory and sympathoinhibitory effects. To date, the latter have been characterized only in animals. During chronic treatment with long-acting dihydropyridines, sympathoexcitatory effects mediated via the arterial baroreflex are unlikely. However, increases in plasma angiotensin II in response to dihydropyridines could contribute to increases in sympathetic activity during chronic treatment. Such increases may be less in older than in young patients. METHODS: We evaluated the effects of 4 weeks of treatment with low-dose nifedipine gastrointestinal therapeutic system (GITS; 20 mg/day) compared with placebo on muscle sympathetic nerve activity and plasma noradrenaline, in relation to changes in plasma renin activity and plasma angiotensin II and blood pressure in young and older patients with mild hypertension. RESULTS: Nifedipine GITS decreased systolic and diastolic blood pressures significantly, by 10 +/- 3 mmHg and 7 +/- 2 mmHg respectively, in older patients (age 67 +/- 2 years), but not in younger patients (age 45 +/- 2 years) (decreases of 1 +/- 3 mmHg and 1 +/- 2 mmHg, respectively). Nifedipine GITS caused only minor changes in plasma renin activity and plasma angiotensin II in young and older patients. Compared with changes in response to placebo (-5.7 +/- 2.4 bursts/min), sympathetic activity was increased significantly by nifedipine GITS in the young patients (2.0 +/- 1.7 bursts/min; P < 0.05), but not in older patients (5.4 +/- 1.3 bursts/min by placebo compared with 4.1 +/- 3.5 bursts/min by nifedipine GITS). CONCLUSION: We conclude that age-related differences in the response of muscle sympathetic nerve activity (and plasma noradrenaline) to low-dose nifedipine GITS in patients with mild hypertension are unlikely to be mediated by plasma angiotensin II. An increase in sympathetic activity may contribute to the absent blood pressure response in young patients with hypertension.

Ruzicka M, Coletta E, Leenen FH. · Hypertension Unit, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Am J Hypertens. · Pubmed #17954368 No free full text.

Abstract: BACKGROUND: Angiotensin II-mediated increases in sympathetic activity may contribute to smaller blood-pressure decreases in response to dihydropyridines in young versus older hypertensive patients. We evaluated whether quinapril unmasks angiotensin II-dependent sympathetic activity on amlodipine. METHODS: In this double-blind, randomized, clinical trial, young mild hypertensives were randomized to quinapril for 1 week (study 1), followed by quinapril + amlodipine for 6 weeks (study 2), followed by amlodipine + placebo for 6 weeks (study 3), or else were randomized to placebo for 1 week (study 1), followed by placebo + amlodipine for 6 weeks (study 2), followed by amlodipine + quinapril for 6 weeks (study 3). Muscle sympathetic nerve activity (MSNA) and plasma hormones were analyzed at the end of each treatment period. Twenty-one subjects completed this study. RESULTS: Quinapril alone decreased BP by 8 +/- 3/6 +/- 3 (mean +/- SD) mm Hg, and amlodipine alone decreased BP by 6 +/- 3/4 +/- 2 (mean +/- SD). Quinapril combined with amlodipine caused a drop of 13 +/- 3/13 +/- 3 (mean +/- SD) mm Hg in one group, and 14 +/- 3/14 +/- 2 (mean +/- SD) mm Hg in the second group. Six weeks after discontinuation of quinapril, amlodipine alone caused no change (0 +/- 3/-2 +/- 3) (mean +/- SD). The MSNA decreased by 3 bursts/100 heartbeats at visits 2 v 1 and 3 v 2 (P = .02 for time effect), regardless of treatment. Angiotensin II showed small increases with each visit in the first group, and small decreases in the second group (P = .02 for treatment effect). CONCLUSIONS: It appears that amlodipine does not activate the renin-angiotensin system to counteract its BP-lowering effect in young hypertensives. Similarly, no angiotensin II-dependent component in MSNA appears to be present at baseline or to be induced by amlodipine.