Showing papers by "Suzanne Oparil published in 2008"

Characterization of Resistant Hypertension : Association Between Resistant Hypertension, Aldosterone, and Persistent Intravascular Volume Expansion

Abstract: Background: Resistant hypertension is a common clinical problem and greatly increases the risk of target organ damage. Methods: We evaluated the characteristics of 279 consecutive patients with resistant hypertension (uncontrolled despite the use of 3 antihypertensive agents) and 53 control subjects (with normotension or hypertension controlled by using ≤2 antihypertensive medications). Participants were prospectively examined for plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, brain-type natriuretic peptide, atrial natriuretic peptide, and 24-hour urinary aldosterone (UAldo), cortisol, sodium, and potassium values while adhering to a routine diet. Results: Plasma aldosterone (P < .001), aldosterone to renin ratio (P < .001), 24-hour UAldo (P = .02), brain-type natriuretic peptide (P = .007), and atrial natriuretic peptide (P = .001) values were higher and plasma renin activity (P = .02) and serum potassium (P < .001) values were lower in patients with resistant hypertension vs controls. Of patients with resistant hypertension, men had significantly higher plasma aldosterone (P = .003), aldosterone to renin ratio (P = .02), 24-hour UAldo (P < .001), and urinary cortisol (P < .001) values than women. In univariate linear regression analysis, body mass index (P = .01), serum potassium (P < .001), urinary cortisol (P < .001), urinary sodium (P = .02), and urinary potassium (P < .001) values were correlated with 24-hour UAldo levels. Serum potassium (P = .001), urinary potassium (P < .001), and urinary sodium (P = .03) levels were predictors of 24-hour UAldo levels in multivariate modeling. Conclusions: Aldosterone levels are higher and there is evidence of intravascular volume expansion (higher brain-type and atrial natriuretic peptide levels) in patients with resistant hypertension vs controls. These differences are most pronounced in men. A significant correlation between 24-hour urinary aldosterone levels and cortisol excretion suggests that a common stimulus, such as corticotropin, may underlie the aldosterone excess in patients with resistant hypertension.

Atrial Natriuretic Peptide Inhibits Transforming Growth Factor β–Induced Smad Signaling and Myofibroblast Transformation in Mouse Cardiac Fibroblasts

Abstract: This study tested the hypothesis that activation of atrial natriuretic peptide (ANP)/cGMP/protein kinase G signaling inhibits transforming growth factor (TGF)-β1–induced extracellular matrix expression in cardiac fibroblasts and defined the specific site(s) at which this molecular merging of signaling pathways occurs. Left ventricular hypertrophy and fibrosis, collagen deposition, and myofibroblast transformation of cardiac fibroblasts in response to pressure overload by transverse aortic constriction were exaggerated in ANP-null mice compared with wild-type controls. ANP and cGMP inhibited TGF-β1–induced myofibroblast transformation, proliferation, collagen synthesis, and plasminogen activator inhibitor-1 expression in cardiac fibroblasts isolated from wild-type mice. Following pretreatment with cGMP, TGF-β1 induced phosphorylation of Smad3, but the resultant pSmad3 could not be translocated to the nucleus. pSmad3 that had been phosphorylated with recombinant protein kinase G-1α was analyzed by use of Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and ion trap tandem mass spectrometry. The analysis revealed phosphorylation of Ser309 and Thr388 residues, sites distinct from the C-terminal Ser423/425 residues that are phosphorylated by TGF-β receptor kinase and are critical for the nuclear translocation and down-stream signaling of pSmad3. These results suggest that phosphorylation of Smad3 by protein kinase G is a potential molecular mechanism by which activation of ANP/cGMP/protein kinase G signaling disrupts TGF-β1–induced nuclear translocation of pSmad3 and downstream events, including myofibroblast transformation, proliferation, and expression of extracellular matrix molecules in cardiac fibroblasts. We postulate that this process contributes to the antifibrogenic effects of the natriuretic peptide in heart.

Thiazide-induced dysglycemia: Call for research from a working group from the national heart, lung, and blood institute

Abstract: There are >70-million hypertensive individuals in the United States, and >45-million persons take antihypertensive medications.1,2 Despite the results of the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT), other trials, and the recommendations in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, well under 50% of these regimens include a thiazide-type diuretic.2,3 In the Department of Veterans’ Affairs, which participated in several of the studies supporting the use of thiazide diuretics, ≈35% of hypertensive patients on pharmacotherapy had a thiazide diuretic included in their hypertension treatment regimens in 2003.4 In private patient encounters, thiazide diuretic use rose from 19% of all of the antihypertensive patient visits in 2002 to 26% in 2004.5 The recommendations for preferred use of thiazide-type diuretics are based on >4 decades of clinical trials, including active-controlled trials, where diuretics were tested against other drugs for their efficacy in preventing hard clinical outcomes, such as myocardial infarction, death, stroke, heart failure, and renal failure. ALLHAT, a randomized, double-blind, active-controlled antihypertensive treatment trial in 42 418 patients assigned to a thiazide-type diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel-blocker, (average follow-up: 4.9 years), or the doxazosin/chlorthalidone comparison (terminated early, average follow-up: 3.2 years) showed that the diuretic was at least as beneficial as the comparator drugs in lowering blood pressure (BP) and preventing cardiovascular (CV) and renal outcomes and was superior for preventing heart failure (versus each comparator arm), combined CV events (versus α-blocker and ACE-inhibitor arms), and stroke (versus ACE inhibitor [black subjects only] and α-blocker).6 The ongoing success of thiazide-type diuretics in large, adequately powered hypertension outcome trials and new guidelines have created the basis for increased diuretic use.2,6 However, clinical trials have also frequently shown potentially …

Transforming growth factor-β signaling mediates hypoxia-induced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung

Abstract: Hypoxia causes abnormal neonatal pulmonary artery remodeling (PAR) and inhibition of alveolar development (IAD). Transforming growth factor (TGF)-β is an important regulator of lung development and repair from injury. We tested the hypothesis that inhibition of TGF-β signaling attenuates hypoxia-induced PAR and IAD. Mice with an inducible dominant-negative mutation of the TGF-β type II receptor (DNTGFβRII) and nontransgenic wild-type (WT) mice were exposed to hypoxia (12% O2) or air from birth to 14 days of age. Expression of DNTGFβRII was induced by 20 μg/g ZnSO4 given intraperitoneally daily from birth. PAR, IAD, cell proliferation, and expression of extracellular matrix (ECM) proteins were assessed. In WT mice, hypoxia led to thicker, more muscularized resistance pulmonary arteries and impaired alveolarization, accompanied by increases in active TGF-β and phosphorylated Smad2. Hypoxia-induced PAR and IAD were greatly attenuated in DNTGFβRII mice given ZnSO4 compared with WT control mice and DNTGFβRII mice not given ZnSO4. The stimulatory effects of hypoxic exposure on pulmonary arterial cell proliferation and lung ECM proteins were abrogated in DNTGFβRII mice given ZnSO4. These data support the conclusion that TGF-β plays an important role in hypoxia-induced pulmonary vascular adaptation and IAD in the newborn animal model.

Increased protein O-GlcNAc modification inhibits inflammatory and neointimal responses to acute endoluminal arterial injury

Abstract: Inflammation plays a major role in vascular disease. We have shown that leukocyte infiltration and inflammatory mediator expression contribute to vascular remodeling after endoluminal injury. This ...

Relation of Dietary Salt and Aldosterone to Urinary Protein Excretion in Subjects With Resistant Hypertension

Abstract: Experimental data indicate that the cardiorenal effects of aldosterone excess are dependent on concomitant high dietary salt intake. Such an interaction of endogenous aldosterone and dietary salt has not been observed previously in humans. We assessed the hypothesis that excess aldosterone and high dietary sodium intake combine to worsen proteinuria in patients with resistant hypertension. Consecutive subjects with resistant hypertension (n=84) were prospectively evaluated by measurement of 24-hour urinary aldosterone (Ualdo), sodium, and protein (Uprot) excretion. Subjects were analyzed according to aldosterone status (high: Ualdo >or=12 microg/24 hours; or normal: <12 microg/24 hours) and dietary salt intake based on tertiles of urinary sodium. The mean clinic blood pressure for all of the subjects was 161.4+/-22.4/89.8+/-13.5 mm Hg on an average of 4.3 medications. There was no blood pressure difference between study groups. Uprot was significantly higher in the 38 subjects with high Ualdo compared with the 46 subjects with normal Ualdo (143.0+/-83.8 versus 95.9+/-81.7 mg/24 hours; P=0.01). Among subjects with high Ualdo, Uprot increased progressively across urinary sodium groups (P<0.05). In contrast, there was no difference in Uprot across sodium tertiles among subjects with normal Ualdo. A positive correlation between Uprot and urinary sodium (r=0.47; P=0.003) was observed in subjects with high Ualdo but not in subjects with normal Ualdo (r=0.18; P value not significant). These results suggest that aldosterone excess and high dietary salt combine to increase urinary protein excretion.

Fenoldopam, a dopamine agonist, for hypertensive emergency: a multicenter randomized trial. Fenoldopam Study Group.

Abstract: UNLABELLED Despite successful therapies for chronic hypertension, hospital admissions for hypertensive emergency more than tripled between 1983 and 1992. OBJECTIVE To examine the safety and efficacy of fenoldopam, the first antihypertensive with selective and specific action on vascular dopamine (DA1) receptors, in a clinical trial involving emergency department patients with true hypertensive emergencies. METHODS Patients with a sustained diastolic blood pressure (DBP) of > or =120 mm Hg and evidence of target organ compromise were randomized in a double-blinded manner to one of four fixed doses of intravenous fenoldopam (0.01, 0.03, 0.1, or 0.3 microg/kg/min) for 24 hours. The primary endpoint was the magnitude of DBP reduction in each of the three higher-dose groups after four hours of fenoldopam treatment compared with the lowest-dose group. RESULTS One hundred seven participants from 21 centers were enrolled, and 94 patients received fenoldopam. Evidence of acute target-organ damage included new renal dysfunction or hematuria (50%), acute congestive heart failure or myocardial ischemia (48%), and papilledema or grade III-IV hypertensive retinopathy (34%). The DBP decreased in a dose-dependent fashion, with significant differences between the 0.1- and 0.3-microg/kg/min groups compared with the lowest-dose group. Treatment was well tolerated, and there were no deaths or serious adverse events during follow-up, up to 48 hours. All patients were successfully transitioned to oral or transdermal antihypertensives with maintenance of blood pressure control. CONCLUSIONS Fenoldopam safely and effectively lowers blood pressure in a dose-dependent manner in patients with hypertensive emergencies. Observations supporting potential risk factors for hypertensive emergency are discussed.

Effects of losartan in women with hypertension and left ventricular hypertrophy: results from the Losartan Intervention for Endpoint Reduction in Hypertension Study

Abstract: Hypertension is a risk factor for cardiovascular disease and outcomes in women. These posthoc analyses from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study evaluated losartan- versus atenolol-based therapy on the primary composite end point of cardiovascular death, stroke, and myocardial infarction and other end points in 4963 women. Fewer events occurred in women versus men. Women in the losartan group had significant reductions in the primary end point (215 [18.2 per 1000 patient-years] versus 261 [22.5 per 1000 patient-years]; hazard ratio [HR]: 0.82 [95% CI: 0.68 to 0.98]; P=0.031), stroke (109 versus 154; HR: 0.71 [95% CI: 0.55 to 0.90]; P=0.005), total mortality (HR: 0.77 [95% CI: 0.63 to 0.95]; P=0.014), and new-onset diabetes (HR: 0.75 [95% CI: 0.59 to 0.94]; P=0.015) versus the atenolol group, with no between-treatment difference for myocardial infarction (HR: 1.02 [95% CI: 0.74 to 1.39]; P=0.925), cardiovascular mortality (HR: 0.86 [95% CI: 0.64 to 1.14]; P=0.282), or hospitalization for heart failure (HR: 0.94 [95% CI: 0.68 to 1.28]; P=0.677). More women in the losartan group required hospitalization for angina (HR: 1.70 [95% CI: 1.16 to 2.51]; P=0.007). Risk reductions for the primary composite end point, stroke, total mortality, and new-onset diabetes were significantly greater with losartan- versus atenolol-based treatment in women with hypertension and left ventricular hypertrophy in the LIFE study. The risk reductions for losartan, along with the tests for the interaction of treatment and gender, indicated that the treatment effect was consistent in men and women for all of the end points tested, with the exception of hospitalization for angina.

Exaggerated Neointima Formation in Human C-Reactive Protein Transgenic Mice Is IgG Fc Receptor Type I (FcγRI)-Dependent

Abstract: Neointima formation after vascular injury is exaggerated in ovariectomized (OVX) human C-reactive protein transgenic mice (CRPtg) compared to nontransgenic mice (NTG). We tested the hypothesis that this CRP-mediated exacerbation requires IgG Fc receptors (FcγRs). OVX NTG, CRPtg, and CRPtg lacking FcγRI, FcγRIIb, FcγRIII, or the common γ chain (FcRγ) had their common carotid artery ligated. Twenty-eight days later neointimal thickening in CRPtg/FcγRI−/− and CRPtg/FcRγ−/− was significantly less than in CRPtg and no worse than in NTG, whereas in CRPtg/FcγRIIb−/− and CRPtg/FcγRIII−/− neointimal thickness was equal to or greater than in CRPtg. Immunohistochemistry revealed human CRP in the neointima of CRPtg, but little or none was observed in those lacking FcγRI or FcRγ. Real-time reverse transcriptase-polymerase chain reaction demonstrated that FcγR types I to III were expressed in the CRPtg arteries, with FcγRI expression increasing by threefold after ligation injury. Levels of serum complement (C3), neointimal deposition of complement (C3d), and cellular composition (monocytes, macrophages, lymphocytes) in the neointima did not differ among the different CRPtg genotypes. However, by immunofluorescence a neointimal population of F4/80+CRP+ cells was revealed only in OVX CRPtg. The exaggerated response to vascular injury provoked by CRP in OVX CRPtg depends on FcγRI and probably requires its expression by F4/80+ cells.

Mechanisms and Treatment of Resistant Hypertension

Abstract: Resistant hypertension is defined as blood pressure (BP) that remains uncontrolled in spite of the use of ≥3 antihypertensive medications. Stricter BP goals, higher obesity rates, older age, and increased use of exogenous BP-elevating substances are related to an increasing prevalence of resistant hypertension. The evaluation of patients with resistant hypertension is focused on identifying contributing and secondary causes of hypertension, including hyperaldosteronism, obstructive sleep apnea, chronic kidney disease, renal artery stenosis, and pheochromocytoma. Hyperaldosteronism is now recognized as the most common cause of resistant hypertension, and all patients with resistant hypertension should be screened with a plasma aldosterone/renin ratio even if the serum potassium level is normal. Treatment includes removal of contributing factors, appropriate management of secondary causes, and use of effective multidrug regimens. Recent studies indicate that the addition of spironolactone to standard treatment induces significant BP reduction in most patients with resistant hypertension.

Role of Matrix Metalloproteinase-2 in Newborn Mouse Lungs under Hypoxic Conditions

Abstract: Hypoxia impairs normal neonatal pulmonary artery remodeling and alveolar development. Matrix metalloproteinase-2 (MMP-2), which regulates collagen breakdown, is important during development. Our objective was to test the hypothesis that hypoxia attenuates the normal postnatal increase in MMP-2 and evaluate alveolar development and pulmonary arterial remodeling in Mmp2−/− mice. C57BL/6 wild-type (WT), Mmp2+/−, Mmp2−/−, and MMP-inhibited (with doxycycline) mice were exposed to hypoxia (12% O2) or air from birth to 2 wk of age. Pulmonary arterial remodeling, alveolar development, and vascular collagen and elastin were evaluated. MMP-2 was estimated by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry, and zymography. We observed that 1) in WT mice, hypoxia led to thicker-walled pulmonary arteries and impaired alveolarization, accompanied by decreased MMP-2 and increased tissue inhibitor of metalloproteinases-2 (TIMP-2); 2) Mmp2−/− mice in air had thicker-walled arteries, impaired alveolarization, and increased perivascular collagen and elastin compared with WT; 3) hypoxia further inhibited alveolarization but did not alter arterial thickening in Mmp2−/− mice. Mmp2+/− and MMP-inhibited mice also had thicker-walled arteries than WT in air, but alveolarization was not different. We conclude that hypoxia reduces the postnatal MMP-2 increase in the lung, which may contribute to abnormal pulmonary arterial remodeling and impaired alveolarization.

Fixed combinations in the management of hypertension: patient perspectives and rationale for development and utility of the olmesartan-amlodipine combination.

Abstract: Although the awareness and control of hypertension has increased, only 37% of hypertensive patients in the US achieve the conservative goal of <140/90 mmHg. Achieving optimal blood pressure (BP) control is the most important single issue in the management of hypertension, and in most hypertensive patients, it is difficult or impossible to control BP with one drug. Blocking two or more BP regulatory systems provides a more effective and more physiologic reduction in BP, and current guidelines have recommended the use of combination therapy as first-line treatment, or early in the management of hypertension. Fixed combination therapy is an efficacious, relatively safe, and may be cost-effective method of decreasing BP in most patients with essential hypertension. Similar to other combinations, fixed-dose combination tablets containing the dihydropyridine calcium channel blocker amlodipine and the angiotensin II receptor blocker olmesartan bring together two distinct and complementary mechanisms of action, resulting in improved BP control and potential for improved target organ protection relative to either class of agent alone.

Marked Regional Left Ventricular Heterogeneity in Hypertensive Left Ventricular Hypertrophy Patients A Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Cardiovascular Magnetic Resonance and Echocardiographic Substudy

Abstract: Concentric hypertensive left ventricular (LV) hypertrophy is presumed to be a symmetrical process. Using MRI-derived intramyocardial strain, we sought to determine whether segmental deformation was also symmetrical, as suggested by echocardiography. High echocardiographic LV relative wall thickness in hypertensive LV hypertrophy allows preserved endocardial excursion despite depressed LV midwall shortening (MWS). Depressed MWS is an adverse prognostic indicator, but whether this is related to global or regional myocardial depression is unknown. We prospectively compared MWS derived from linear echocardiographic dimensions with MR strain(in) in septal and posterior locations in 27 subjects with ECG LV hypertrophy in the Losartan Intervention for Endpoint Reduction in Hypertension Study. Although MRI-derived mass was higher in patients than in normal control subjects (124.0+/-38.6 versus 60.5+/-13.2g/m(2); P<0.001), fractional shortening (30+/-5% versus 33+/-3%) and end-systolic stress (175+/-22 versus 146+/-28 g/cm(2)) did not differ between groups. However, mean MR(in) was decreased in patients versus normal control subjects (13.9+/-6.8% versus 22.4+/-3.5%), as was echo MWS (13.4+/-2.8% versus 18.2+/-1.4%; both P<0.001). For patients versus normal control subjects, posterior wall(in) was not different (17.8+/-7.1% versus 21.6+/-4.0%), whereas septal(in) was markedly depressed (10.1+/-6.6% versus 23.2+/-3.4%; P<0.001). Although global MWS by echocardiography or MRI is depressed in hypertensive LV hypertrophy, MRI tissue tagging demonstrates substantial regional intramyocardial strain(in) heterogeneity, with most severely depressed strain patterns in the septum. Although posterior wall 2D principal strain was inversely related to radius of curvature, septal strain was not, suggesting that factors other than afterload are responsible for pronounced myocardial strain heterogeneity in concentric hypertrophy.

Aliskiren and valsartan in stage 2 hypertension: subgroup analysis of a randomized, double-blind study

Abstract: Patients with stage 2 hypertension require large absolute reductions in blood pressure (BP) to achieve recommended BP goals. Combination therapy with the direct renin inhibitor, aliskiren, and the angiotensin receptor blocker, valsartan, has been shown to produce greater BP reductions than either agent alone in a double-blind study in 1797 hypertensive patients. This post-hoc analysis evaluated the BP-lowering efficacy of aliskiren in combination with valsartan in a subset of patients (n=581) with stage 2 hypertension (baseline mean sitting systolic BP [msSBP] ≥160 mmHg). Patients were randomized to receive aliskiren/valsartan 150/160 mg, aliskiren 150 mg, valsartan 160 mg, or placebo once daily for 4 weeks followed by 4 weeks at double the initial dose. Mean changes from baseline in msSBP and mean sitting diastolic BP were assessed at week-8 endpoint (intent-to-treat population). Aliskiren/valsartan 300/320 mg reduced BP from baseline by 22.5/11.4 mmHg at week-8 endpoint. BP reductions with combination therapy were significantly greater than with aliskiren 300 mg (17.3/8.9 mmHg, P<0.05), valsartan 320 mg (15.5/8.3 mmHg, P<0.01), or with placebo (7.9/3.7 mmHg, P<0.0001). BP control rates (<140/90 mmHg) were also significantly higher (P<0.05) with aliskiren/valsartan 300/320 mg (29.8%) compared with either aliskiren 300 mg (19.0%) or valsartan 320 mg (13.8%) monotherapy, or placebo (8.9%). All treatments were generally well tolerated. Combination therapy with aliskiren and valsartan provided significantly greater BP reductions over aliskiren or valsartan monotherapy and is an appropriate option for management of BP in patients with stage 2 hypertension.

Renin inhibition: should it supplant ACE inhibitors and ARBS in high risk patients?

Abstract: Purpose of review The direct renin inhibitor aliskiren has recently been approved for the treatment of hypertension in humans. The potential for these newer agents having an advantage over the existing renin-angiotensin-aldosterone system (RAAS) antagonists in the treatment of hypertension and related target organ damage has drawn the interest of several investigators. In this review, we discuss the potential advantages and disadvantages of this newest antihypertensive class over other available RAAS antagonists. Recent findings The antihypertensive efficacy of aliskiren monotherapy has been compared with that of other RAAS antagonists and combinations of aliskiren with these agents. These studies have shown that aliskiren is equally effective as angiotensin receptor blockers and may be slightly more effective than angiotensin converting enzyme inhibitors in lowering blood pressure. In contrast to the other RAAS antagonists, aliskiren shuts down the entire downstream RAAS cascade. This results in greatly increased plasma renin concentration due to removal of angiotensin II-mediated feedback inhibition of renin release, which has raised concerns about whether direct renin inhibition adds anything to inhibition of downstream components of the RAAS cascade. Summary The potential advantages and disadvantages of aliskiren therapy versus existing RAAS antagonists in treating hypertension and target organ damage are under investigation.

Results of an olmesartan medoxomil-based treatment regimen in hypertensive patients.

Abstract: The efficacy and safety of an olmesartan medoxomil (OM)-based treatment algorithm was tested in a double-blind, randomized, placebo-controlled titration study in 276 patients with stage 1 or 2 hypertension. After placebo run-in, patients were randomized to placebo (12 weeks) or OM 20 mg/d (weeks 1-3). OM was up-titrated to 40 mg/d (weeks 4-6), then OM/hydrochlorothiazide (HCTZ) 40/12.5 mg/d (weeks 7-9) and OM/HCTZ 40/25 mg/d (weeks 10-12) were started if blood pressure (BP) remained > or =120/80 mm Hg at each time interval. End points were change from baseline in mean systolic BP (primary) and mean diastolic BP (secondary). OM-based treatment was well tolerated and changed BP by -22.3/-12.1 mm Hg from baseline vs -0.1/+0.8 mm Hg for placebo (P<.0001). Cumulative goal BP (<140/90 mm Hg) was achieved in 74.1% and 30.7% of OM- compared with placebo-treated patients, respectively (P<.0001). BP normalized (<120/80 mm Hg) in 44.8% of OM- vs 1.4% of placebo-treated patients with stage 1 hypertension (P<.0001).

Renin inhibition: should it supplant ACE inhibitors and ARBS in high risk patients?

Abstract: Purpose of review The direct renin inhibitor aliskiren has recently been approved for the treatment of hypertension in humans The potential for these newer agents having an advantage over the existing renin-angiotensin-aldosterone system (RAAS) antagonists in the treatment of hypertension and related target organ damage has drawn the interest of several investigators In this review, we discuss the potential advantages and disadvantages of this newest antihypertensive class over other available RAAS antagonists Recent findings The antihypertensive efficacy of aliskiren monotherapy has been compared with that of other RAAS antagonists and combinations of aliskiren with these agents These studies have shown that aliskiren is equally effective as angiotensin receptor blockers and may be slightly more effective than angiotensin converting enzyme inhibitors in lowering blood pressure In contrast to the other RAAS antagonists, aliskiren shuts down the entire downstream RAAS cascade This results in greatly increased plasma renin concentration due to removal of angiotensin II-mediated feedback inhibition of renin release, which has raised concerns about whether direct renin inhibition adds anything to inhibition of downstream components of the RAAS cascade Summary The potential advantages and disadvantages of aliskiren therapy versus existing RAAS antagonists in treating hypertension and target organ damage are under investigation

A double-blind, randomized study evaluating losartan potassium monotherapy or in combination with hydrochlorothiazide versus placebo in obese patients with hypertension

Abstract: Objectives: The objective of this study was to evaluate the effects of losartan ± hydrochlorothiazide (HCTZ) versus placebo in obese patients with systolic and diastolic hypertension.Research design and methods: Randomized patients (n = 261) were non-diabetic with systolic blood pressure (SBP) ≥ 140 and ≤ 180 mmHg and diastolic BP (DBP) ≥ 95 and ≤ 115 mmHg, body mass index > 30 kg/m2, and waist circumference > 40 (males)/> 35 (females) inches. Patients were randomized to placebo or a forced titration of losartan 50 mg titrated at 4-week intervals to losartan 100 mg, losartan 100 mg/HCTZ 12.5 mg, and losartan 100 mg/HCTZ 25 mg. Primary efficacy measurements were change from baseline in SBP and DBP at 12 weeks. Secondary measurements were change from baseline in BPs at 8 and 16 weeks, percent responders at 12 and 16 weeks, and safety/tolerability. Post-hoc analyses were BP at 4 weeks and achieve­ment of controlled BP (SBP < 140 and/or DBP < 90 mmHg) at 12 and 16 weeks.Results: Losartan 50 mg reduced...

Combining RAAS and calcium channel blockade: ACCOMPLISH in perspective

Abstract: The Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial was the first trial to compare the cardiovascular outcomes of initial fixed-dose combination angiotensin-converting enzyme inhibitor (ACEI)/calcium channel blocker (CCB) and ACEI/diuretic therapy in patients with hypertension and high risk of cardiovascular events. The initial combination therapy was effective in this population, with ACEI/CCB therapy providing the greatest benefit (reduction in risk of cardiovascular events). Whether or not the findings of ACCOMPLISH can be applied to other renin-angiotensin-aldosterone system (RAAS) inhibitor/CCB combinations, such as angiotensin receptor blocker (ARB)/CCB combinations, has yet to be investigated. The present report reviews the results of ACCOMPLISH, data from trials comparing ARB and ACEI therapies, and findings from studies of ARB/CCB combination therapy that support the use and further study of combination therapy with RAAS inhibitors and CCBs.

Hyperaldosteronism causes volume overload cardiac hypertrophy in patients with resistant hypertension

Abstract: Objective: Primary aldosteronism is a common cause of resistant hypertension with a prevalence of approximately 20%. Racial differences in the prevalence of hyperaldosteronism in patients with resistant hypertension have not been previously described. Methods: Consecutive subjects referred to the University of Alabama at Birmingham hypertension clinic for resistant hypertension were prospectively evaluated with a plasma aldosterone concentration (PAC), plasma renin activity (PRA), and a 24-hr urine collection for aldosterone, sodium, and potassium during the patient’s usual diet. All subjects were on a stable antihypertensive regimen without use of potassium sparing diuretics. Results: A total of 295 patients with resistant hypertension were evaluated, including 157 white and 138 black subjects. There were 86 black females and 64 white females. Clinic BP was higher in blacks compared to whites (148±20/89 ±16 vs. 143 ±20/83 ± 13, p 0.034) while receiving a similar number of prescribed medications. Diuretic use was the same, but whites were more likely on an ACE inhibitor and beta blocker than blacks. Whites had a higher plasma aldosterone (14.3 ± 9.5 vs. 11.0 ±8.0 ng/dl, p<0.001) and higher urinary potassium excretion (75.1± 34.4 vs. 52.2 ± 23.7 mEq/24-hr, p<0.001). Blacks had a lower PRA (1.9±3.3 vs. 2.8 ± 4.4 ng/ml/hr, p ns). Urinary aldosterone excretion tended to be higher in white compared to black subjects (13.7± 11.3 vs.11.9 ±7.6 mcg/24-hr, p=ns). In spite of higher aldosterone levels in white subjects, the prevalence of hyperaldosteronism based on a PRA<1.0 and urine aldo≥12 was not different in white (25.5%) vs. black subjects (26.1%). Hyperaldosteronism was more common in both black and white males compared to females (white males 38.7% vs. white females 6.3 %, p<0.001; black males 38.5% vs. black females 18.6%, p=0.018). Conclusion: These data demonstrate that hyperaldosteronism is equally common in African American and white patients with resistant hypertension. Males in both races have a higher prevalence of hyperaldosteronism than females. These findings support equal vigor in screening African American and white patients with resistant hypertension for primary aldosteronism.

A stunning day in hypertension research – Results of ONTARGET, ACCOMPLISH and HYVET

Abstract: As exciting as it can be, with plenary session jammed with interested delegates in numbers of many thousands, three new breathtaking double‐blinded randomized clinical trials were released within 4...

Achieving better blood pressure control.

Abstract: Primary hypertension is a polygenic condition with variable contribution from environmental factors. Not surprisingly, there are differential responses to both non-pharmacological and pharmacological antihypertensive treatments within the population of hypertensive patients. In order to achieve maximal risk reduction, blood pressure (BP) should be reduced to below 140/90 mmHg in lower risk hypertensive patients, and even lower (v130/ 80 mmHg) if additional risk factors such as diabetes or renal disease are present (1). Despite the availability of multiple classes of antihypertensive agents that lower BP by different mechanisms, the treatment of hypertension remains a difficult task. In terms of BP lowering effects, it is usually not possible to predict which type of agent is the most appropriate for a given patient. Consequently, in most hypertensive patients, target BPs are usually not reached by the use of monotherapies (2,3). However, a strategy of combining medications acting by different mechanisms makes it possible to achieve considerable gains in terms of antihypertensive efficacy. This is due to the synergistic effects on the cardiovascular system of antihypertensive medications that have distinct mechanisms of action (4). When combining two or several antihypertensive medications from different classes, it is important to select combinations of drugs that have complementary effects on BP lowering as well as reduction of adverse events (1). In recent years, use of fixed-lowdose combinations of antihypertensive medications as first-line treatment has increased greatly, since studies have shown that this approach is likely to both increase the chance of controlling the patient’s BP and limit the occurrence of dose-related adverse effects (5,6). In the present issue of Blood Pressure, Ruilope and co-workers (7) argue for wider use of fixeddose antihypertensive combinations based on both individual patient benefits and, importantly, also on greater public health and societal value. This Drug Therapeutic Supplement also deals with the issue of which drugs to combine. As demonstrated by Tuomilehto et al. (8) and Schumacher and Mancia (9), a fixed-dose angiotensin II receptor blocker (ARB)-diuretic combination has greater or comparable antihypertensive efficacy than ARB treatment alone without reduced tolerability. Most combination regimens currently available for clinical use include an inhibitor of the renin–angiotensin system (RAS) and a diuretic, but a fixed-dosed combination regimen that includes a calcium-channel blocker and an angiotensin-converting enzyme (ACE) inhibitor is also widely used and has recently been shown to have outcome advantages over a combination of the same ACE inhibitor and a diuretic in the ACCOMPLISH trial (10). Ueng et al (11) demonstrate that the dihydropyridine calcium-channel blocker amlodipine and the ACE inhibitor benazepril, when combined, have complementary effects on BP, with impressive efficacy in rapid attainment of BP targets as well as levels of BP achieved. Importantly, as pointed out by Ruilope and coworkers (7), combinations of drugs from different antihypertensive classes may have both synergistic or additive antihypertensive properties and the ability to diminish each others’ untoward hemodynamic or metabolic effects. Importantly, beneficial fixed-dose combinations containing optimal doses can be selected as initial therapy, thereby facilitating rapid BP control and minimizing adverse effects in the newly diagnosed hypertensive (6). Poor control of hypertension remains an issue in most parts of the world. Failure to attain BP goals is related to multiple factors, e.g. insufficient efficacy of available single antihypertensive agents, poor adherence to prescribed medication, and reluctance of many physicians to treat aggressively, including Blood Pressure. 2008; 17 (Suppl 1): 3–4

Urgent need to address quality control issues of out-of-office blood pressure measurement and patient risk assessment.

Abstract: Blood pressure (BP) assessment and evaluation is becoming more complex and for many practicing physicians it is increasingly a numbers game where the rules keep changing. Conventionally, high BP is interpreted as increased clinic systolic and/or diastolic pressure. However, high pressures with or without increased clinic systolic or diastolic values may also be assessed by ambulatory or home measurements, where the actual mmHg normal values often differ from the clinic values. In isolated office hypertension the clinic BP values are higher, while in the masked hypertensives, only the out-of-office values are increased. There is accumulating evidence that any form of high BP is dangerous if not properly controlled (1,2). Although the weight of the evidence differs, the future risk for stroke, heart attack, congestive heart failure or kidney damage is increased, whether or not it is the clinic, ambulatory or home BP that is elevated. In the present issue of Blood Pressure, Dilek and coworkers (3) show that self-assessment of BP is rather extensive in Turkey by the use of a variety of both automatic arm as well as wrist devices. The different devices were assessed against a conventional mercury manometer and checked whether readings were within 4 mmHg of the reference mercury sphygmomanometer. Surprisingly, about 60% of the automatic manometers and about 80% of the wrist devices were judged inaccurate by this comparison. In addition to the equipment-related errors, in the real setting there are also observer-, technique-, environmentaland patient-related factors that may contribute to the potential lack of accuracy in devices for home BP assessment. Thus, with an increasing use of home devices by patients for self-assessment, there will be an increasing need for patient education and training, in addition to information on which devices are recommended as well as regular check-up and calibration of devices used at home by patients. This is an area where we currently have insufficient knowledge, since we lack large pieces of information from the real world on the practical outcome and reliability of out-of-office devices when used by common patients over extended periods. In an earlier study, Gasowski et al. (4) assessed patient-related factors during use of ambulatory and home devices by metabolic syndrome patients. In their patient cohort with excess cardiovascular (CV) risk, the relative accuracy of office, home and ambulatory BP measurements was clearly unsatisfactory. In particular, there was a deviation of home measurements in a dose-dependent fashion, which correlated with the intensity of the metabolic syndrome. Thus, in such patients at excess CV risk, there seems to be an even greater need for standardized measurement and equipment protocols when assessing BP readings and treatment efficacy. Also, earlier studies (5) indicate that there may be a greater proportion of masked hypertensive patients among high-risk diabetics with microalbuminuria as compared with low-risk hypertensives, which by itself may be an argument in favour of an increased use of out-of-office BP measurements. Additionally, Márquez Contreras et al. (6) demonstrated in the Spanish HICAP study that a high proportion of hypertensive patients in primary care present with a high CV global risk. Also, CV risk factor control, especially among patients at higher CV global risk, was clearly insufficient in their cohort. Blood Pressure. 2008; 17: 5–6

More is Less? Optimal Combination Therapy for Adequate Blood Pressure Lowering in Hypertension

Abstract: Fixed dose formulations of rational antihypertensive drug combinations are being used increasingly early in the management of hypertension (1). Fixed combinations for hypertension management were long viewed with suspicion, although the scientific and medical community widely accepted combination treatments in many other fields of medicine, e.g Parkinson’s disease (L-dopa plus an extracerebral dopa-decarboxylase inhibitor) or infectious diseases (trimethoprim and sulfamethoxazole as cotrimoxazole). Today, however, there is a strong interest in the use of fixed low-dose combination therapy as well as an increasing recognition that the combination approach may offer significant benefits for the hypertensive patient population, not only for the sake of simplicity, but also in terms of efficacy and tolerability (2). The Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial was the first study to compare the cardiovascular outcomes of initial fixed-dose combination angiotensinconverting enzyme inhibitor (ACEI)/calcium channel blocker (CCB) and ACEI/diuretic therapy in patients with hypertension at high risk for cardiovascular events (3–6). Results indicate that initial combination therapy is effective in this population, with ACEI/ CCB therapy providing the greater benefit with the largerreduction in risk for cardiovascular events (7). The potential to extend the findings of ACCOMPLISH to other renin-angiotensin-aldosterone system (RAAS) inhibitor/CCB combinations, such as angiotensin II type 1 receptor blocker (ARB)/CCB combinations, has yet to be investigated. In the absence of direct comparisons of ACEI/ CCB and ARB/CCB combinations, it appears reasonable to explore the possibility that the beneficial results of ACCOMPLISH extend to other RAAS inhibitor/CCB combinations. Data from multiple clinical studies in a range of patient populations indicate that ACEI and ARB provide similar cardiovascular benefits. Comparable morbidity and mortality outcomes have been reported for patients with vascular disease or high-risk diabetes (8), acute myocardial infarction (9,10) and heart failure (11–14). Furthermore, in patients with heart failure, the ARB candesartan was as effective as enalapril in preventing left ventricular remodelling (15). In general, tolerability was comparable or greater in the ARB (vs. ACEI) treatment groups in these studies. In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial (13), the ARB candesartan was used successfully in patients who were intolerant to ACEI therapy. Furthermore, results of a systematic review of data from 61 comparative studies indicate that ACEIs and ARBs have no clinically meaningful differences in terms of benefits for individuals with hypertension (16). Both classes of drugs provide similar BP control and comparable effects on death, cardiovascular events, major adverse events, quality of life, and cardiovascular risk factors including lipid levels, diabetes mellitus, and left ventricular mass and function. The only clinically significant difference between ACEIs and ARBs found in this analysis was the incidence of cough, which was higher with ACEIs (mean rate, 10% for ACEI vs. 3% for ARB). In addition, ARBs were also associated with higher rates of persistence during initial therapy. Despite the availability of a wide variety of treatment options, the full benefits of early fixed Blood Pressure. 2008; 17: 132–133

Should we prefer different drugs to treat hypertension in older and younger adults? Practical implications of clinical trials: American perspective

Abstract: Whether older and younger persons derive similar benefit from antihypertensive treatment and whether treatment choices should be tailored to the age of the patient are unresolved issues about which there is a paucity of evidence. The Blood Pressure Lowering Treatment Trialists' Collaboration has attempted to address this deficiency in a meta-analysis that included 31 trials with 190,606 participants. They compared the proportionate risk reductions achieved with different classes of antihypertensive drugs in younger ( 65 years) adults. They reported that there was no clear evidence to support recommendations for particular antihypertensive drug classes in older or younger adults. In this paper we discussed the Trialists' paper and its limitations and strenghts, current guidelines recommendations, and the major conclusions that are important for clinicians.

Benefits of hypertension management in diabetes: an opportunity not to be missed

Abstract: The prevalence of diabetes mellitus is increasing rapidly worldwide and is projected to rise from approximately 2.8% in 2000 to 4.4% by 2030. In terms of patient numbers, this translates into a ris...

Beyond brachial pressure effect.

Abstract: Introduction: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study was designed to compare the effects of losartan-based therapy with atenolol-based therapy on major clinical end points in 9193 patients with untreated or treated hypertension and left ventricular hypertrophy. Treatment with losartan reduced risk of the primary composite end point (cardiovascular death, stroke, and myocardial infarction) by 13%; stroke was reduced by 25%. Reduction in offi ce systolic blood pressure was similar with the two regimens.Aims: The present substudy was undertaken to assess the effect of losartan- and atenolol-based treatment on 24-hour ambulatory blood pressure monitoring (ABPM) and heart rate burden in LIFE patients at baseline and after 1 year of randomized treatment.Methods: The substudy included 110 patients recruited from centers in Denmark. Patients were randomized to 50 mg of either losartan or atenolol. To achieve blood pressure control, doses of either drug could be increased to 100 mg and hydrochlorothiazide and other agents could be added as necessary. ABPM was done at baseline and after 1 year of treatment.Results: Baseline characteristics, including office and daytime and nighttime ambulatory blood pressure and heart rate did not differ significantly between groups. Minor differences between groups in hourly average blood pressure were observed at baseline, especially during the night and early morning. Similar reductions in office and mean 24-hour ambulatory blood pressure were observed in the two groups from baseline to 1 year. No significant differences in daytime or nighttime blood pressure were observed between groups at 1 year. Early morning surges in systolic and diastolic blood pressure were similar in both groups. Nondipping status was more frequent in the losartan than the atenolol group at 1 year.Discussion: The comparable blood pressures achieved with losartan and atenolol determined by 24-hour ABPM provide compelling evidence that the difference in outcome seen in the LIFE study is due to differences in treatment regimens that are independent of blood pressure control. The early morning surge in blood pressure, which is associated with increased stroke risk, was similar in both groups at 1 year of treatment; therefore, this could not offer an explanation for the LIFE outcome. Paradoxically, nondipping status, which is generally associated with worse outcome, was more frequent in the losartan group.