Hypertension Research: 2002-2006
     
Curr Hypertens Rep. 2006 Oct;8(5):425-32.
New drugs for hypertension: what do they offer?
Gradman AH, Vivas Y.
Chief, Division of Cardiovascular Diseases,The Western Pennsylvania Hospital, 4800 Friendship Avenue,Suite 3411 N, Pittsburgh, PA 15224, USA.

A new drug might make a positive contribution to existing therapies for hypertension by: 1) reducing blood pressure (BP) via a novel pharmacologic mechanism; 2) possessing pharmacologic or pharmacokinetic properties that make it superior to other members of its class; or 3) facilitating BP control in refractory patients. In this paper, we review four experimental agents that promise to advance therapeutics by one of these mechanisms. Aliskiren is the first in a new class of potent, orally effective renin inhibitors. Aliskiren produces dose-dependent BP reduction with few side effects and constitutes a novel pharmacologic approach to renin-angiotensin-aldosterone inhibition. Nebivolol is a third-generation, cardioselective beta-blocker that produces vasodilation and improves endothelial function via the l-arginine/nitric oxide pathway. Clevidipine is an ultra-short-acting, vascular-selective, dihydropyridine calcium antagonist that is being developed for intravenous use in acute hospitalized patients. Darusentan is an endothelin(A) selective endothelin receptor antagonist that is effective in achieving BP control in a significant percentage of patients who remain uncontrolled despite treatment with three or more antihypertensive drugs.

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Curr Hypertens Rep. 2006 Oct;8(5):420-4.
Electrical Stimulation of theCarotid Sinus for the Treatmentof Resistant Hypertension.
Filippone JD, Sloand JA, Illig KA, Bisognano JD.
Program in Heart Failure and Transplantation, Universityof Rochester, Cardiology Division, 601 Elmwood Avenue,Box 679T, Rochester, New York 14642-8679, USA.

Hypertension is a major cause of morbidity and mortality worldwide. Despite a myriad of oral agents, many patients fail to reach their target blood pressure. Electrical stimulation of the carotid sinus, an old therapeutic concept, lowers blood pressure by initiating the baroreflex and reducing sympathetic tone. Recent evidence suggests that the baroreflex is more important in the setting of chronic hypertension than originally believed. The carotid stimulator may be a safe and effective therapeutic option for patients with resistant hypertension.

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Curr Hypertens Rep. 2006 Oct;8(5):377-83.
Treatment of isolated systolic hypertension.
Stokes GS.
P.O. Box 666, Mona Vale, NSW 2103, Australia.

Isolated systolic hypertension (ISH) is the dominant form of hypertension in the elderly. It is associated with increased arterial pulse pressure, to which an early-returning and magnified pulse-wave reflection makes an important contribution. Treatment of ISH with diuretics, calcium channel blockers (CCBs), and angiotensin II inhibitors is effective in reducing systolic blood pressure, preventing cardiovascular morbid events, and lowering mortality; these agents may have to be used in combination to achieve the systolic blood pressure goal of < 140 mm Hg. Treatment with beta-blockers appears to be less effective. The relative efficacy of various classes of antihypertensive drugs for lowering pulse pressure and systolic blood pressure is determined in part by their differing abilities to reduce pulse-wave reflection. In patients with ISH that is refractory to dual or triple therapy, measurement of the reflected wave by applanation tonometry may be useful in determining which additional antihypertensive agent to use.

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Curr Hypertens Rep. 2006 Oct;8(5):409-12.
Lessons from the African-American Study of Kidney Disease andHypertension: An Update.
Toto RD.
Mary M. Conroy Professorship in Kidney Disease,The University of Texas Southwestern Medical Center Dallas,5323 Harry Hines Boulevard, Dallas, Texas 75390-8856, USA.

Hypertension is the second leading attributable cause of end-stage renal disease in the United States today. The African-American Study of Kidney Disease and Hypertension was a randomized, double-blind, controlled trial designed to determine whether strict blood pressure (BP) control, angiotensin-converting enzyme inhibitor (ACEI)-based, or calcium channel blocker (CCB)-based regimens were superior to less strict BP control and beta-blocker (BB)-based regimens, respectively. The study enrolled 1093 African Americans with hypertensive nephrosclerosis and followed them for 4 years with repeated direct measurement of glomerular filtration rate (GFR) and monitoring of end points, including rapid decline in GFR, end-stage kidney disease, and death. From this landmark study, we learned that strict BP control is achievable in this study population, but it did not slow progression of kidney disease, and we learned that an ACEI-based therapy was superior to either a BB- or CCB-based regimen. In addition, we learned that proteinuria is the most important predictor of progression of kidney disease; ACEI and CCB have differential effects on proteinuria; and a CCB-based regimen combined with strict BP control may be the next best choice to an ACEI-based regimen in this population.

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Curr Hypertens Rep. 2006 Oct;8(5):368-76.
Estrogen and hypertension.
Ashraf MS, Vongpatanasin W.
Divisions of Hypertension and Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center,5323 Harry Hines Boulevard, J4 134, Dallas, TX 75390-8586, USA.

Menopause is accompanied by a dramatic rise in the prevalence of hypertension in women, suggesting a protective role of endogenous estradiol on blood pressure (BP). Both animal experimental and human clinical investigations suggest that estrogen engages several mechanisms that protect against hypertension, such as activation of the vasodilator pathway mediated by nitric oxide and prostacyclin and inhibition of the vasoconstrictor pathway mediated by the sympathetic nervous system and angiotensin. However, emerging evidence from recent clinical trials indicates a small increase, rather than decrease, in systolic BP with oral estrogen administration in postmenopausal women, without anydetectable effect on diastolic BP. Mechanisms underlyingthis selective rise in systolic BP in postmenopausal women and oral contraceptive-induced hypertension in premenopausal women remain unknown, but the rise may be related to supraphysiologic concentration of estrogen in the liver. To date, transdermal delivery of estrogen, which avoids the first-pass hepatic metabolism of estradiol, appears to have a small BP-lowering effect in postmenopausal women and may be a safer alternative in hypertensive women.

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Curr Med Res Opin. 2006 Sep;22(9):1849-58.
Efficacy and tolerability of the perindopril/indapamide combination therapy for hypertension: the PRIMUS study.
Holzgreve H, Risler T, Trenkwalder P.
Kardiologische Praxis, Munich, Germany.

BACKGROUND: Tight blood pressure (BP) control is required to reduce cardiovascular morbidity and mortality.OBJECTIVE: To evaluate the efficacy and tolerability of the first line combination perindopril/indapamide in hypertension in daily practice.Design and methods: In this prospective, open-label, observational trial, 1892 general practitioners in Germany recruited patients with hypertension (n = 8023; mean age 59.6 years, 48.1% males, body mass index 27.6 kg/m(2), systolic BP >/= 140 mmHg and/or diastolic BP >/= 90 mmHg) between October 2002 and December 2004. Patients received perindopril 2 mg/indapamide 0.625 mg for 12 weeks. BP measured in the general practice setting, safety, and tolerability were evaluated after 4 and 12 weeks.RESULTS: At baseline, most patients had moderate to severe hypertension (78%); initial BP was 164.6/95.8 mmHg. At inclusion, 38% of the patients were newly diagnosed hypertensives (mean BP 166.1/97.2 mmHg) and 58% of patients had uncontrolled BP despite preexisting antihypertensive treatment (163.5/94.9 mmHg). Previous treatment consisted of beta-blockers (49.5%), ACE inhibitors (36.4%), calcium-antagonists (29.3%), diuretics (28.8%), AT-I receptor antagonists (7.1%), and other treatments (8.1%). In the entire study cohort, treatment with perindopril/indapamide significantly decreased systolic BP (27.9 mmHg), diastolic BP (13.7 mmHg), and pulse pressure (14.2 mmHg), compared with baseline (p < 0.0001); 96% of patients responded to treatment and in 50% of patients BP was normalized (< 140/90 mmHg). Treatment dose was doubled in 9.5% of patients. Similar results were found in various subgroup analyses (newly diagnosed patients, the elderly, and patients with isolated systolic hypertension, additional cardiovascular risk factors, associated diseases, or target organ damage). The most frequent adverse events (< 1% of patients) were dry cough and nausea.CONCLUSIONS: The open-label, observational study PRIMUS, extends the existing evidence that the first line combination treatment of hypertension with perindopril/indapamide is effective, safe, and well tolerated in a representative cross-section of patients with newly diagnosed or pretreated but uncontrolled hypertension in daily practice.

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J Hum Hypertens. 2006 Sep 7; [Epub ahead of print]
Treatment of allergic rhinitis can improve blood pressure control.
Magen E, Yosefy C, Viskoper RJ, Mishal J.
1Internal Medicine 'B' Department, WHO Collaborative Center for Prevention of CVD, Barzilai Medical Center Campus, Ben-Gurion University of the Negev, Ashkelon, Israel.

Owing to high prevalence of arterial hypertension (AH) and allergic rhinitis (AR), these diseases frequently coexist. The study aimed to assess whether improvement of AR by conventional treatment can improve blood pressure (BP) control in this population. Sixty-eight subjects of both sexes aged 35-60 years with AR and AH were randomized into two groups to receive in addition to their antihypertensive medications: treatment group (n=34) Fluticasone nasal 50 mug/spray b.i.d. and Fenoxifenadine 180 mg tablets q.d., and control group (n=34) 0.9% NaCl nasal drops b.i.d. Office BP and AR severity (using the Relative Quality of Life Questionnaire (RQLQ)) and high-sensitive C-reactive protein (hs-CRP) were measured at study entry and after 8 weeks in both groups, without changing of antihypertensive medications. In Treatment group an improvement in RQLQ, significant reduction of systolic BP (SBP) (DSBP 7.4+/-4.3 mm Hg, P=0.006) and reduction of hs-CRP level (DCRP 2.05+/-1.08; P=0.028) were observed, whereas diastolic BP (DBP) remained unchanged (DDBP 0.9+/-1.7 mm Hg, P=0.7). There was a significant correlation between DRQLQ and DSBP (r=0.86; P=0.019) and between DCRP and DSBP (r=0.56; P=0.027). No statistically significant changes of RQLQ, BP and CRP were observed in the control group. In patients with coincidence of AH and AR, medications meant to improve AR attenuate low-grade systemic inflammation and can lower SBP, but not DBP.Journal of Human Hypertension advance online publication, 7 September 2006; doi:10.1038/sj.jhh.1002088.

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Proc Am Thorac Soc. 2006 Sep;3(7):594-600.
Medical therapies for chronic thromboembolic pulmonary hypertension: an evolving treatment paradigm.
Bresser P, Pepke-Zaba J, Jais X, Humbert M, Hoeper MM.
Department of Pulmonology, Academic Medical Center (AMC), P.O. Box 22660, Amsterdam 1100 DD, The Netherlands. p.bresser@amc.uva.nl.

Pulmonary endarterectomy (PEA) is recommended as the treatment of choice for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, only a proportion of patients fulfill the criteria for surgical intervention. In addition, operated patients with CTEPH may experience a gradual hemodynamic and symptomatic decline related to a secondary hypertensive arteriopathy in the small precapillary pulmonary vessels. It has also been questioned what can be done to reduce risks from PEA surgery to improve outcome in "high risk" patients with CTEPH with substantial impairment of pulmonary hemodynamics before surgery. Such patients may benefit from preoperative reduction of pulmonary vascular resistance by means of medical therapy. Conventional medical treatments, such as anticoagulation, diuretics, digitalis, and chronic oxygen therapy, show low efficacy in the treatment of CTEPH as they do not affect underlying disease processes. Over the last decade, several novel therapies have been developed for pulmonary arterial hypertension (PAH), including prostacyclin analogs (epoprostenol, beraprost, iloprost), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase-5 inhibitors (sildenafil). Evidence of efficacy in PAH, coupled with studies showing histopathologic similarities between CTEPH and PAH, provides a rationale to extend the use of some of these medications to the treatment of CTEPH. However, direct evidence from clinical trials in CTEPH is limited to date. This article reviews evidence supporting, and issues surrounding, the possible use of novel PAH medications in CTEPH.

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Int J Clin Pharmacol Ther. 2006 Aug;44(8):344-57.
Nebivolol: a review of its clinical and pharmacological characteristics.
Gielen W, Cleophas TJ, Agrawal R.
European College of Pharmaceutical Medicine, Lyon, France.

Nebivolol is a cardioselective lipophilic beta-blocker devoid of intrinsic sympathomimetic and membrane-stabilizing actions. The pharmacological profile differs from that of conventional cardioselective beta3-blockers in that it displays nitric oxide- (NO) mediated vasodilator activity. The net hemodynamic effect of nebivolol is the result of a balance between the depressant effects of beta3-blockade and an action that tends to maintain cardiac output, presumably connected with its afterload reducing vasodilator effect. Recent studies suggest that nebivolol may also restore endothelial dysfunction. Long-term follow-up studies indicate that the compound is efficacious and safe both in patients with mild hypertension and those with stable angina. An interesting effect of chronic nebivolol therapy in elderly patients with mild hypertension is the reversal of a depressor effect into a pressor effect on standing. This action indicates that nebivolol has advantages over other antihypertensive drugs and that it may protect elderly hypertensive patients from orthostatic complaints. The observation that nebivolol improves exercise capacity in non-claudicant hypertensives is also of clinical interest. Nebivolol resembles serotonin reuptake inhibitors in that it is metabolized by CYP450 2D6 and, therefore, concomitant treatment with serotonin uptake inhibitors may lead to overdosing. Nebivolol compared to placebo does not significantly reduce the mortality risk in elderly subjects. The effects of biological age and comorbidities may be responsible for this finding. In conclusion, clinical studies suggest that nebivolol is effective and safe in patients with hypertension, angina pectoris and heart failure. The beneficial effects on endothelial function, autonomic control and exercise capacity are of considerable clinical interest.

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J Hum Hypertens. 2006 May 4; [Epub ahead of print]
Aggressive antihypertensive strategies based on hydrochlorothiazide, candesartan or lisinopril decrease left ventricular mass and improve arterial compliance in patients with type II diabetes mellitus and hypertension.
Spoelstra-de Man AM, van Ittersum FJ, Schram MT, Kamp O, van Dijk RA, Ijzerman RG, Twisk JW, Brouwer CB, Stehouwer CD.
[1] 1Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands [2] 2Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.

We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on left ventricular mass (LVM) index and arterial stiffness in hypertensive type II diabetic individuals. Seventy hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mm Hg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mm Hg. After titration, patients were treated for 12 months. Mean blood pressures were 157/93, 151/94 and 149/93 mm Hg at baseline in the hydrochlorothiazide (n=24), candesartan (n=24) and lisinopril (n=22) groups, and 135/80, 135/82 and 131/80 mm Hg after titration. About 70% reached target blood pressures, with the median use of three antihypertensive drugs. Left ventricular mass index and all estimates of arterial stiffness showed significant improvement after 12 months: that is, LVM index (-11 g/m(2); -8%); carotid distensibility coefficient (DC; +2.8 x 10(-3) kPa(-1); +27%), compliance coefficient (CC; +0.13 mm(2)/kPa; +21%) and elastic modulus (-0.19 kPa; -16%); femoral DC (+1.6 x 10(-3) kPa(-1); +50%) and CC (+0.08 mm(2)/kPa; +26%); brachial DC (+2.1 x 10(-3) kPa(-1); +39%) and CC (+0.03 mm(2)/kPa; +27%) and total systemic arterial compliance (+0.29 ml/mm Hg; +16%). No differences in outcome variables between treatment groups were observed. Aggressive antihypertensive treatment, although difficult to achieve, resulted in substantial reductions of LVM index and arterial stiffness in relatively uncomplicated hypertensive type II diabetic individuals. Strategies based on renin-angiotensin system inhibitors were not clearly superior to conventional (i.e. diuretic-based) strategies.Journal of Human Hypertension advance online publication, 4 May 2006; doi:10.1038/sj.jhh.1002025.

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J Hum Hypertens. 2006 May 4; [Epub ahead of print]
Blood pressure response to calcium supplementation: a meta-analysis of randomized controlled trials.
van Mierlo LA, Arends LR, Streppel MT, Zeegers MP, Kok FJ, Grobbee DE, Geleijnse JM.
1Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.

Calcium plays a role in blood pressure (BP) regulation, but the importance of supplemental calcium intake for the prevention of hypertension is still debated. We conducted a meta-analysis of randomized controlled trials to determine the effect of calcium supplementation on BP. A systematic search for randomized trials of calcium supplementation and BP in non-pregnant subjects was performed in Medline from 1966 to June 2003. Seventy-one trials were identified, 40 of which met the criteria for meta-analysis (total of 2492 subjects). Two persons independently extracted data from original publications on changes in calcium intake and BP. In addition, data were collected on subjects' characteristics, that is, age, gender, initial BP and initial calcium intake. A random effects model was used to obtain the effect of calcium supplementation on BP, overall and in predefined population subgroups. Calcium supplementation (mean daily dose: 1200 mg) reduced systolic BP by -1.86 mm Hg (95% confidence interval: -2.91 to -0.81) and diastolic BP by -0.99 mm Hg (-1.61 to -0.37). In people with a relatively low calcium intake (</=800 mg per day) somewhat larger BP estimates were obtained, that is, -2.63 (-4.03 to -1.24) for systolic BP and -1.30 (-2.13 to -0.47) for diastolic BP. Our study suggests that an adequate intake of calcium should be recommended for the prevention of hypertension. More research on BP in people with calcium-deficient diets is warranted.Journal of Human Hypertension advance online publication, 4 May 2006; doi:10.1038/sj.jhh.1002038.

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Circulation. 2006 May 1; [Epub ahead of print]
Role of Diuretics in the Prevention of Heart Failure. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.
Davis BR, Piller LB, Cutler JA, Furberg C, Dunn K, Franklin S, Goff D, Leenen F, Mohiuddin S, Papademetriou V, Proschan M, Ellsworth A, Golden J, Colon P, Crow R.
University of Texas School of Public Health, Houston; National, Heart, Lung, and Blood Institute, Bethesda, Md; Wake Forest University School of Medicine, Winston-Salem, NC; University of California at Irvine, Irvine; University of Ottawa Heart Institute, Ottawa, Ontario, Canada; Creighton Cardiac Center, Omaha, Neb; Veterans Affairs Medical Center, Washington, DC; University of Washington, Seattle; Penderbrook Medical Center, Fairfax, Va; Centro Cardiovascular de Caguas, Caguas, Puerto Rico; and University of Minnesota, Minneapolis.

BACKGROUND: Hypertension is a major cause of heart failure (HF) and is antecedent in 91% of cases. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) stipulated assessment of the relative effect of chlorthalidone, lisinopril, and amlodipine in preventing HF. METHODS AND RESULTS: ALLHAT was a double-blind, randomized, clinical trial in 33 357 high-risk hypertensive patients aged >/=55 years. Hospitalized/fatal HF outcomes were examined with proportional-hazards models. Relative risks (95% confidence intervals; P values) of amlodipine or lisinopril versus chlorthalidone were 1.35 (1.21 to 1.50; <0.001) and 1.11 (0.99 to 1.24; 0.09). The proportional hazards assumption of constant relative risk over time was not valid. A more appropriate model showed relative risks of amlodipine or lisinopril versus chlorthalidone during year 1 were 2.22 (1.69 to 2.91; <0.001) and 2.08 (1.58 to 2.74; <0.001), and after year 1, 1.22 (1.08 to 1.38; P=0.001) and 0.96 (0.85 to 1.10; 0.58). There was no significant interaction between prior medication use and treatment. Baseline blood pressures were equivalent (146/84 mm Hg) and at year 1 were 137/79, 139/79, and 140/80 mm Hg in those given chlorthalidone, amlodipine, and lisinopril. At 1 year, use of added open-label atenolol, diuretics, angiotensin-converting enzyme inhibitors, and calcium channel blockers in the treatment groups was similar. CONCLUSIONS: HF risk decreased with chlorthalidone versus amlodipine or lisinopril use during year 1. Subsequently, risk for those individuals taking chlorthalidone versus amlodipine remained decreased but less so, whereas it was equivalent to those given lisinopril. Prior medication use, follow-up blood pressures, and concomitant medications are unlikely to explain most of the HF differences. Diuretics are superior to calcium channel blockers and, at least in the short term, angiotensin-converting enzyme inhibitors in preventing HF in hypertensive individuals.

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Rev Med Suisse. 2006 Apr 5;2(60):942-6.
[When can the treatment of isolated systolic hypertension be avoided?]
[Article in French]
Vischer UM, Benetos A.
Hopital de geriatrie 3, ch. Du Pont Bochet 1226 Thonex. ulrich.vischer@hcuge.ch

The treatment of isolated systolic hypertension (ISH) in the elderly reduces the cardiovascular (CV) risk, in particular in patients with diabetes or previous CV events. However, in the very old (> 80-85 years) the treatment of ISH may increase global mortality, although it still decreases the risk of stroke. The benefits of treatment on the risk of dementia remain uncertain. To verify the indication for therapy, the diagnosis of ISH should be confirmed by ambulatory blood pressure monitoring. Since the absolute benefit of treatment is related to its duration, a limited life expectancy may restrict the real impact of treatment. The advantages and limitations of anti-hypertensive therapy in the elderly should be discussed individually, respecting the patient's autonomy.

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Crit Care Med. 2006 Apr 25; [Epub ahead of print]
Treatment of acute hypertension in patients with intracerebral hemorrhage using American Heart Association guidelines*
Qureshi AI, Harris-Lane P, Kirmani JF, Ahmed S, Jacob M, Zada Y, Divani AA.
>From the Clinical Trials Division, Zeenat Qureshi Stroke Research Center, Department of Neurology and Neurosciences, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ.

OBJECTIVE:: To determine the feasibility and safety of treatment of acute hypertension in patients with intracerebral hemorrhage within 24 hrs of symptom onset. Elevated blood pressure, observed in up to 56% of patients with intracerebral hemorrhage, may predispose to hematoma expansion; on the other hand, reduction of blood pressure may reduce hematoma expansion and subsequent death and disability. DESIGN:: Single-center prospective registry supplemented by retrospective chart review. SETTINGS:: University-affiliated medical center with dedicated stroke service. PATIENTS:: All patients admitted to the stroke service with spontaneous intracerebral hemorrhage and acute hypertension within 24 hrs of symptom onset. INTERVENTION:: Patients were treated with intravenous nicardipine within 24 hrs of symptom onset to reduce and maintain mean arterial pressure of <130 mm Hg. The mean arterial pressure goal was consistent with the American Heart Association guidelines. MEASUREMENTS AND MAIN RESULTS:: The primary outcome was the tolerability of the treatment as assessed by achieving and maintaining the mean arterial pressure goals for 24 hrs after initiation of intravenous nicardipine infusion. Other end points ascertained were: neurologic deterioration defined by a decline in Glasgow Coma Scale from pretreatment assessment by >/=2 points or increase in National Institutes of Health Stroke Scale score by >/=2 points and hemorrhage growth defined as an increase in the volume of intraparenchymal hemorrhage of >33% as measured by image analysis on the 24-hr computed tomographic scan compared with the baseline computed tomographic scan. Rates of favorable outcome and death were ascertained at 1 month. Of the total 46 patients admitted with intracerebral hemorrhage in our service, 29 patients were treated. Mean age of the treated patients was 58 +/- 13 yrs; ten were women. Initial National Institutes of Health Stroke Scale ranged from 1 to 38. The primary outcome of tolerability was achieved in 25 of the 29 patients (86%). Neurologic deterioration was observed in 4 of 29 patients. Hematoma enlargement was observed in five patients. Favorable outcome (defined as modified Rankin scale of </=2) and death at 1-month mortality was observed in 11 (38%) and 9 (31%) of the 29 patients, respectively. CONCLUSIONS:: We observed a high rate of tolerability among patients with intracerebral hemorrhage who were treated with intravenous nicardipine using mean arterial pressure goals de- fined by American Heart Association guidelines within 24 hrs of symptom onset.

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J Clin Hypertens (Greenwich). 2006 Jan;8(1 Suppl 1):31-9.
Building on the Specialist's Antihypertensive Treatment Recommendation: It's Just the Beginning.
Saunders E.
University of Maryland School of Medicine, Baltimore, MD 21201 esaunder@medicine.umaryland.edu.

Patients with established cardiovascular disease are a top priority for preventive medicine. Evidence from clinical trials supports the merits of aggressive risk reduction therapies in survivors of an acute event. Improving their cardiovascular risk factor profile prolongs survival, reduces the incidence of recurrent atherosclerotic events, and improves quality of life. Blood pressure (BP) control is an essential component of cardiovascular disease secondary prevention programs; however, many patients are not receiving adequate antihypertensive therapy to meet their BP goal. By building on the specialist's discharge antihypertensive prescription, primary care physicians are ideally positioned to assume responsibility for ensuring BP goals are achieved and maintained over the long term in patients who have survived an acute event. Current hypertension management guidelines define appropriate BP goals and incorporate clear advice on how these goals can be met. BP should be lowered slowly and carefully through lifestyle modifications and pharmacologic therapy. Antihypertensive treatment should be given according to guidelines for primary prevention, although specific antihypertensive classes are indicated for initial use in post-myocardial infarction and post-stroke patients. In many cases, BP goal attainment will require the use of combination therapy with two or more drugs from different classes. With the availability of effective and safe antihypertensive drug therapies, including fixed-dose combinations, a BP goal of <140/90 mm Hg should be achievable in most patients.

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J Clin Hypertens (Greenwich). 2006 Jan;8(1 Suppl 1):21-30.
Hypertension-related morbidity and mortality in african americans-why we need to do better.
Ferdinand KC, Saunders E.
Heartbeats Life Center, Xavier University College of Pharmacy, New Orleans, LA kcferdmd@aol.com.

Almost one third of adults in the United States have hypertension. Prevalence data among different racial or ethnic groups indicate that a disproportionate number of African Americans have hypertension compared with non-Hispanic whites and Mexican Americans. Earlier onset of high blood pressure and greater severity of hypertension contribute to a greater burden of hypertensive target organ damage in African Americans and may be a factor in the shorter life expectancy of this population compared with white Americans. There is a clear need for improved management of hypertension in African Americans via therapeutic lifestyle interventions and pharmacotherapy. While there is some evidence that particular antihypertensive agent classes provide blood pressure-lowering advantages over others, there is no support for withholding agents of any one class. When given as monotherapy, diuretics and calcium channel blockers may be relatively more effective in lowering blood pressure in African Americans than beta blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. However, when combined with a diuretic, African Americans respond as well to these agents as other racial groups. Combination therapy using antihypertensive agents with differing modes of action provides additive antihypertensive efficacy and is well tolerated. Recent guidelines recommend combination therapy as the standard of care for patients with significant blood pressure elevation, especially those with diabetes mellitus and renal disease. These comorbidities are more common in African Americans and indicate the potential need for initial therapy with more than one agent or a combination of agents in one pill.

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J Clin Hypertens (Greenwich). 2006 Jan;8(1 Suppl 1):12-20.
Hypertension-a treatable component of the cardiometabolic syndrome: challenges for the primary care physician.
Manrique CM, Lastra G, Palmer J, Stump CS, Sowers JR.
University of Missouri-Columbia and Harry S. Truman VA Medical Center, Columbia, MO 65212 sowersj@health.missouri.edu.

Patients with the cardiometabolic syndrome (CMS) have an adverse cardiovascular risk factor profile, placing them at increased risk of stroke, coronary artery disease, chronic kidney disease, and type 2 diabetes mellitus. Although no specific treatments for CMS are available per se, prompt recognition and treatment of the individual components of the condition can prevent or delay the development of comorbidities. Primary care physicians are ideally positioned to identify patients with CMS and implement early intervention strategies. Hypertension contributes to many complications of CMS, and rigorous blood pressure control will help to delay or prevent end-organ vascular damage. Achieving blood pressure control to current guideline standards should be eagerly sought in the majority of patients through a combination of lifestyle modifications and appropriate pharmacologic therapy. Antihypertensive drug choice should be personalized, taking into account the CMS determinants present and any compelling indications for specific agents. As an initial approach, a thiazide diuretic is suitable for most cases of uncomplicated hypertension, although many patients will require additional antihypertensives from other classes to achieve their blood pressure goal. It is predicted that, due to the increase in unhealthy lifestyles, the prevalence of CMS will rise in the coming years. Therefore, by meeting the challenge of attaining and maintaining blood pressure control in patients with CMS, primary care physicians have the unique opportunity to markedly improve the health of the nation.

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J Clin Hypertens (Greenwich). 2006 Jan;8(1 Suppl 1):4-11.
Dispelling the myth of "aggressive" antihypertensive therapy.
Ofili EO.
Morehouse School of Medicine, Atlanta, GA 30310 eofili@msm.edu.

Data from well designed randomized trials have proven the effectiveness of an intensive approach to hypertension management in reducing morbidity and mortality. Based on these data, guidelines recommend a blood pressure goal of <140/90 mm Hg in the general population, with lower goals for high-risk patients. Clinical trials also show that most patients will require at least two antihypertensive agents to reach goal. Despite this evidence base, only about one third of individuals with hypertension receive sufficient therapy to attain a blood pressure of <140/90 mm Hg. Physicians may be reluctant to use multiple antihypertensive agents to achieve this goal because they may consider it to be "aggressive" and not always in the best interests of the patient, especially in those deemed at low risk. Such perceptions may be founded on several myths: 1) the approach demands a complex, time-consuming titration-to-response strategy, during which the patient may be lost to follow-up; 2) it increases the pill burden, which will decrease patient compliance; 3) it increases treatment-related side effects; and 4) it is not cost-effective. The availability of fixed-dose combinations containing two antihypertensive agents should help to dispel these myths. Careful selection of efficacious, well tolerated, once-daily, fixed-dose combinations allows goal blood pressure to be achieved quickly in a broad range of patients and encourages patient concordance with therapy. Such formulations are also cost-effective. Thus, reducing blood pressure using multiple drugs as fixed-dose combinations is a strategy that recognizes the multiple pathophysiologic changes that lead to hypertension.

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Tex Heart Inst J. 2005;32(4):467-71.
Management of systemic and pulmonary hypertension.
Levy JH.
Department of Anesthesiology, Emory University School of Medicine, and Cardiothoracic Anesthesiology, Emory Healthcare, Atlanta, Georgia, USA.

The major therapeutic approach to systemic and pulmonary hypertension and vasospasm in cardiac surgery patients involves the use of parenteral agents that reverse systemic vasoconstriction and produce vasodilation. Potential pharmacologic approaches include 1) alpha1-adrenergic receptor blockers, ganglionic blockers, and calcium channel blockers; 2) central alpha2-adrenergic receptor agonists, dopamine1-adrenergic receptor agonists, potassium channel modulators, and vascular cyclic nucleotide stimulators; 3) phosphodiesterase enzyme inhibitors, and 4) angiotensin-converting enzyme inhibitors. Of the currently available intravenous vasoactive therapies, the mainstay agents are the nitrovasodilators and the dihydropyridine-type calcium channel blockers. The nitrovasodilators, a diverse group of drugs that achieve vascular relaxation by stimulating cyclic nucleotides and thereby releasing nitric oxide, include nitroglycerin and sodium nitroprusside. Although these drugs are useful, rapid development of tolerance is a drawback to nitroglycerin, while nitroprusside can cause coronary steal and increase intracranial pressure. Intravenous dihydropyridine-type calcium channel blockers inhibit mechanical responses of cardiac muscle and vascular smooth muscle by blocking inward calcium currents. Nicardipine is an arterial specific vasodilator. Treatment for vasospasm is usually empiric; pharmacologic options include nitroglycerin, but dihydropyridine calcium channel blockers and phosphodiesterase inhibitors should also be considered.

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Z Kardiol. 2005 Dec;94(Supplement 4):iv19-iv23.
[Risk adapted therapy in vascular diseases: Antihypertensive treatment in peripheral arterial disease.]
[Article in German]
Sternitzky R.
Praxisklinik Herz und Gefasse Kardiologie-Angiologie-Radiologie-Nuklearmedizin, Forststr. 3, 01099, Dresden, r.sternitzky@praxisklinik-dresden.de.

Arterial hypertension must also be consistently treated in patients with PAD. Current guidelines and recommendations have to be considered, although in some patients the walk performance may be affected temporary by blood pressure dropping. In PAD, ideal antihypertensives are ACE inhibitors, AT1 receptor antagonists, calcium channel blockers and also alpha receptor blockers in combination. Beta receptor blockers-indicated in coronary heart disease-do not influence pain-free walking distance (PFWD) in patients with PAD. Diuretics should only be given in low dosage and in combination with other antihypertensive drugs in order to avoid a decrease of blood flow ability with clinical events.

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Prev Cardiol. 2006 Winter;9(1):35-41.
Optimal vascular protection: a case for combination antihypertensive therapy.
Vogel RA.
University of Maryland School of Medicine, Baltimore, MD 21201 rvogel@heart.umaryland.edu.

Endothelial dysfunction is an important factor in the pathogenesis of atherosclerosis, hypertension, and heart failure. The endothelium mediates vascular tone, structure, and function by the release and regulation of multiple vasoactive substances that promote or inhibit vasodilation, vasoconstriction, cell growth, and other mechanisms. The effect of antihypertensive drugs on endothelial function may be an important indicator of their ability to reduce risks for cardiovascular morbidity and mortality. Endothelium-dependent vasodilation induced by various antihypertensive drugs is accurately measured with high-resolution ultrasound of flow-mediated dilation of the brachial artery. Calcium channel blockers and angiotensin-converting enzyme inhibitors have been shown to reverse endothelial dysfunction. The benefits of angiotensin-converting enzyme inhibitors and calcium channel blockers on the endothelium are believed to derive from their effects on nitric oxide production and antioxidant effects, possibly independent of blood pressure reduction. Due to their complementary mechanisms of action, it has been hypothesized that the combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker will provide superior cardiovascular protection, in part by producing an additive effect of increased nitric oxide availability, when compared with either agent alone.

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Diabetes Metab. 2005 Dec;31 Spec No 2:82-91.
Management of hypertension in elderly diabetic patients.
Blickle J.
Service de Medecine Interne, Diabete et Maladies Metaboliques, Hopitaux Universitaires de Strasbourg, Strasbourg, France.

Hypertension is a major vascular risk factor in the elderly diabetic. The benefit of proper management is well recognized, even if treatment has no influence on overall mortality or might even tend to increase it in very elderly subjects. Globally, the efficacy of the major classes of antihypertensive drugs, diuretics, beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin II receptor antagonists appears to be equivalent so that the therapeutic choice depends on the type of hypertension, systolic or systolic-diastolic, and the rapidity of the desired effect, co-morbid conditions, particularly coronary or renal disease, or drug tolerance. Blood pressure goals are similar to those in middle-aged persons, except in very old, frail or sick subjects.

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Pharmacol Rep. 2005;57 Suppl:97-107.
Polyphenols as potential therapeutical agents against cardiovascular diseases.
Curin Y, Andriantsitohaina R.
Laboratoire de Pharmacochimie de la Communication Moleculaire, UMR 7081 CNRS, Faculte de Pharmacie, 74 route du Rhin, 67401 Illkirch, France. ramaroson.andriantsitohaina@univ-angers.fr.

Increasing evidence suggests that polyphenols from fruits, vegetables and beverages such as wine and tea may exert protective effects on the cardiovascular system. Indeed, research in the field of polyphenols points out their antioxidant and free radical scavenging properties, leading to lower low-density lipoprotein (LDL) oxidation and platelet aggregation. These compounds are also able to modulate the generation of nitric oxide (NO) from vascular endothelium and to interfere with the mechanisms leading to inflammation and endothelial apoptosis, contributing to the prevention of the endothelial dysfunction, known to play a central role in the pathogenesis of cardiovascular diseases. This article reviews the potential targets of polyphenols involved in the complex pathophysiological events occurring in cardiovascular diseases, such as hypertension, atherosclerosis and stroke.

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Can J Neurol Sci. 2005 Nov;32(4):403-8.
Hypertension and stroke: 2005 Canadian Hypertension Educational Program recommendations.
Boulanger JM, Hill MD; CHEP (Canadian Hypertension Educational Program).
Canadian Hypertension Educational Program, Foothills Hospital, Calgary, Alberta, Canada.

BACKGROUND: Hypertension is the most important modifiable cause of stroke. The Canadian Hypertension Educational Program, representing Canada's experts in the field of hypertension, publishes annual evidence-based recommendations on the diagnosis and treatment of hypertension. METHODS: We present the 2005 Canadian Hypertension Educational Program guidelines regarding the management of hypertension in patients with stroke. RESULTS: The diagnosis of hypertension should be expedited and can be made as early as the second visit in patients with stroke. Unless contraindicated, a combination of angiotensin-converting-enzyme (ACE) inhibitors and diuretics is the preferred therapy in these patients. A target blood pressure below 140/90 mmHg for non-diabetic patients, below 130 mmHg/80 mmHg for diabetic patients and below 125 mmHg/75 mmHg for those with renal disease and proteinuria (> 1 gram per day) should be reached. Lifestyle interventions may be as effective as medication and should be used in conjunction with medical management. Waist circumference should be less than 102 cm for men and 88 cm for women. There remains uncertainty about the management of high blood pressure in the context of acute stroke. CONCLUSIONS: A combination of ACE-inhibitors and diuretics is recommended in hypertensive stroke patients. Blood pressure should be maintained below 140/90 mmHg.

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J Hypertens. 2005 Nov;23(11):2083-92.
Adding hydrochlorothiazide to olmesartan dose dependently improves 24-h blood pressure and response rates in mild-to-moderate hypertension.
Sellin L, Stegbauer J, Laeis P, Rump LC.
aKlinikum der Ruhr-Universitat Bochum, Marienhospital Herne, Bochum bSankyo Pharma, Munich, Germany.

OBJECTIVE: To test whether adding hydrochlorothiazide (HCTZ) (12.5 or 25 mg) to olmesartan 20 mg improves 24-h blood pressure in patients whose conventional diastolic blood pressure is inadequately controlled by olmesartan monotherapy. PATIENTS: Male and female patients >/= 18 years with mean sitting diastolic blood pressure (DBP) of 100-115 mmHg, mean sitting systolic blood pressure (SBP) greater than 150 mmHg, mean 24-h DBP of at least 84 mmHg, and at least 30% of DBP daytime readings > 90 mmHg. INTERVENTIONS: Four weeks of single-blind treatment with olmesartan 20 mg once daily, followed in non-responders by 8 weeks of randomized double-blind treatment with placebo or HCTZ (12.5 or 25 mg) once-daily, added to olmesartan. RESULTS: HCTZ 25 mg added to olmesartan 20 mg decreased mean daytime DBP significantly more (P = 0.0012) than placebo added to olmesartan 20 mg. Compared to olmesartan monotherapy, mean 24-h DBP and SBP were significantly reduced by combination therapy with olmesartan/HCTZ 20/12.5 mg (-1.9 mmHg, P = 0.0167 and -3.9 mmHg, P = 0.0018, respectively) and 20/25 mg (-3.7 and -7.4 mmHg respectively, P < 0.0001 for both). Mean 24-h DBP and SBP and mean night-time SBP reductions were significantly greater for HCTZ 25 mg than for HCTZ 12.5 mg. Response rates (mean daytime DBP assessed by ambulatory blood pressure measurement </= 85 mmHg) approximately doubled following the addition of HCTZ (12.5 mg = 57.6% and 25 mg = 69.5%). CONCLUSION: Combination of olmesartan 20 mg with HCTZ provides significantly better 24-h blood pressure reduction than olmesartan monotherapy in patients with mild-to-moderate hypertension. Moreover, increasing the dose of HCTZ from 12.5 to 25 mg is a reasonable step to reach better daytime and night-time blood pressure control.

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J Hypertens. 2005 Nov;23(11):1947-51.
How many alcoholic drinks might benefit an older person with hypertension?
Bulpitt CJ.
Faculty of Medicine, Imperial College London, UK.

Lowering alcohol intake reduces blood pressure and hence cardiovascular risk. However, abstainers have an increase in cardiovascular risk and the advice to reduce intake to low levels may not be sound. This review examines the effects of lowering alcohol consumption in terms of blood pressure and coronary heart disease (CHD). The relationship between both CHD and stroke and alcohol consumption, and the benefits and disadvantages of alcohol consumption in the general population, are discussed. Where available, the results of large meta-analyses are reported. It is concluded that the hypertensive patient over the age of 60 who drinks over 16 drinks per week should be advised to reduce his or her alcohol intake but a daily drink may be advisable and the patient should not stop drinking entirely. It is not suggested that the non-drinker should start drinking, but most hypertensives are over the age of 60 when community studies suggest that drinking alcohol does more good than harm.

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Am J Hypertens. 2005 Oct;18(10):1360-3.
Antihypertensive effect of sweetie fruit in patients with stage I hypertension.
Reshef N, Hayari Y, Goren C, Boaz M, Madar Z, Knobler H.
Metabolic Unit, Kaplan Medical Center, Rehovot, Israel.

BACKGROUND: Interventional studies have shown that increased intake of fruit and vegetables reduces blood pressure (BP). However, the contribution of specific dietary components has not been evaluated. The aim of the present study was to determine, in patients with stage I hypertension, the antihypertensive effect of juice of the so-called sweetie fruit (a hybrid between grapefruit and pummelo) with and without high flavonoid content. METHODS: A double-blind, cross-over study was conducted in 12 patients. Each patient received alternately high-flavonoid (HF) sweetie juice and low-flavonoid (LF) sweetie juice, each for a 5-week period. The LF sweetie juice had 25% of naringin and 30% of narirutin content compared with the original HF sweetie juice. RESULTS: The HF sweetie juice was more effective than LF sweetie juice in reducing diastolic blood pressure (P = .04). Systolic blood pressure declined in both groups; however there was no significant difference between subjects given HF sweetie versus those given LF sweetie juice. CONCLUSIONS: In this study HF sweetie juice was shown to have a significant beneficial effect in reducing diastolic blood pressure, compared with the effect observed with LF sweetie juice, in patients with stage I hypertension. These data suggest that the active ingredients associated with the antihypertensive effect of sweetie juice are the flavonoids naringin and narirutin.

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Am J Hypertens. 2005 Oct;18(10):1313-9.
Felodipine-metoprolol combination tablet: maintained health-related quality of life in the presence of substantial blood pressure reduction.
Dahlof B, Degl' Innocenti A, Elmfeldt D, Puig JG, Gundersen T, Hosie J, Januszewicz W, Lindstrom CJ, Magometschnigg D, Tanser P, Toutouzas P, Waeber B, Wiklund I.
Clinical Experimental Research Laboratory, Department of Medicine, Sahlgrenska University Hospital/Ostra, Goteborg, Sweden.

BACKGROUND: Most treated hypertensive patients do not achieve adequate blood pressure (BP) control. Initiating therapy with two drugs has been suggested when BP is >20/10 mm Hg above goal. To ensure patients' compliance, such treatment needs to be well tolerated and must not compromise health-related quality of life (HRQL). The primary objective of this study was to compare the effects on HRQL of initiating treatment with felodipine + metoprolol (F+M) fixed combination tablets, or enalapril (E), or placebo (P). METHODS: A total of 947 patients of both sexes with primary hypertension (diastolic BP 95 to 110 mm Hg), aged 20 to 70 years, participated in this randomized, double-blind, parallel group, 12-week, multicenter trial. Treatment was initiated with F+M 5 + 50 mg, or E 10 mg, or P. Doses were doubled after 4 or 8 weeks if diastolic BP was >90 mm Hg. The HRQL was measured at baseline and at the last visit using two validated questionnaires: the Psychological General Well-being Index (PGWB) and the Subjective Symptom Assessment Profile (SSA-P). Office BP was measured at trough, that is, 24 h after the previous dose. RESULTS: The HRQL was high at baseline and generally well maintained during the study. For example, the mean (SD) PGWB total score was 104 (16) at baseline and 105 (16) at 12 weeks in all three treatment groups. The BP reductions after F+M (18/14 mm Hg) and E (12/9 mm Hg) were significantly greater than after P (7/7 mm Hg), and the reduction after F+M was significantly greater than after E. CONCLUSIONS: The HRQL is maintained in the presence of substantial BP reduction during antihypertensive treatment with F+M fixed combination tablets.

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Am J Hypertens. 2005 Oct;18(10):1300-1305.
Increased Sodium Intake Correlates With Greater Use of Antihypertensive Agents by Subjects With Chronic Kidney Disease.
Boudville N, Ward S, Benaroia M, House AA.
Department of Medicine, University of Western Ontario, London, Ontario, Canada; Division of Nephrology, London Health Sciences Centre, London, Ontario, Canada; School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.

BACKGROUND: Hypertension is a common disease in patients with chronic kidney disease (CKD) and predisposes to heart disease, stroke, and progression of renal failure. In the general population, sodium restriction has been shown to improve blood pressure (BP) control, but this is not widely recommended in CKD patients. The aim of this study was to assess the sodium balance in a CKD clinic and its effect on BP management. METHODS: We retrospectively reviewed charts from June 1998 through to June 2003 and included all patients with an estimated glomerular filtration rate (GFR) of <30 mL/min who completed a 24-h urine collection for sodium. Patients were divided into tertiles based upon their 24-h sodium excretion and analyzed by ANOVA. RESULTS: We included 141 CKD patients who had a mean (+/- SE) sodium excretion of 145.7 +/- 4.7 mmol/day. There were a significantly greater number of antihypertensive agents used with increasing sodium excretion (2.00 +/- 0.16, 2.61 +/- 0.20, and 2.77 +/- 0.19 medications, respectively for each tertile; P = .01). This difference was even more prominent when only those patients with a GFR </=15 mL/min (n = 77) were examined (1.69 +/- 0.19, 2.52 +/- 0.27, and 3.08 +/- 0.26 medications, respectively; P = .001). Control of BP was equivalent in all groups. Multivariable analysis revealed sodium excretion (P = .00005) and age (P = .007) to be significantly associated with use of antihypertensive medication. CONCLUSIONS: We have demonstrated that increased sodium intake is associated with an increased number of antihypertensive medications to achieve comparable BP control in a population with CKD.

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Semin Nephrol. 2005 Jul;25(4):261-71.
Renovascular hypertension: current concepts.
Garovic V, Textor SC.
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.

Hypertension produced by renal artery occlusive disease is an important secondary form of hypertension. Clinicians commonly encounter forms of renal arterial disease of varying severity, many of which are of little hemodynamic significance when first detected. Experimental studies emphasize that transient activation of the renin-angiotensin-aldosterone system is necessary for initiation of renovascular hypertension. At some point, angiotensin II activates additional mechanisms responsible for sustained increased blood pressure including sodium retention, endothelial dysfunction, and vasoconstriction related to production of reactive oxygen species. Widespread application of agents that block the renin-angiotensin system, including angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, render many patients with unilateral renal arterial disease manageable primarily by medical means for many years. In the setting of high a priori likelihood of renovascular disease, recognizing the potential for disease progression during medical therapy and individually evaluating the risks and benefits of renal revascularization are important tasks. Recent prospective studies show limited, but real, benefit regarding blood pressure control for patients with atherosclerotic disease. Whether earlier renal revascularization offers benefits regarding improved morbidity and mortality from cardiovascular end point reduction is an important question to be addressed in multicenter, prospective, randomized trials. Our paradigm stresses the fact that patients with renovascular hypertension require intensive blood pressure control and cardiovascular risk factor intervention, both before and after revascularization. Hence, management of such patients requires close attention and periodic review regarding restenosis and progression of vascular disease.

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Semin Nephrol. 2005 Jul;25(4):252-60.
Hypertension in kidney transplantation.
Castillo-Lugo JA, Vergne-Marini P.
Dallas Nephrology Associates, Dallas TX; and the Transplantation and Renal Disease Unit, Methodist Medical Center, Dallas, TX.

Arterial hypertension in renal transplant patients plays a major role in the progression to chronic allograft failure, and in morbidity and mortality associated with cardiovascular disease. Its cause is diverse, with contributions not only from donor and/or recipient factors, but it also is influenced strongly by the type of immunosuppressive regimen. Despite increased awareness of the adverse effects of hypertension in both graft and patient survival, long-term studies have shown that arterial hypertension in the transplant population has not been controlled adequately. Ambulatory blood pressure measurements provide the advantage of a better assessment of the diurnal blood pressure variation, a predictor of target organ damage and cardiovascular morbidity and mortality events. Although the available data do not support the recommendation of any class of antihypertensive medication as preferred agents for blood pressure management in the transplant population, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers have shown beneficial effects beyond their antihypertensive effects. Clinical data in transplant recipients are emerging that suggest that applying interventions proven to be effective in reducing cardiovascular morbidity and mortality in the general population may be effective for the transplant population.

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Semin Nephrol. 2005 Jul;25(4):236-45.
Hypertension and the kidney.
Wiederkehr M, Toto R, Fenves AZ, Ram CV.
Baylor University Medical Center; Dallas Nephrology Associates; Dallas Texas.

Hypertension is an important and widely prevalent risk factor for the development of chronic kidney disease (CKD), which unfortunately may progress to end-stage renal disease. CKD is a progressive condition that causes significant morbidity and mortality. Diabetes is the leading cause of end-stage renal disease in the Western world. Both hypertension and diabetes are the causative factors for the occurrence of CKD and its consequences. Aggressive control of hypertension and diabetes is indicated to reduce the risk for kidney disease in the community. Certainly, effective control of hypertension is a proven modality to prevent renal disease. The concept of decreasing the systemic blood pressure as well as the intraglomerular pressure has led to the application of rational therapeutic options in patients with renal insufficiency. Although treatment of hypertension alone is critical, drugs that block the renin-angiotensin system have been shown to have special renal (and cardiovascular) benefits. Early detection and treatment of microalbuminuria is an integral part of disease management. This article reviews the pathophysiologic and therapeutic implications of the link between hypertension and the kidney.

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Semin Nephrol. 2005 Jul;25(4):227-35.
Therapeutic controversies in hypertension.
Messerli FH, Grossman E.
St. Lukes-Roosevelt Hospital Center, New York, NY; Internal Medicine D and Hypertension Unit, The Chaim Sheba Medical Center, Tel-Hashomer, Israel.

Although numerous prospective randomized trials since the Veterans Administration studies clearly have attested to the efficacy and safety of antihypertensive therapy, there remain some controversial issues with all classes of antihypertensive drugs. Thiazide diuretics increase the risk for new-onset diabetes and their long-term safety has been questioned. Alpha-blockers do not reduce morbidity and mortality in uncomplicated hypertension but are well known to cause a variety of poorly tolerated side effects. The safety of calcium antagonists has been questioned for many years, although recent large prospective randomized trials such as Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, International Verapamil-Trandolapril Study, Intervention as a Goal in Hypertension, Valsartan Antihypertensive Long-Term Use Evaluation and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) have attested to their safety and efficacy. Angiotensin-converting enzyme inhibitors, in general, are well tolerated but have potentially fatal adverse effects in a few patients. Angiotensin-receptor blockers are exceedingly well tolerated, but may be less-efficacious antihypertensive agents than other drug classes. Most antihypertensive drug classes have an effect on new-onset diabetes that should be taken into account in patients at risk. No head-to-head comparison of combination therapy looking at efficacy and safety has been available. The long-term safety of antihypertensive therapy is documented poorly because most trials only last 4 to 6 years. Despite these drawbacks and concerns, the benefits of antihypertensive therapy clearly outweigh its potential risk.

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Semin Nephrol. 2005 Jul;25(4):198-209.
Hypertension treatment guidelines: practical implications.
Choi KL, Bakris GL.
Rush Hypertension Center, Department of Preventive Medicine, Rush University Medical Center, Chicago, IL.

The focus of blood pressure (BP) lowering is to prevent or reduce the risk for cardiovascular and renal events. This rationale forms the basis for the recent guideline statements issued by the Seventh Joint National Committee, the American Diabetes Association, the European Society of Hypertension, and the Kidney Disease Outcomes Quality Initiative. The goal BP in the majority of hypertensive patients should be less than 140/90 mm Hg, with a lower goal of less than 130/80 mm Hg in patients with diabetes or kidney disease. Meta-analyses of clinical trials with renal end points make it clear that the presence of 1 gram or more of proteinuria mandates a BP approaching 115 mm Hg to slow the progression of advanced nephropathy adequately. Compelling indications also exist for the use of certain antihypertensive agents in the setting of kidney dysfunction, diabetes, heart failure, and coronary artery disease. Initiation with 2 antihypertensive agents should be considered strongly for patients with a BP of more than 20 mm Hg greater than the systolic BP goal. This means that those with a goal BP of less than 130 mm Hg should be started on 2 antihypertensive medications with complementary actions when the systolic BP is 150 mm Hg or greater. In patients with kidney disease, reaching the BP goal requires multiple agents that should include an appropriate diuretic and an agent that blocks the renin-angiotensin-aldosterone system to slow the progression of kidney disease.

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Blood Press. 2005 Jul 1;14 Suppl 1:39-44.
A calcium-channel blocker, benidipine, improves forearm reactive hyperemia in patients with essential hypertension.
Makino H, Aoki M, Hashiya N, Yamasaki K, Shimizu H, Miwa K, Ogihara T, Morishita R.
Department of Geriatric Medicine, Osaka University Medical School, Osaka, Japan.

The pathophysiological role of endothelial cells is important in the mechanism of progression of atherosclerosis and improvement of endothelial function may be important for cardiovascular morbidity. Calcium antagonists are reported to have protective effects on the endothelium in vitro and in vivo. In this clinical study, we investigated the effect of calcium antagonist, benidipine, on endothelial function in the patients with essential hypertension, which causes endothelial dysfunction. Twenty-five patients with hypertension without other risk factors for atherosclerosis were treated with monotherapy (8 mg benidipine, n = 25) for 8 weeks. Blood pressure was reduced significantly. Endothelial function was evaluated using forearm blood flow by strain-gauge plethysmography after 8 weeks of treatment. Changes in vasodilator response to reactive hyperemia were significantly improved (p<0.01), while the response to nitroglycerin was not changed, suggesting the improvement of endothelial function. Moreover, we focused on hepatocyte growth factor (HGF), which is a novel angiogenic growth factor with an anti-apoptotic action on endothelial cells, and evaluated involvement of HGF in improvement of endothelial function. Serum HGF concentration in subjects treated with benidipine was significantly elevated at 8 weeks (p<0.05). Overall, these results demonstrated that benidipine improved endothelial dysfunction in patients with hypertension. Interestingly, an increase in serum HGF concentration by benidipine might contribute to the improvement of endothelial dysfunction.

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Blood Press. 2005 Jul 1;14 Suppl 1:23-31.
Effect of irbesartan monotherapy compared with ACE inhibitors and calcium-channel blockers on patient compliance in essential hypertension patients: A multicenter, open-labeled, three-armed study.
Koylan N, Acarturk E, Canberk A, Caglar N, Caglar S, Erdine S, Guneri S, Ilerigelen B, Kabakci G, Onder R, Sagkan O, Buyukozturk K.
Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey.

Objectives. This multicenter, three-armed, open-labeled study investigated patient compliance of patients receiving irbesartan, angiotensin-converting enzyme (ACE) inhibitors or calcium-channel blockers (CCB) for essential hypertension for a 6-month period. Patients were either newly diagnosed or switched from existing antihypertensive medication due to lack of efficacy or side-effects. Methods. Patients were started monotherapy with irbesartan (n = 377), ACE inhibitors (n = 298) or CCB (n = 308) and were reevaluated on 1st, 3rd, and 6th months of the treatment. The primary endpoint was patient compliance, assessed by proportion of patients who had taken their study medication every day. Efficacy was recorded as mean reductions in blood pressure and the proportion of patients whose blood pressure normalized. Tolerability was assessed by reported adverse events. Results. Significantly more patients receiving irbesartan had complied with study medication after 3 and 6 months of treatment than ACE inhibitors or CCB. Significantly fewer patients receiving irbesartan needed to change their antihypertensive medication. All three study treatments exhibited similar efficacy profiles, but irbesartan had significantly less adverse events. Conclusions. This study demonstrated that patient compliance to irbesartan was significantly superior to other study treatments. Irbesartan is therefore a suitable first-line therapy for essential hypertension in everyday clinical practice.

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Blood Press. 2005 Jul 1;14 Suppl 1:14-22.
Effects of nifedipine GITS 20 mg or enalapril 20 mg on blood pressure and inflammatory markers in patients with
mild-moderate hypertension.
Rosei EA, Morelli P, Rizzoni D.
Chair of Internal Medicine, Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy.

Objective. Calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and other drug classes either alone or in combination have been recommended for the treatment of hypertension. Nifedipine gastrointestinal therapeutic system (GITS) 20 mg is a new low-dose formulation with an improved tolerability. The aim of the present study was to compare the effects of nifedipine GITS 20 mg and enalapril 20 mg on blood pressure and circulating adhesion molecules in hypertensive patients. Methods. This randomized, double-blind, multicentre trial compared the blood pressure lowering effects of a 12-week treatment of nifedipine GITS 20 mg vs enalapril 20 mg in 264 patients with mild-to-moderate hypertension. Results. Nifedipine GITS 20 mg induced a reduction of clinic blood pressure, which was similar to that observed with enalapril 20 mg. Nifedipine GITS and enalapril lowered mean sitting diastolic blood pressure by 11.8 and 12.4 mmHg, respectively, while systolic blood pressure was reduced by 15.3 and 16.3 mmHg, respectively. Ambulatory blood pressure monitoring-derived blood pressure data showed similar results in both groups without any statistically significant differences between treatments. Both enalapril and nifedipine tended to reduce ICAM-1 and E-selectin, while only nifedipine reduced von Willebrand factor. Both treatments were well tolerated. Conclusions. Our findings demonstrate a similar antihypertensive effectiveness of a low dose (20 mg) of nifedipine GITS in comparison with a standard dose of enalapril (20 mg). Given its clinical efficacy and good tolerability, low-dose nifedipine GITS may be considered a valuable treatment option for hypertensive patients.

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Blood Press. 2005 Jul 1;14 Suppl 1:6-13.
Fixed combination of manidipine and delapril in the treatment of mild to moderate essential hypertension: Evaluation by 24-hour ambulatory blood pressure monitoring.
Mugellini A, Vaccarella A, Celentano A, Scanferla F, Zoppi A, Fogari R.
Dipartimento di Medicina Interna e Terapia Medica, Clinica Medica II, Universit di Pavia, IRCCS Policlinico San Matteo.

This present study assessed the antihypertensive efficacy of the fixed combination of manidipine and delapril by ambulatory blood pressure monitoring in patients with hypertension inadequately controlled by monotherapy with either component. After a 2-week placebo period, 55 mild to moderate hypertensive patients were randomized to manidipine 20 mg o.d. or delapril 30 mg b.i.d. for 4 weeks. After this period, 30 patients, aged 30-76 years (18 males and 12 females) whose diastolic blood pressure was not adequately controlled (>/=90 mmHg) by monotherapy were treated with the fixed combination of manidipine 10 mg plus delapril 30 mg o.d. for 8 weeks. A 24-h ambulatory blood pressure monitoring recording was performed at the end of the placebo washout, of the monotherapy and of the combination therapy. Blood pressure control over the 24 h was quantified by the trough-to-peak ratio and the smoothness index. As compared to placebo, the fixed combination of manidipine and delapril produced a statistically significant (p<0.01) decrease in sitting clinic (18+/-9/14+/-5 mmHg) and 24-h blood pressure (12+/-7/10+/-5 mmHg) without affecting heart rate. This reduction was greater than that observed with single components. At the end of the 8-week combination treatment period, the rate of normalilized patients was 73%. Treatment with the fixed combination was associated with a positively high smoothness index (1.2+/-0.7/13.8+/-0.8) and with a relatively good trough-to-peak ratio (0.46/0.60). The combination of manidipine and delapril produced significant and smooth reductions in blood pressure values, which persisted over the 24-h dosing interval. These results support the use of fixed manidipine-delapril combination in the treatment of mild to moderate hypertensive patients inadequately controlled by monotherapy.

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J Hum Hypertens. 2005 Jul 21; [Epub ahead of print]
Effects of low-dose aspirin on blood pressure and endothelial function of treated hypertensive hypercholesterolaemic subjects.
Magen E, Viskoper JR, Mishal J, Priluk R, London D, Yosefy C.
1WHO Collaborative Center for Prevention of CVD, Barzilai Medical Center, Ben Gurion University of Negev, Ashkelon, Israel.

The main objective of this study was to assess whether aspirin 100 mg QD can improve blood pressure (BP) control and endothelial function in subjects with arterial hypertension (AH) and hypercholesterolaemia. In total, 21 patients of both sexes (52.1+/-11.5 years) with treated AH and hypercholesterolaemia on antihypertensive and statin therapy were included in the treatment group. In the control group, 20 matched patients of both sexes (51.3+/-12.7 years), but without statin therapy, were recruited. Treatment group subjects received aspirin (100 mg QD) for a duration of 12 weeks at randomization (Treatment phase-1), followed by single blind matching placebo for 12 weeks (Placebo phase) and then again received aspirin (100 mg QD) for an additional 12 weeks (Treatment phase-2). The control group participated in Treatment phase-1, but did not continue Placebo phase and Treatment phase-2. At randomization and at the end of each study phase, mean 24-h systolic BP (SBP) and diastolic BP (DBP) were assessed by 24-h ambulatory blood pressure monitoring (ABPM) and endothelium-dependent (flow mediated, FMD) and -independent (nitroglycerin induced, NTG) vasodilatations of brachial artery were measured using high-resolution ultrasound. In Treatment phase-1, reduction of SBP and DBP (DeltaSBP 5.7+/-2.6 mmHg, P=0.008; DeltaDBP 3.8+/-1.7 mmHg, P=0.014) and improvement of FMD (4.1+/-0.6%, P=0.019), in Placebo phase an elevation of SBP and DBP (DeltaSBP -6.2+/-2.9 mmHg, P=0.002; DeltaDBP -4.2+/-1.9 mmHg, P=0.031) and worsening of FMD (-3.8+/-0.9%, P=0.027), and in Treatment phase-2 reduction of SBP and DBP (DeltaSBP 4.9+/-2.3 mmHg, P=0.005; DeltaDBP 4.1+/-1.3 mmHg, P=0.024) and improvement of FMD (4.5+/-1.3%, P=0.009) were observed in the treatment Group but not in the control group. Addition of low-dose aspirin to antihypertensive medications and statins in hypertensive and hypercholesterolaemic subjects can reduce both SBP and DBP by improvement of endothelial function.Journal of Human Hypertension advance online publication, 21 July 2005; doi:10.1038/sj.jhh.1001910.

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MMW Fortschr Med. 2005 Jun 23;147(25):38-40.
[Which cardiac patients may be allowed to travel by air?]
[Article in German]
Flesch M.
Klinik III fur Innere Medizin der Universitat zu Koln. markus.flesch@uni-koeln.de

During airline flights, cardiological patients in particular are put at stress by the decrease in pressure in the passenger cabin and the associated decrease in oxygen partial pressure in the blood. Possible risks are, in particular, rhythm disorders, myocardial ischemic states or an excessive increase in pulmonary artery pressure. Flight travel may be permitted at the earliest two weeks after a myocardial infarction or coronary event. It should be forbidden in patients with decompensated cardiac failure, instable angina pectoris, severe pulmonary arterial or arterial hypertension, uncontrolled arrhythmias and surgery on the heart within a period of 2 weeks prior to the intended flight.

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Curr Pharm Des. 2005;11(17):2235-42.
Antihypertensive therapy: role of aldosterone antagonists.
Grandi AM.
Professor of Internal Medicine, Department of Clinical Medicine, University of Insubria, Varese, Italy. amgrandi@libero.it

The interest for the therapeutic potential of aldosterone antagonists in essential hypertension comes from the recently discovered nonclassical pathways of aldosterone actions, above all the presence of extra-adrenal aldosterone production and the discovery of aldosterone's proinflammatory and profibrotic actions. The review begins with the discussion of experimental studies on animals, demonstrating the role of aldosterone in cardiovascular remodeling and the effects of aldosterone blockade on hypertensive target organ damage. Then recent clinical studies are presented, that confirm in humans the deleterious role of aldosterone, in particular in the development of myocardial hypertrophy, cardiovascular fibrosis and arterial stiffness. After a brief description of the new selective aldosterone antagonist, eplerenone, compared to the well-known non-selective aldosterone antagonist, spironolactone, the results of studies on essential hypertensive patients are discussed, evaluating the efficacy of aldosterone antagonists in lowering blood pressure, but, more important, in protecting against target organ damage.

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Int J Cardiol. 2005 May 11;101(1):97-104.
Doxazosin GITS versus standard doxazosin in mild to moderate hypertension.
Calvo C, Gil-Extremera B, Gomez-Fernandez P, Masramon X, Pueyo C, Armada B.
Unidad de Hipertension y Riesgo Vascular, Hospital Clinico Univeritario, Travesia de la Choupana s/n, 15706 Santiago de Compostela, Spain.

BACKGROUND: The selective alpha(1)-adrenoceptor antagonist doxazosin in both standard formulation and gastrointestinal therapeutic system (GITS) controlled-release formulation is effective for hypertension without having a negative impact on serum lipids. This study was designed to compare the relative efficacy of these two formulations of doxazosin on clinic and ambulatory blood pressure and serum lipids in patients with mild to moderate hypertension. METHODS: Hypertensive patients aged 18-70 years (n=335) were evaluated in a multi-center prospective randomized study. Following a 2-week placebo run-in phase, patients were randomized to receive doxazosin 2 or 4 mg, with dose titration, or doxazosin GITS 4 mg, no dose titration, for 9 weeks. RESULTS: Both doxazosin formulations reduced clinic diastolic and systolic blood pressure from baseline (P<0.0001). Doxazosin GITS and doxazosin 4 mg had similar blood pressure-lowering effects. Doxazosin GITS reduced sitting diastolic and systolic blood pressure compared with doxazosin 2 mg (P<0.01 for both). A greater proportion of the doxazosin GITS group reached goal blood pressure (</=140/90 mm Hg) after 9 weeks compared with the doxazosin 2-mg group. All doses of doxazosin reduced 24-h and daytime (7:00 am to 10:00 pm) ambulatory blood pressure from baseline (all P<0.01). Doxazosin GITS significantly reduced nighttime (10:00 pm to 7:00 am) ambulatory blood pressure from baseline. A neutral effect on serum lipids was observed with doxazosin. CONCLUSIONS: Doxazosin GITS and doxazosin were effective in reducing clinic and ambulatory blood pressure. The GITS formulation reduced the need for dose titration. Both doxazosin formulations were well tolerated.

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Am J Ophthalmol. 2005 May;139(5):855-9.
The use of acetazolamide in idiopathic intracranial hypertension during pregnancy.
Lee AG, Pless M, Falardeau J, Capozzoli T, Wall M, Kardon RH.
Departments of Ophthalmology, University of Iowa Hospitals and Clinics, Iowa City, Iowa; Neurology, University of Iowa Hospitals and Clinics, Iowa City, Iowa; Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa.

PURPOSE: To describe the pregnancy outcomes after the use of acetazolamide in pregnant patients with idiopathic intracranial hypertension (IIH). DESIGN: Observational case series. METHODS: setting: Two tertiary care academic neuro-ophthalmology units. patient population: Patients with IIH treated with acetazolamide. observation procedure: Documentation of pregnancy outcome. main outcome measures: Normal pregnancy, fetal loss, or congenital malformation. RESULTS: Twelve patients were treated with acetazolamide for IIH during pregnancy, and there were no adverse pregnancy outcomes. A critical review of the English language literature on the subject failed to demonstrate any convincing evidence for any adverse effect on pregnancy for acetazolamide. CONCLUSIONS: Acetazolamide at high doses may produce birth defects in animals, but there is little clinical or experimental evidence to support any adverse effect of the drug on pregnancy outcomes in humans. If the clinical situation warrants the use of acetazolamide in IIH, then the drug probably can be offered after appropriate informed consent.

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Prev Cardiol. 2005 Spring;8(2):87-92.
Effect of Fixed-Dose ACE-Inhibitor/Calcium Channel Blocker Combination Therapy vs. ACE-Inhibitor Monotherapy on Arterial Compliance in Hypertensive Patients With Type 2 Diabetes.
Winer N, Folker A, Murphy JA, Hung E, Bard M, Perkelvald A, Sowers JR, Bakris GL.
SUNY Downstate Medical Center, Brooklyn, NY nathaniel.winer@downstate.edu.

Assessment of vascular compliance may be a useful measurement of the clinical effects of antihypertensive treatment. Both angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers are known to improve vascular elasticity. A study was performed to test the hypothesis that combined therapy with an ACE inhibitor and a calcium channel blocker would have additive benefits on vascular compliance at similar levels of blood pressure (BP), as compared with monotherapy with an ACE inhibitor. This 12-week, double-blind study was a substudy of a larger clinical hypertension study conducted in patients with hypertension and type 2 diabetes. Subjects (N=20) were randomized to either a fixed-dose combination of amlodipine besylate/benazepril HCl or to enalapril monotherapy. BP, heart rate, large- and small-vessel compliance, systemic vascular resistance, and urinary microalbumin excretion were assessed at baseline and after treatment. Both treatments were similarly effective in lowering BP, reducing systemic vascular resistance, and decreasing urinary microalbumin excretion. Improvement in large-vessel compliance was significantly greater among subjects who received ACE-inhibitor/calcium channel blocker combination therapy (52%) as compared with those who received ACE-inhibitor monotherapy (32%; p<0.05). No significant change in small-vessel compliance was observed with either treatment. Greater improvement in large-vessel compliance with combination therapy was independent of BP lowering.

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J Clin Hypertens (Greenwich). 2005 Apr;7(4 Suppl 1):27-31.
Comparison of blood pressure control with amlodipine and controlled-release isradipine: an open-label, drug substitution study.
Ganz M, Mokabberi R, Sica DA.
Clinical Research Center of Cleveland, CCH-Eastern Region, Cleveland, OH mganz@cchseast.org.

An open-label drug substitution study showed that controlled-release isradipine (Dynacirc-CR) can be safely substituted for amlodipine on a mg-for-mg basis in patients with mild-to-moderate hypertension. When controlled-release isradipine was substituted for amlodipine, blood pressure was more effectively controlled, and edema rates were reduced. When subjects resumed amlodipine therapy, the previous gain in blood pressure reduction and lessening of edema vanished. The basis for this more favorable pattern of efficacy and side-effects with controlled-release isradipine, although mechanistically unresolved, may relate to a lesser degree of sympathetic nervous system activation.

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J Clin Hypertens (Greenwich). 2005 Apr;7(4 Suppl 1):15-20.
Management of hypertensive chronic kidney disease: role of calcium channel blockers.
Toto RD.
University of Texas Southwestern Medical Center, Dallas, TX robert.toto@utsouthwestern.edu.

Both the prevalence and incidence of end-stage renal disease have been increasing in the United States over the past two decades. Diabetes and hypertension are the attributable causes for more than three fourths of all new cases of end-stage renal disease. The overwhelming majority of diabetics with nephropathy are hypertensive, and lowering blood pressure is indicated in all patients with chronic kidney disease because of the increased risk for cardiovascular morbidity and mortality. Multiple studies indicate that reaching goal systolic blood pressure in patients with chronic kidney disease generally requires three to four antihypertensive agents. A number of medication combinations can effectively reduce blood pressure in the chronic kidney disease patient. In this regard, adding a calcium channel blocker to an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker helps in reaching goal blood pressure while preserving renal function in both diabetics and nondiabetics with proteinuria.

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J Clin Hypertens (Greenwich). 2005 Apr;7(4 Suppl 1):9-14.
Therapeutic considerations in the african-american patient with hypertension: considerations with calcium channel blocker therapy.
Flack JM, Sica DA.
Wayne State University, University Health Center, Detroit, MI jflack@intmed.wayne.edu.

African Americans have a higher prevalence, earlier onset, and more rapid progression of hypertensive end-organ disease, as well as excessive hypertensive mortality compared with other racial/ethnic groups. Most differences in hypertension and pressure-related complications between African Americans and whites appear to be quantitative and not qualitative. Improving the diagnosis, treatment, and control of hypertension in this highly vulnerable population is a major health care goal for the new millennium. In this regard the dietary pattern to be promoted for reduction of hypertension risk in African Americans is one of increased consumption of dairy products, fruit, and vegetables as well as a continued emphasis on decreased Na+ intake. When pharmacologic therapy is considered, multi-drug approaches are generally required, with diuretics, angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers), and calcium channel blocker therapy as oft-selected components of most such treatment regimens.

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Int J Clin Pract. 2005 Feb;59(2):214-24.
Redefining efficacy of antihypertensive therapies beyond blood pressure reduction--the role of angiotensin II antagonists.
Conlin PR.
Endocrinology, Diabetes and Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. pconlin@partners.org

Antihypertensive efficacy must be redefined beyond blood pressure (BP) lowering per se to include reducing the cardiovascular complications of hypertension. Treatment decisions should be based on results from large clinical trials with relevant clinical outcomes. Several recent morbidity and mortality trials with angiotensin II receptor antagonists (AIIAs) provide an evidence-based rationale for the use of AIIAs in patients with hypertension. Studies with AIIAs in comparison to conventional antihypertensive agents showed improved morbidity and mortality outcomes in patients with hypertension and left ventricular hypertrophy (losartan) and diabetes mellitus (losartan and irbesartan). Trials with some members of the AIIA class (candesartan and valsartan) have not demonstrated such benefits in comparison to conventional agents, possibly due to differences in BP control during the trials. The results of these AIIA outcome trials have impacted on recently issued clinical guidelines for management of hypertension.

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Adv Ther. 2004 Nov-Dec;21(6):357-69.
Therapeutic profile of manidipine and lercanidipine in hypertensive patients.
Casiglia E, Mazza A, Tikhonoff V, Basso G, Martini B, Scarpa R, Pessina AC.
Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy.

Manidipine and lercanidipine are considered effective and safe in the treatment of chronic arterial hypertension and are equipotent in reducing blood pressure (BP) levels. Their main side effect is ankle-foot edema. After a 2-week placebo run-in period, these 2 drugs were compared in a controlled parallel-group study lasting 3 months, involving 53 patients with mild-to-moderate essential hypertension (26 assigned to manidipine and 27 to lercanidipine). At the end of the active treatment period, BP was significantly reduced in comparison with the end of the placebo phase in both the manidipine and the lercanidipine groups, without significant differences between the 2 drugs. Daytime BP was significantly reduced by 5.5%/5.6% with manidipine and by 3.8%/6.6% with lercanidipine, while smaller reductions were seen at nighttime. The smoothness index was the same with both drugs. Unlike lercanidipine, manidipine significantly reduced both basal (-30%) and minimal vascular resistance (-39%), qualifying it as a potent vasodilator. Despite vasodilation, heart rate was not increased but was even slightly reduced by treatment. Ankle-foot edema was observed with both drugs but was less pronounced with manidipine, probably because of greater postcapillary dilatation. In conclusion, manidipine and lercanidipine are both effective and safe in mild-to-moderate essential hypertension, although the former seems to have a more favorable tolerability profile than the latter.

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J Hypertens. 2005 Feb;23(2):445-453.
Controlled-release nifedipine and candesartan low-dose combination therapy in patients with essential hypertension: the NICE Combi (Nifedipine and Candesartan Combination) Study.
Hasebe N, Kikuchi K; for the NICE Combi Study Group.
First Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Japan bSee Appendix.

OBJECTIVE: To compare the clinical efficacy of low-dose controlled-release (CR) nifedipine (20 mg/day) plus candesartan (8 mg/day) combination therapy with that of up-titrated candesartan (12 mg/day) monotherapy. DESIGN: Randomized, double-blind study. SETTING: Outpatient study. PATIENTS AND PARTICIPANTS: Patients with essential hypertension, who did not achieve their target blood pressure with baseline treatment of candesartan 8 mg/day for 8 weeks. MAIN OUTCOME MEASURES: Blood pressure, pulse pressure, urinary microalbumin excretion. RESULTS: Blood pressure was significantly reduced in both groups (P < 0.05), but the reduction was significantly greater in the combination therapy group (12.1 +/- 1.4/8.7 +/- 0.9 mmHg) than in the up-titrated monotherapy group (4.1 +/- 1.4/4.6 +/- 0.9 mmHg) (P < 0.0001). The reduction in pulse pressure was significantly greater in the combination therapy group (3.3 +/- 1.2 mmHg) than in the up-titrated monotherapy group (0.7 +/- 1.2 mmHg) (P = 0.0031). Urinary microalbumin excretion decreased significantly in the combination therapy group (from 61.9 to 40.5 mg/g creatinine; P < 0.05), but not in the up-titrated monotherapy group. CONCLUSIONS: These findings suggest that the low-dose combination therapy of nifedipine CR and candesartan is superior to the up-titrated monotherapy of candesartan in terms of blood pressure control and renal protection in patients with essential hypertension.

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Coron Artery Dis. 2005 Feb;16(1):67-73.
The vascular effects of doxazosin in hypertension complicated by metabolic syndrome.
Dell'omo G, Penno G, Pucci L, Pellegrini G, Scotti A, Prato SD, Pedrinelli R.
aDipartimento Cardio Toracico bDipartimento di Endocrinologia e Metabolismo, Universita' di Pisa, Pisa, Italy cLaboratorio Analisi Chimiche e Microbiologiche, Azienda Ospedaliera Pisana dItalfarmaco Spa, Milano, Italy.

AIMS: To evaluate the vascular effects of doxazosin, an alpha-1 antagonist, in hypertensive patients with metabolic syndrome in whom the drug has previously been shown to exert beneficial metabolic actions on lipids and insulin metabolism. EXPERIMENTAL PROTOCOL: Twelve untreated non-diabetic hypertensive patients with National Cholesterol Education Program (NCEP) ATP-III defined metabolic syndrome were assigned to three-months of treatment with doxazosin (5.5+/-1.9 mg/die). Study variables were measured at baseline and after treatment. End-points: forearm blood flow (strain-gauge plethysmography) responses to graded intra-arterial acetylcholine and sodium nitroprusside infusion to test endothelium-dependent and independent vasodilatation respectively. Minimum forearm vascular resistance, the ratio of mean blood pressure and post-ischaemic maximal blood flow, as an index of arteriolar structure; transcapillary albumin escape rate (the 1-h decay rate of I-albumin, 6-8 muC ev) as a measure of systemic capillary permeability. Lipids, fasting and post-glucose insulin were measured at baseline and after treatment. RESULTS: Doxazosin reduced blood pressure, augmented acetylcholine-mediated vasodilatation, decreased minimum resistance and, although not to a statistically significant extent, transvascular albumin leakage increased high-density lipoprotein (HDL) cholesterol while triglycerides and post-stimulative hyperinsulinemia decreased. CONCLUSIONS: Doxazosin improved endothelial-mediated vasomotor function and reversed abnormal arteriolar structure in hypertensive patients with metabolic syndrome while improving lipid profile and blunting post-glucose hyperinsulinemia.

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Am J Ther. 2005 January/February;12(1):3-8.
Regression of Left Ventricular Hypertrophy With Moexipril, an Angiotensin-Converting Enzyme Inhibitor, in Hypertensive Patients.
Sayegh F, Topouchian J, Hlawaty M, Olzewska M, Asmar R.
L'Institut Cardio Vasculaire, Paris, France.

Left ventricular hypertrophy (LVH) is a common complication of essential hypertension and an independent risk factor for the development of cardiovascular disease. Therefore, antihypertensive treatment should decrease blood pressure (BP) and reverse LVH. However, antihypertensive drugs have been shown to have different effects on LVH despite similar effects on BP reduction. Although lowering BP produces a beneficial effect on LVH per se, metaanalyses of clinical trials have indicated that angiotensin-converting enzyme (ACE) inhibitors decrease left ventricular mass (LVM) to a greater extent than do some other antihypertensives. The aim of this study was to evaluate the effect of a 24-week treatment with the ACE inhibitor moexipril (15 mg once daily) on the regression of LVH in hypertensive patients. This was a multicenter, international, single-blind, single-group, nonrandomized study. After a wash-out placebo period of 2 weeks, 15 mg moexipril once daily was administered for 24 weeks followed by a 2-week follow-up placebo period. Subjects with mild to moderate essential hypertension were screened; those with LVH [defined as an LVM indexed for body surface area (LVMIs) >111 g/m in men and LVMIs >106 g/m in women] were eligible to participate in this study. Echocardiograms were recorded on videotape and sent to a centralized laboratory for reading by 2 independent experts blinded for treatment, center, and visit; the mean values of these readings were calculated and used for analysis. Valid echocardiographic data were obtained from 72 patients (50 males, 22 females) with a mean age of 49 +/- 11 years. Analysis showed significant decrease of LVMIs (121 +/- 20 versus 103 +/- 17 g/m; P < 0.001) and BP (152 +/- 12/96 +/- 9 versus 140 +/- 13/86 +/- 9 mm Hg; P < 0.001) with moexipril. For patients who met LVMI inclusion criteria after centralized, blinded readings, the decrease from baseline in LVMIs was 23.4 g/m. The decrease in LVMIs was independent from the regression to the mean phenomenon as observed from the follow-up placebo period. Moexipril 15 mg once daily administered for 24 weeks resulted in a significant reversal of LVH in patients with essential hypertension. The result compares favorably with results previously obtained in trials of similar duration with other ACE inhibitors.

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J Hum Hypertens. 2005 Jan 20; [Epub ahead of print]
Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan.
Chrysant SG, Chrysant GS, Desai A.
1Cardiology, University of Oklahoma, Oklahoma Cardiovascular and Hypertension Center, Oklahoma City, OK, USA.

Poorly controlled hypertension is a major risk for cardiovascular morbidity and mortality, strokes, heart failure and renal failure. Despite these devastating complications, blood pressure control of </=140/90 mmHg, which is above the current standard, is very poor worldwide, accounting for 34% of hypertensive patients in the United States, and 6% in other countries. The reasons for this poor control of blood pressure include lack of aggressive treatment by physicians, especially for the systolic blood pressure, drug selection and patient compliance. The blood pressure follows a circadian rhythm and is the highest between 0600 to 1200 h, when most complications occur. Long-acting drugs that extend their action to cover this vulnerable period are preferable, especially those that block the renin-angiotensin-aldosterone system, such as ACE inhibitors and angiotensin receptor blockers, and are the most effective in controlling blood pressure and preventing or reducing its cardiovascular and renal complications. With respect to the angiotensin receptor blockers, telmisartan has been demonstrated by several studies to be the longest acting among its class of drugs and to effectively prevent the early morning rise of blood pressure.Journal of Human Hypertension advance online publication, 20 January 2005; doi:10.1038/sj.jhh.1001808.

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Hypertension. 2005 Jan 17; [Epub ahead of print]
Antihypertensive Therapy Increases Cerebral Blood Flow and Carotid Distensibility in Hypertensive Elderly Subjects.
Lipsitz LA, Gagnon M, Vyas M, Iloputaife I, Kiely DK, Sorond F, Serrador J, Cheng DM, Babikian V, Cupples LA.
Hebrew Rehabilitation Center for Aged.

Many physicians are reluctant to lower blood pressure to recommended levels in elderly hypertensive patients because of concern about producing cerebral hypoperfusion. Because hypertension is associated with potentially reversible structural and functional alterations in the cerebral circulation that may improve with treatment, we investigated whether long-term pharmacological reduction of systolic blood pressure will improve, rather than worsen, cerebral blood flow and its regulation. Three groups of elderly subjects 65 years of age or older were studied prospectively: normotensive subjects (N=19), treated hypertensive subjects with systolic pressure <140 mm Hg (N=18), and uncontrolled hypertensive subjects with systolic pressure >160 mm Hg at entry into the study (N=14). We measured beat-to-beat blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasonography), finger arterial pressure (photoplethysmography), and pulsatile distensibility of the carotid artery (duplex Doppler ultrasonography) at baseline and after 6 months of observation or antihypertensive therapy. After baseline hemodynamic measurements, uncontrolled hypertensive subjects underwent aggressive treatment with lisinopril with or without hydroclorothiazide or, if not tolerated, nifedipine or an angiotensin receptor blocker to bring their systolic pressure <140 mm Hg for 6 months. The other 2 groups were observed for 6 months. After 6 months of successful treatment, uncontrolled hypertensive subjects had significant increases in cerebral blood flow velocity and carotid distensibility that was not seen in the other groups. Treatment reduced cerebrovascular resistance and did not impair cerebral autoregulation. Therefore, judicious long-term treatment of systolic hypertension in otherwise healthy elderly subjects does not cause cerebral hypoperfusion.

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Cochrane Database Syst Rev. 2005 Jan 25;1:CD005182.
Interventions used to improve control of blood pressure in patients with hypertension.
Fahey T, Schroeder K, Ebrahim S.
Division of Community Health Sciences, University of Dundee, MacKenzie Building, Kirsty Semple Way, Dundee, UK, DD2 4AD.

BACKGROUND: It is well recognized that patients with high blood pressure (hypertension) in the community frequently fail to meet treatment goals- a condition labeled as "uncontrolled" hypertension. The optimal way in which to organize and deliver care to patients who have hypertension so that they reach treatment goals has not been clearly identified. OBJECTIVES: To determine the effectiveness of interventions to improve control of blood pressure in patients with elevated blood pressure. To evaluate the ability of reminders to improve the follow-up of patients with elevated blood pressure. SEARCH STRATEGY: All-language search of all articles (any year) in the Cochrane Controlled Trials Register (CCTR), Medline and Embase from June 2000. SELECTION CRITERIA: Randomised controlled trials (RCTs) of patients with hypertension that evaluated the following interventions: (1) self-monitoring(2) educational interventions directed to the patient(3) educational interventions directed to the health professional(4) health professional (nurse or pharmacist) led care(5) organisational interventions that aimed to improve the delivery of care(6) appointment reminder systemsOutcomes assessed were: (1) mean systolic and diastolic blood pressure(2) control of blood pressure (3) proportion of patients followed up at clinic DATA COLLECTION AND ANALYSIS: Two authors extracted data independently and in duplicate and assessed each study according to the criteria outlined by the Cochrane Collaboration Handbook. MAIN RESULTS: 59 RCTs met our inclusion criteria. The methodological quality of included studies was variable. An organized system of regular review linked to vigorous antihypertensive drug therapy was shown to reduce blood pressure (weighted mean difference -8.2/-4.2 mmHg, -11.7/-6.5 mmHg, -10.6/-7.6 mmHg for 3 strata of entry blood pressure) and all-cause mortality at five years follow-up (6.38% versus 7.78%, difference 1.4%) in a single large RCT- the Hypertension Detection and Follow-Up study. Other interventions had variable effects. Self-monitoring was associated with moderate net reduction in diastolic blood pressure (weighted mean difference (WMD): -2.03 mmHg, 95%CI: -2.69 to -1.38 mmHg, respectively. Appointment reminders increased the proportion of individuals who attended for follow-up. RCTs of educational interventions directed at patients or health professionals were heterogeneous but appeared unlikely to be associated with large net reductions in blood pressure by themselves. Health professional (nurse or pharmacist) led care may be a promising way of delivering care, with the majority of RCTs being associated with improved blood pressure control, but requires further evaluation. AUTHORS' CONCLUSIONS: Family practices and community-based clinics need to have an organized system of regular follow-up and review of their hypertensive patients. Antihypertensive drug therapy should be implemented by means of a systematic stepped care approach when patients do not reach target blood pressure levels.

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Curr Treat Options Cardiovasc Med. 2004 Dec;6(6):451-458.
Pulmonary Arterial Hypertension: New Management Options.
Huffman MD, McLaughlin VV.
University of Michigan Medical Center, Division of Cardiovascular Medicine, Department of Internal Medicine, 1500 East Medical Center Drive, L3119 Women's Hospital, Ann Arbor, MI 48109-0273, USA. vmclaugh@umich.edu.

The past decade has realized remarkable advances in the treatment of pulmonary arterial hypertension (PAH), a progressive and potentially fatal disease. A small proportion of patients will have a dramatic hemodynamic response to acute vasodilator testing performed at the time of right heart catheterization and may be candidates for calcium channel blocker therapy. The vast majority of patients with PAH will not benefit from calcium channel blockers and should be treated with one of the three US Food and Drug Administration-approved therapies for PAH; bosentan, treprostinil, or epoprostenol. Because of the ease of administration relative to other therapies, the majority of patients with functional class III symptoms should be treated with the oral nonselective endothelin antagonist bosentan. Randomized controlled trials with treprostinil have demonstrated improvements in exercise endurance and hemodynamics. Patients who are critically ill, with functional class IV symptoms, should be started on epoprostenol because it is the most rapidly effective therapy. Intravenous epoprostenol improves exercise endurance, quality of life, hemodynamics, and survival in PAH. Investigational therapies on the horizon include phosphodiesterase inhibitors, prostacyclin analogues with alternative delivery routes (eg, inhaled, oral), and selective endothelin A receptor antagonists. The future of PAH therapy will likely include combinations of these therapies based on the multiple mechanisms of action.

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Curr Cardiol Rep. 2004 Nov;6(6):421-6.
Combination drug treatment of hypertension: have we come full circle?
Taylor AA.
Section on Hypertension and Clinical Pharmacology, Department of Medicine, Baylor College of Medicine, 6565 Fannin, MS F504, Houston, TX 77030-2704, USA. ataylor@bcm.tmc.edu.

Only 30% of hypertensive patients achieved and maintained adequate blood pressure control on a single drug in recent clinical trials. For the majority of patients who require two or more drugs to lower blood pressure to the currently recommended goals of 140/90 mm Hg or to 130/80 if they are diabetic or have chronic kidney disease, combinations of two or more drugs in a single pill offers an attractive alternative to taking multiple single drugs each day. Research has shown that the simpler the drug regimen the more likely patients are to be compliant in taking medications. Because a reduction in cardiovascular risk is linked to the extent to which elevated blood pressure is reduced, this benefit is not realized by patients who either discontinue their medications or are noncompliant. Carefully selected low doses of two antihypertensive drugs combined in a single pill offers other advantages including greater efficacy compared with high-dose monotherapy, a lower incidence of adverse effects, improved persistence in taking medications, fewer patient visits, and reduced cost to the health care system.

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J Hypertens. 2004 Nov;22(11):2043-8.
Lifestyle interventions or drugs for patients with essential hypertension: a systematic review.
Nicolson DJ, Dickinson HO, Campbell F, Mason JM.
National Guidelines Research and Development Unit, Centre for Health Services Research, 21 Claremont Place, University of Newcastle, Newcastle Upon Tyne, NE2 4AA, UK.

OBJECTIVE: To compare the effectiveness of lifestyle and drug interventions for treating patients with essential hypertension. METHODS: Systematic review of randomized controlled trials (RCTs), with 8 or more weeks follow-up, enrolling patients with blood pressure of at least 140/85 mmHg, which directly compared lifestyle and drug interventions. Planned outcome measures were cardiovascular morbidity and mortality and blood pressure. RESULTS: We found five RCTs meeting our inclusion criteria and additionally included one quasi-randomized trial. These trials enrolled between 27 and 64 participants, mean age 55 years, with follow-up of less than 1 year; none reported cardiovascular outcomes. The lifestyle and drug interventions and patient populations were heterogeneous. Overall, the trials were of poor quality and had inconsistent results. Although dietary interventions did not always lower blood pressure as much as antihypertensive drugs, secondary analysis suggested that they might be better at lowering cholesterol levels. CONCLUSIONS: In the short term, lifestyle treatment may be effective at reducing blood pressure for some individuals. A healthier diet, by lowering blood pressure and cardiovascular risk, may reduce, delay or remove the need for long-term drug therapy in some patients. However, further comparisons of lifestyle and drug interventions for hypertension are required, with larger clinical trials of longer duration and better quality. Future trials should aim to identify the characteristics of patients most likely to benefit from lifestyle changes.

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Cochrane Database Syst Rev. 2004 Oct 18(4):CD003562.
Sildenafil for pulmonary hypertension.
Kanthapillai P, Lasserson T, Walters E.
Luton and Dunstable NHS Trust, Lewsey Road,, Luton, Hertfordshire, UK, LU4 0DZ.

BACKGROUND: Pulmonary Hypertension (PH) can be either of un