Nebivolol/valsartan combination for the treatment of hypertension: a review.

Nebivolol (N) is a ß1-adrenoreceptor antagonist that is approved for treatment of hypertension in the USA. Effective treatment of hypertension is becoming an increasingly difficult process that often requires multiple drug combinations to meet target guidelines. This has resulted in the increasing introduction of multidrug single-pill combinations (SPCs) to facilitate cost and compliance issues. Some of the SPCs have added valsartan (V), an angiotensin receptor blocker, which is an increasingly advocated antihypertensive class. Pharmacological profiles of N and V, alone and combined, are well characterized. In 2007, the SPC of N and V, 5 and 80 mg, respectively, was approved by the US FDA for treatment of hypertension. This paper will summarize and update key issues in pharmacology, clinical use and benefit.

Novel Pathophysiological Mechanisms in Hypertension.

Hypertension is the most common disease affecting humans and imparts a significant cardiovascular and renal risk to patients. Extensive research over the past few decades has enhanced our understanding of the underlying mechanisms in hypertension. However, in most instances, the cause of hypertension in a given patient continues to remain elusive. Nevertheless, achieving aggressive blood pressure goals significantly reduces cardiovascular morbidity and mortality, as demonstrated in the recently concluded SPRINT trial. Since a large proportion of patients still fail to achieve blood pressure goals, knowledge of novel pathophysiologic mechanisms and mechanism based treatment strategies is crucial. The following chapter will review the novel pathophysiological mechanisms in hypertension, with a focus on role of immunity, inflammation and vascular endothelial homeostasis. The therapeutic implications of these mechanisms will be discussed where applicable.

Methodological evaluation of the noninvasive estimation of central systolic blood pressure in nontreated patients: the Bogalusa Heart Study.

OBJECTIVES: This study sought to compare the estimation of central systolic blood pressure (cSBP) obtained by two different noninvasive devices, in addition to its comparisons with measured peripheral systolic blood pressure (pSBP), in a biracial (Black/White) community-based cohort. PARTICIPANTS AND METHODS: Estimations of cSBP by applanation tonometry were obtained in 586 participants of the Bogalusa Heart Study (mean age: 43.5 years; 69% White, 54% women) using two different commonly used instruments: Omron HEM-9000AI and SphygmoCor CPV. pSBP was measured using a standard auscultatory technique. RESULTS: The estimation of cSBP by the Omron device was higher than that of the SphygmoCor device (124.2±17.1 vs. 111.4±15.2 mmHg, P<0.001). Moreover, cSBP by Omron was significantly higher than peripheral blood pressure (124.2±17.1 vs. 119.4±15.6 mmHg, P<0.001), whereas cSBP by SphygmoCor was significantly lower than pSBP (111.4±15.2 vs. 119.4±15.6 mmHg, P<0.001). Similar results were observed in race-specific and sex-specific analyses. CONCLUSION: These findings support the hypothesis that notable differences exist in the estimation of cSBP provided by the instruments utilized in this study. Further standardization studies are required to establish the most appropriate noninvasive estimation of cSBP before this parameter may be considered in the assessment, prediction, and prevention of cardio-metabolic risk and overt cardiovascular disease in clinical practice.

Chagas Cardiomyopathy in New Orleans and the Southeastern United States.

BACKGROUND: Chagas disease (CD), caused by Trypanosoma cruzi, affects 6-7 million people worldwide annually, primarily in Central and South America, and >300,000 people in the United States. CD consists of acute and chronic stages. Hallmarks of acute CD include fever, myalgia, diaphoresis, hepatosplenomegaly, and myocarditis. Symptoms of chronic CD include pathologic involvement of the heart, esophagus, and colon. Myocardial involvement is identifiable by electrocardiogram and cardiac magnetic resonance imaging showing inflammation and left ventricular wall functional abnormalities. CASE REPORTS: We present two cases of CD identified in a single hospital in the Southeastern United States. Case 1 presents a patient with symptoms of anginal chest pain and associated shortness of breath with myocardial involvement suggestive of ischemic infarction but normal coronary arteries. Case 2 describes a patient with no physical symptoms and echocardiogram with ejection fraction of 50% with posterolateral and anterolateral wall hypokinesis but normal coronary arteries. CONCLUSION: With a growing number of immigrants from Central and South America in the United States, it is imperative for clinicians to include CD as part of the differential diagnosis for patients presenting with heart disease who have a history of exposure to T. cruzi endemic areas.

Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension.

Recent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact "lower is better," with blood pressure targets < 120/80 mm Hg appropriate for many hypertensive patients. Two drug combinations are often indicated as initial therapy if a 20/10 mm Hg or greater blood pressure reduction is necessary to reach target. Combinations consisting of ß-blockers and renin-angiotensin-aldosterone system inhibitors have previously been deemed "less effective," based on partially overlapping mechanisms of action and limited clinical trial evidence. Nebivolol is a vasodilating ß1-selective blocker and ß3- adrenoceptor agonist; ß3-adrenoceptor activation increases nitric oxide concentrations and thus explains the vasodilatory effect. A recent 8-week randomized trial (N=4,161) in individuals with stage 1-2 hypertension demonstrated that single-pill fixed dose combinations (FDC) of nebivolol and valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other ß-blockers, and will further support the pharmacological advantages of this particular combination.

Prehypertension: Defining the Transitional Phenotype.

More than a simple "transitional stage" defined by covenanted cut points of systolic pressure from 120 to 139 mm of mercury (mm Hg) or a diastolic pressure from 80 to 89 mm Hg, prehypertension should be referred to as a categorical term that defines a specific phenotype in the progression from the "absence of disease" to clinically overt disease. While the currently utilized definition of prehypertension stresses the use of blood pressure cut points to establish the diagnosis, it is of relevance to direct our attention to the structural and functional hemodynamic alterations that occur in response to the two cardinal abnormalities in the development of prehypertension and hypertension: autonomic dysfunction and arterial remodeling. Our current review addresses these aspects of the pathophysiology or prehypertension on its progression to hypertension and suggests a new approach to its classification.

Nebivolol and valsartan as a fixed-dose combination for the treatment of hypertension.

INTRODUCTION: The fixed-dose combination of nebivolol and valsartan drug has been clinically evaluated and demonstrated to represent a unique combination of nebivolol, a selective ß1-adrenoceptor antagonist and a ß3-adrenoceptor agonist; ß3 receptor activation increases endothelial nitric oxide and produces vasodilation. Valsartan is highly selective angiotensin AT1 receptor blocker and exerts its major pharmacological effect by decreasing angiotensin II-induced vasoconstriction and production of aldosterone. The addition of nebivolol counteracts the effects of increased angiotensin II concentrations resulting from potent AT1 blockade. This review describes a recently completed trial establishing the efficacy of the nebivolol/valsartan combination. AREAS COVERED: This review provides a literature search of pertinent pharmacological and clinical data that describes the mechanisms of both drugs individually and the results of a clinical trial comparing fixed-dose combinations of nebivolol with valsartan as compared with each drug as monotherapy. EXPERT OPINION: Fixed-dose combination drugs are intended to improve patient compliance and reduce drug costs, as well as to reduce long-term cardiovascular event rates and block counter-regulatory effects due to monotherapy. The vast majority of hypertensive patients will require at least two medications. We believe that the clinical evidence suggests that the combination of nebivolol with valsartan offers a definite clinical benefit, combining ß1-adrenoceptor and angiotensin AT1 receptor blockade with ß3 receptor activation and resultant increase in nitric oxide and vasodilation.

Stress Cardiomyopathy in the Setting of COPD Exacerbation.

Introduction. Stress cardiomyopathy, or takotsubo cardiomyopathy, is an acute, reversible left ventricular dysfunction usually initiated by a psychological or physical stress. We report this case of stress cardiomyopathy following a chronic obstructive pulmonary disease exacerbation and the subsequent treatment. Case Description. A 49-year-old white female with a history of chronic obstructive pulmonary disease presented to the emergency room via emergency medical services with worsening severe shortness of breath and productive cough for 2 weeks but denied any chest pain on arrival. On presentation, she was noted to be tachypneic, using her accessory muscles and with bilateral coarse expiratory wheezing on lung auscultation. Initial electrocardiogram demonstrated sinus tachycardia. She was treated with multiple albuterol treatments. Soon afterwards, the course was complicated by hypoxic respiratory failure eventually requiring intubation. Her repeat electrocardiogram showed acute changes consistent with myocardial infarction, and an echocardiograph demonstrated apical akinesia with an ejection fraction of 25% to 30%. The patient was urgently taken for cardiac catheterization, which showed no angiographic evidence of coronary artery disease. Three days after initial presentation, a repeat transthoracic echocardiogram showed overall left ventricular systolic function improvement. Discussion. This case provided a unique look at the difficulty of balancing catecholamines in a patient with bronchospasm and stress cardiomyopathy.

Digital plethysmography and arginine metabolism in prehypertension: effect of nebivolol therapy.

Prehypertension is an important phenotype for cardiovascular risk and development of established hypertension. To better understand the early circulatory changes in this group, the authors studied 34 patients with prehypertension (blood pressure 120-139/80-89 mm Hg) using digital plethysmography for measurement of blood flow and reactive hyperemic index (RHI). Arterial augmentation index (AI) was also measured. Because prehypertension is associated with endothelial dysfunction and decreased availability of nitric oxide (NO), indices of arginine metabolism (l-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, and l-citrulline) were measured. Nebivolol (5 mg/d), a vasodilating ß1 -antagonist with ß3 -agonist activity, was studied in a double-blind fashion for 8 weeks. Nebivolol increases the bioavailability of NO. Prehypertension was associated with normal RHI and baseline digital blood flow. AI was abnormal and associated with diastolic blood pressure. ADMA concentration was increased at baseline. After 8 weeks of nebivolol therapy, RHI, ADMA, symmetric dimethylarginine, and AI showed no significant change, but digital blood flow and l-citrulline levels were significantly increased. Prehypertension is associated with increased ADMA and evidence of increased arterial stiffness and preserved RHI. Nebivolol therapy is associated with digital vasodilation and increased NO production, as depicted by increased levels of l-citruline and mean digital blood flow.

Women have significantly greater difference between central and peripheral arterial pressure compared with men: the Bogalusa Heart Study.

Gender differences in the relationship between central and peripheral blood pressure (BP) are not well described. We sought to investigate gender differences between central systolic blood pressure (cSBP) and peripheral systolic blood pressure (pSBP) in adults in the Bogalusa study population. This study enrolled adults in a cross sectional survey conducted in 2007 to 2010. BP was measured with a standard cuff and Omron applanation tonometer. Data were available from 876 participants. Participants were 57.9% female and 42.1% male (mean age, 43.5 ± 4.4 years). Mean (standard deviation) for cSBP - pSBP was 1.0 (6.9) for males and 7.4 (5.2) for females (P < .001). Augmentation index (AI) was higher in women (men, 70.8 ± 14 vs. women: 85.5 ± 13; P < .01), as well as AI standardized to heart rate (HR) of 75 (AI@75; men, 68.5 ± 13 vs. women, 84.4 ± 11.8; P < .01). Female participants had greater difference between cSBP and pSBP than males. This suggests that, given similar peripheral BP, females might be at higher risk for developing target organ damage. Women in this study had higher AI, which may contribute to the difference found between cSBP and pSBP. These findings may explain why women have more age-related left ventricular hypertrophy, and poorer prognosis following myocardial infarction compared with males.

Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial-derived hyperpolarizing factors, and prostaglandins.

Under resting conditions the arterial vasculature exists in a vasoconstricted state referred to as vascular tone. Physiological dilatation in response to increased flow, a function of normal endothelium is necessary to maintain normal blood pressure. Endothelial dysfunction in vascular smooth muscle cells thus results in loss of normal vasorelaxant function and the inability of arteries to appropriately dilate in response to increased blood flow in either a systemic or regional vascular bed, resulting in increased blood pressure, a sequence that may represent a common pathway to hypertension. Normal vasorelaxation is mediated by a number of endothelial systems including nitric oxide (NO), prostaglandins (PGI2 and PGE2), and a family of endothelial-derived hyperpolarizing factors (EDHF). In response to hemodynamic shear stress, endothelium continuously releases NO, EDHF, and PGI2 to provide vasodilatation. EDHF, not a single molecule but rather a group of molecules that includes epoxyeicosatrienoic acids, hydrogen peroxide, carbon monoxide, hydrogen sulfide, C-natriuretic peptide, and K+ itself, causes vasodilatation by activation of vascular smooth muscle cell K+ channels, resulting in hyperpolarization and thus vasorelaxation. The understanding and effective management of blood pressure requires an understanding of both physiologic and pathophysiologic regulation of vascular tone. This review describes molecular mechanisms underlying normal endothelial regulation and pathological states, such as increased oxidative stress, which cause loss of vasorelaxation. Possible pharmacological interventions to restore normal function are suggested.

What is the blood pressure goal for the elder patient 75 years of age or older?

High blood pressure (BP), once believed to represent a normal and progressive component of the aging process, is now recognized as a manifestation of structural and physiologic abnormalities of arterial function. Two phenotypes exist in the older patient: elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) with a normal pulse pressure (PP), and elevated SBP with an increased PP. Elevated SBP and increased PP unquestionably increase the risk of both fatal and nonfatal cardiovascular events, including stroke, myocardial infarction, and heart failure. Isolated systolic hypertension, defined as an SBP ≥140 mm Hg with a DBP less than 90 mm Hg, affects the majority of individuals ages 60 years and older. A number of clinical trials have clearly demonstrated that treatment of hypertension significantly reduces the cardiovascular event rate in older patients. However, controversy continues as to the choice of antihypertensive agents and combinations of agents. It is both appropriate and necessary to treat elderly hypertensive patients aggressively to the same target BPs identified for younger patients. It is also appropriate to initiate treatment with lower doses of antihypertensive agents and to bring the pressure down more slowly, monitoring for orthostatic hypotension, impaired cognition, and electrolyte abnormalities.

Resistant hypertension: concepts and approach to management.

Resistant hypertension (RH), defined simply, is blood pressure (BP) requiring the use of four or more antihypertensive agents, whether controlled or uncontrolled. RH is an increasingly common problem in elderly patients and may affect as many as 20% of the hypertensive population. Unfortunately, at least 30% of patients evaluated for RH are actually adequately controlled when more carefully assessed by home BP monitoring or ambulatory BP monitoring, thus representing a white coat effect. It is also essential to exclude pseudoresistance resulting from improper BP recording techniques or failure of the patient to adhere to the prescribed treatment regimen. Concurrent use of drugs that may interfere with prescribed antihypertensive agents, including many over the counter herbal preparations, must also be excluded. The underlying mechanisms principally driving true RH include pathophysiologic abnormalities of aldosterone signaling, sodium and water retention, excessive sympathetic nervous system activity, and obstructive sleep apnea. Appropriate treatment regimens will usually include an inhibitor of the renin-angiotensin-aldosterone system, a calcium channel blocker, and a diuretic. An aldosterone receptor blocker can be instituted at any step, and is very effective as a fourth drug. Beta-blockers can also be integrated into these treatment plans and may be especially helpful when excessive sympathetic nervous system activity is suspected. Novel device therapies that interrupt sympathetic nerve stimulation at the carotid sinus and kidney are under investigation, and may add entirely new directions in the management of RH. What is most important is that treatment regimens should be targeted to specific patient profiles.

Histologically measured cardiomyocyte hypertrophy correlates with body height as strongly as with body mass index.

Cardiac myocytes are presumed to enlarge with left ventricular hypertrophy (LVH). This study correlates histologically measured myocytes with lean and fat body mass. Cases of LVH without coronary heart disease and normal controls came from forensic autopsies. The cross-sectional widths of myocytes in H&E-stained paraffin sections followed log normal distributions almost to perfection in all 104 specimens, with constant coefficient of variation across the full range of ventricular weight, as expected if myocytes of all sizes contribute proportionately to hypertrophy. Myocyte sizes increased with height. By regression analysis, height(2.7) as a proxy for lean body mass and body mass index (BMI) as a proxy for fat body mass, exerted equal effects in the multiple correlation with myocyte volume, and the equation rejected race and sex. In summary, myocyte sizes, as indexes of LVH, suggest that lean and fat body mass may contribute equally.