A Modern Perspective on β-Blocker Use in Hypertension: Clinical Trials and Their Influence on Clinical Practice

National guidelines recommend β-blockers as second step agents after diuretic therapy in patients without compelling indications despite little clinical trial evidence of cardiovascular outcome benefits in uncomplicated essential hypertension. In high-risk patients with hypertension, such as those with a previous myocardial infarction or diabetes, heart failure, or coronary artery disease, β-blockers have been shown to reduce the risk of cardiovascular mortality and to reduce events beyond those ascribed to blood pressure (BP) lowering. The use of a β-blocker-based regimen in patients with diabetes has been shown to reduce cardiovascular mortality, progression of diabetic nephropathy, and stroke. Lowering BP in hypertensive patients is a primary goal, but it is also essential that goal BP be achieved with the fewest adverse consequences (ie, by choosing agents that do not worsen concomitant conditions or cause unacceptable side effects). Physicians must consider issues of possible worsening insulin resistance and dyslipidemia associated with some β-blockers. These metabolic concerns, however, are not an issue for the combined β-/αblocker carvedilol. This review highlights historical data and important clinical trials that underscore the importance of β-blockade in specific patients and delineates situations where β-blockers benefit patients with hypertension and/or cardiovascular disease.     

Comparison of a Chronotherapeutically Administered β Blocker vs. a Traditionally Administered β Blocker in Patients With Hypertension

Increasing systolic blood pressure and heart rate during the early morning results in increased myocardial oxygen demand. The use of β blockers during this period may decrease cardiac workload, particularly in β-blocker sensitive patients. The impact of a new chronotherapeutic β blocker was assessed in 44 hypertensive patients. Patients were randomized to delayed-release propranolol (INP) dosed at 10 p.m. or to traditionally dosed propranolol (ILA) dosed at 8 a.m. for 4 weeks, following which they were switched to the alternative formulation for 4 weeks. Thirty-four-hour ambulatory blood pressure monitoring and pharmacokinetic measurements were obtained. INP and ILA resulted in significant reductions in mean 24-hour blood pressure (−9.01-6.9 mm Hg and −10.41-7.7 mm Hg, respectively). The top 25% of responders to highdose propranolol (sensitive patients) were compared on each formulation. Mean trough reductions were −8.0/-6.7 mm Hg and −7.61-5.8 mm Hg, respectively. Mean blood pressure reductions in the β-blocker sensitive patients (n=11) between 6 a.m. and noon were −15.2/-11.9 mm Hg on INP and -8.0/-4.6 mm Hg on ILA. Heart rate reduction was −14.1 bpm and double product reduction was −3319 in the INP patients between 6 a.m. and 12 noon compared with −10.5 and −2209 in the ILA patients. This study suggests that INP and ILA are effective once-a-day β blockers, but the use of delayed-release propanolol results in a greater reduction in double product between 6 a.m. and noon in β-blocker sensitive patients than does traditionally dosed propranolol.     

Severe paroxysmal hypertension (Pseudopheochromocytoma)

Paroxysmal hypertension always engenders a search for a catecholamine-secreting pheochromocytoma. Yet 98% of people with paroxysmal hypertension do not have this tumor. The cause and management of paroxysmal hypertension remain a mystery, and the subject of remarkably few papers. This review presents an approach to understanding and successfully treating this disorder. Patients experience symptomatic blood pressure surges likely linked to sympathetic nervous system stimulation. A specific personality profile associated with this disorder suggests a psychological basis, attributable to repressed emotion related to prior emotional trauma or a repressive (nonemotional) coping style. Based on this understanding, three forms of intervention, alone or in combination, appear successful: antihypertensive therapy with agents directed at the sympathetically mediated blood pressure elevation (eg, combined α- and β-blockade or central α-agonists such as clonidine); psychopharmacologic interventions including anxiolytic and/or antidepressant agents; and psychological intervention, particularly reassurance and increased psychological awareness. An appropriately selected intervention can reduce or eliminate attacks in most patients.     

Diagnosis of thalassaemia by non-isotope detection of α/β and ζ/α mRNA ratios

Summary. The α/β and ζ/α messenger RNA (mRNA) ratios in the thalassaemia syndromes were investigated by polymerase chain reaction (PCR) with silver staining of the PCR products. In this study we used the PCR to amplify cDNA copies of circulating erythroid cell mRNA in order to measure the relative amounts of α-, β- and ζ-globin contained within. Quantitation was performed by scanning the silver stain of specific globin cDNA bands. We found that there were significant differences of α/β-mRNA and ζ/α-mRNA in patients with Hb H disease and α-thalassaemia-1 compared to normal subjects. There was a marked increase in the α/β-mRNA ratio but not in the ζ/α-mRNA ratio in patients with β-thalassaemia. In two β-thalassaemia cases abnormal increases of ζ-globin bands were noted and they were confirmed through DNA analysis to be combined with α-thalassaemia-1. This method provides a simple, rapid and non-radioactive approach to detect thalassaemia syndromes, and can help to screen cases of β-thalassaemia with α-thalassaemia-1.     

Haemoglobin Tak: a β-Chain Elongation

In Haemoglobin Tak two normal α-chains are combined with two β-chains elongated by 11 residues beyond the C-terminus. Unlike in the α-chain abnormal Hb Constant Spring, the elongation cannot result from a point mutation of a stop codon. It is probably due to an unequal crossing-over near the 3' end of the β-chain structural gene. This could cause either a deletion of the normal stop codon or a shift in the reading frame. Oxygen dissociation of purified Hb Tak shows no cooperativity but in Hb A + Tak haemolysates there is no interaction between the two above 40% O₂ saturation. Heterozygotes for Hbs A and Tak show an imbalance of globin chain synthesis (α/non α= 1.5), the synthesis of β Tak resembles that of the β-chain in β⁺ thalassaemia.     

The interaction of α thalassaemia with heterozygous β thalassaemia

S ummary . The α globin genotypes of 55 β thalassaemia heterozygotes have been determined by restriction endonuclease analysis to identify those with interacting α thalassaemia genes. A comparison of the haematological and haemoglobin synthesis findings of individuals with normal α genotypes (αα/αα) with those with one (- α/αα) or two (-α/-α) α genes deleted shows that the latter two groups have more balanced globin chain synthesis ratios, higher haemoglobin levels, and larger, better haemoglobinized red cells. This suggests that the degree of globin chain imbalance is a significant factor in determining the red cell characteristics in heterozygous β thalassaemia. Screening programmes for thalassaemia, based on the detection of low MCVs, could miss cases of the interaction of α and β thalassaemia.     

Haemoglobin Synthesis in β-Thalassaemia

S ummary . The incorporation of radioactive amino acids into the polypeptide chains of haemoglobin has been studied in reticulocyte preparations from five patients with β-thalassaemia and four control patients. In both groups of patients an intracellular pool of free α-chains has been found, but the pool is much larger in patients with β-thalassaeniia major. The α-chains exist in two forms: α-dimers and α-monomers, but the results suggest that they are released as dimers from the ribosomes and that the α-chains for Hb-A and Hb-F synthesis are derived from the α-dimer pool. The α-dimers are also gradually converted to the monomers, and this may be the first stage in the denaturation of this protein. The results also show that the α-dimer can exchange with the α-chains of Hb-A and that this exchange is more rapid in the presence of in vivo aged Hb-A. In one patient with thalassaemia it was shown that there was no pool of unreleased β-chains on the ribosomes. There is also no evidence for the release of incompleted β-chains in our patients.     

Realities of Newer β-Blockers for the Management of Hypertension

β-blockers are prescribed for a variety of cardiovascular conditions including hypertension, heart failure, primary treatment of myocardial infarction (MI), and secondary prevention of ischemic cardiac events. Yet they remain underprescribed in populations at increased risk for cardiovascular disease because of tolerability and safety concerns. β-Blockers are heterogeneous with respect to pharmacokinetic and pharmacodynamic effects. "Original" agents were nonselective, blocking both β₁-adrenoceptors and β₂-adrenoceptors. Later, new agents were developed with selectivity for β₁-adrenoceptors, and were subsequently followed by β-blockers, which exhibit additional effects, such as vasodilation. Among newer agents, labetalol, carvedilol, and nebivolol have been approved for use in the United States. Nebivolol possesses both β₁-selectivity and nitric oxide–mediated vasodilatory effects, while carvedilol has attractive effects on insulin resistance and exhibits antioxidant effects. Newer β-blockers may overcome concerns about efficacy, adverse effects, and tolerability, while delivering cardiovascular protection.     

The latest generation of beta-blockers: New pharmacologic properties

β-Blockers have generally demonstrated smaller reductions in cardiovascular events, compared with other antihypertensive classes, despite similar reductions in blood pressure. This may be due to the ineffectiveness of traditional β-blockers, such as atenolol, in reducing central aortic pressure, a strong, independent predictor of cardiovascular outcome. However, the β-blocker class is heterogeneous, and some newer β-blockers, which exhibit vasodilatory effects independent of β-blockade, provide beneficial effects on arterial stiffness and endothelial dysfunction, which may lead to reductions in central aortic pressure and improvements in clinical outcomes. For example, the vasodilating β-blocker nebivolol was shown to improve forearm blood flow and arterial stiffness and, in a large clinical study, to significantly reduce morbidity and mortality, independent of left ventricular ejection fraction, among patients with chronic heart failure. Further research is warranted to investigate any potential differences between traditional and newer vasodilating β-blockers on cardiovascular outcomes.     

Early Initiation of β Blockade in Heart Failure: Issues and Evidence

Despite clinical trials demonstrating that inhibitors of the renin-angiotensin and sympathetic nervous systems can reduce the mortality and morbidity risk associated with heart failure, these drugs have remained underutilized in general clinical practice. In particular, many patients with heart failure due to left ventricular systolic dysfunction fail to receive β blockers, although this class of drugs, as well as other antihypertensive agents such as angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, are recommended as part of routine heart failure therapy by national expert consensus guidelines. In-hospital initiation of β-blocker therapy may improve long-term utilization by physicians and compliance by patients through obviating many of the misperceived dangers associated with β blockade. The following review of the clinical trial data from the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial, the Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial, and the Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial on the efficacy, safety, and tolerability of β blockers indicates that early initiation can be safely achieved and can improve patient outcomes.     

The Clinical and Biosynthetic Characterization of αβ-Thalassaemia

A Cypriot family is described in which three thalassaemia genes, α-thalassaemia 1, α-thalassaemia 2, and β–thalassaemia, are segregating. Two siblings are heterozygous for both α-thalassaemia 1 and β-thalassaemia while a third child has typical haemoglobin H disease. The α-thalassaemia β-thalassaemia combination, which is associated with an α/β chain production ratio of unity, produces a moderate degree of anaemia with marked hypochromia and morphological changes of the red cells together with increased rates of flux of potassium across the membranes, but the red cell survival is normal. These changes m red cell morphology and metabolism are very similar to those found in the sibling with haemoglobin H disease in whom there is gross imbalance of globin chain synthesis and shortened red cell survival. These results suggest that imbalanced globin chain production is the primary cause of shortened red cell survival in thalassaemia and that changes in membrane permeability are probably of secondary importance and may, at least in part, result from factors other than globin chain imbalance.     

Heart Failure and Its Management With β-Blockade: Potential Applications of Once-Daily Therapy

Heart failure (HF) due to left ventricular (LV) systolic dysfunction is a progressive disease beginning with a primary injury that activates compensatory cardiovascular mechanisms including varying degrees of neurohormonal activation. Within the neurohormonal cascade, activation of the sympathetic nervous system is in part responsible for ongoing myocardial injury, progressive LV remodeling, and functional deterioration eventually leading to symptomatic HF. Large randomized clinical trials of certain β-blockers added to standard therapies have shown unequivocal benefits in patients with chronic systolic HF resulting in reduced remodeling, fewer total and cardiovascular deaths, and less risk of hospitalization for worsening HF. Evidence-based clinical guidelines recommend β-blockers as part of the regimen for patients with systolic HF as well as LV dysfunction following myocardial infarction. Based on published clinical trial results, bisoprolol, carvedilol, and sustained-release metoprolol succinate are recommended for systolic HF. Carvedilol, propranolol, and timolol are recommended for post-myocardial infarction LV dysfunction. Unfortunately, these evidence-based therapies are often underused in actual practice. Various strategies to increase β-blocker use in HF have been attempted, including in-hospital initiation of β-blocker therapy. Simplifying dosing regimens may also improve adherence to prescribed medications. Use of controlled-release carvedilol may encourage better adherence in patients with LV dysfunction and help overcome at least one barrier to optimal evidence-based care.     

δβ-Thalassaemia in a Chinese Family

S ummary . δβ-Thalassaemia has been observed for the first time in individuals of Chinese origin. The clinical and haematological features have been characterized in the heterozygous state and in the double heterozygous state withβ-thalassaemia. Studies of haemoglobin synthesis indicate that the degree of globin chain imbalance in β-thalassaemia is less than that found in β-thalassaemia. Analysis of the foetal haemoglobin has shown that all individuals carrying the δβ-thalassaemia gene in this family synthesize only the α₂γ₂^{136 glycine} variety. This type of foetal haemoglobin has been found previously only in two Negro individuals heterozygous for hereditary persistence of foetal haemoglobin (HPFH). The genetic relationships between δβ-thalassaemia and HPFH are discussed in the light of these new findings.     

Treatment of Hypertension in the Institutionalized Elderly

The goal of antihypertensive therapy in elderly institutionalized persons is to reduce the blood pressure to <140/90 mm Hg if possible. Elderly persons with diastolic hypertension should have their diastolic blood pressure lowered to 80–85 mm Hg. Elderly persons with stage 2 or 3 hypertension, stage 1 hypertension and target organ damage, evidence of clinical cardiovascular disease, or diabetes mellitus should be treated with antihypertensive drug therapy immediately in addition to lifestyle modification. The initial antihypertensive drug in elderly persons without associated medical conditions should be a diuretic or β-blocker because these drugs have been shown to decrease cardiovascular morbidity and mortality in controlled clinical trials. The initial antihypertensive drug in elderly persons should depend on the associated medical condition. If a second antihypertensive drug is indicated, a drug from another class should be administered. If a diuretic is not the initial drug, it is usually indicated as the second drug. If the antihypertensive response is inadequate after reaching the full dose of two classes of drugs, a third drug from another class should be added. Causes of secondary hypertension should be identified and treated.     

Globin Synthesis in Sideroblastic Anaemia I α AND β PEPTIDE CHAIN SYNTHESIS

S ummary . The in vitro synthesis of the α and β peptide chains of globin have been measured in 11 patients suffering from sideroblastic anaemia (four congenital and seven idiopathic acquired). In the I0 patients who were anaemic the findings were similar. The synthesis of the globin chains was found to be defective in two respects; firstly, synthesis was asynchronous with an apparent deficiency of the synthesis of α chains, and, secondly, a large proportion of both α and β chains synthesized were not associated with haem but were free in the cell in the form of αβ dimers. Addition of haem to the incubation mixture greatly stimulated the synthesis of both chains, removed the free dimer pool and appeared to stimulate a chain synthesis. The finding that a large proportion of the α and β chains synthesized are not associated with haem but are free within the cell as a dimer pool, is very strong evidence that the underlying defect in sideroblastic anaemia is haem deficiency. The defective synthesis of a chains relative to β chains is as yet unexplained but may account for the low haemoglobin A₂ associated with this condition.     

Current concepts of pharmacotherapy in hypertension: combination calcium channel blocker therapy in the treatment of hypertension

Effective control of blood pressure is usually achieved only with the use of two or more antihypertensive medications. The treatment options for hypertension are numerous, and the number of possible combinations large. The selection of a specific combination drug regimen has often been linked to the perceived need for diuretic therapy as first- or second-step therapy; thus, the popularity of such drug combinations as an angiotensin-converting enzyme (ACE) inhibitor/diuretic, an angiotensin-receptor blocker/diuretic, or a β blocker/diuretic. Rational alternatives exist, including an ACE inhibitor/calcium channel blocker (CCB) or a dihydropyridine CCB/β blocker combination. Traditionally, recommendations have advised against the use of combination therapy with two drugs from the same therapeutic class. However, because of the different binding and pharmacologic characteristics of CCBs, a rationale exists for combining different agents in this class in the management of hypertension and/or symptomatic coronary artery disease. In the treatment of either hypertension or angina, combination CCB therapy can prove uniquely successful.     

α- and β-haemoglobin chain induced changes in normal erythrocyte deformability: comparison to β thalassaemia intermedia and Hb H disease

Summary The α and β-thalassaemias are characterized by decreased erythrocyte deformability. To determine what effects excess α and β-haemoglobin (globin) chains have on cellular and membrane deformability, purified haem-con-taining α and β-chains were entrapped within normal erythrocytes. Entrapment of purified α-chains in normal erythrocytes resulted in a significant decrease in cellular and membrane deformability similar to that observed in β-thalassaemia intermedia. The decreased deformability was correlated with α-chain membrane deposition, an alteration in membrane proteins and a decrease in membrane reactive thiol groups. These changes in membrane and cellular deformability were time dependent and closely correlated with membrane α-chain deposition. The membrane changes and the loss of membrane deformability appeared to account for the loss of cellular deformability in the α-chain loaded cells. While both β-chain loaded and Hb H erythrocytes demonstrated a significant loss of cellular deformability, this loss was less pronounced than in the α-chain loaded and β-thalassaemic cells and may arise from either the increased intracellular viscosity of the β-chain loaded cells or to the smaller amount of membrane bound globin. In summary, these studies demonstrate that alteration of cellular and membrane deformability occurs very rapidly and as a direct consequence of the autoxidation and membrane binding of the unpaired globin chains.     

Globin Biosynthesis in Erythroid Bursts of Heterozygous α or β Thalassaemia

S ummary . We examined globin chain synthesis in erythroid bursts (BFU-E) of patients with heterozygous α or β thalassaemia. BFU-E were cloned from circulating mononuclear cells, labelled with [H]leucine and globin chains purified by gel filtration and column chromatography. In six patients heterozygous for β thalassaemia, globin synthesis in BFU-E was nearly balanced, with an α/non α ratio of 1.05 0α12. These BFU-E produced 33.8 12.7%γ globin chain, an amount similar ( P >1 0.05) to that found in 10 controls with sickle cell anaemia (25.6 6.7) but greater ( P <0.05) than that of five normal controls (17.2 2.2). The balanced globin synthesis appeared due to the large amounts of γ chain made by BFU-E. In two α thalassaemia carriers, who also had sickle cell trait, the BFU-E α/non-α ratio was 0.67 and 0.79. These BFU-E produced 15% and 20%γ chain and 39% and 45%β^S globin. The synthesis of β^S globin in BFU-E exceeded the erythrocyte levels of 20% and 29% HbS and indicated nearly equal expression of β^A and β^B globin genes in these proliferating erythroid precursors. This provides further evidence that the low levels of HbS in sickle cell carriers with α thalassaemia are due to post-translational events resulting from the differing affinity of β^S and β^A globin for α chain and the destruction of excessive β^S chain.     

Expression of CD8β and alteration of cell surface phenotype in adult T-cell leukaemia cells

Typical adult T-cell leukaemia (ATL) cells have a CD4⁺CD8⁻ cell surface phenotype, but atypical phenotypes such as CD4⁺CD8⁺ and CD4⁻CD8⁺ have also been reported. The CD8 molecule is composed of α and β chains and commonly used monoclonal antibodies against CD8 molecule detect only CD8α. Since it has been reported that CD8α can be induced in mature CD4⁺ T cells by cell activation, but not CD8β, we studied whether ATL cells which express CD8α may also express CD8β. We found some cases of CD8α⁺ ATL were also positive for CD8β. Furthermore, we experienced a case whose ATL cell surface phenotype changed from CD4⁺CD8α⁺CD8β⁺ to CD4⁻CD8α⁺CD8β⁺ and finally to CD4⁺CD8α⁻CD8β⁻. Southern blot analysis revealed that the monoclonal integration of human T lymphotropic virus type I (HTLV-I) was identical throughout the course of the study, indicating that a single clone had demonstrated the alterations. These data suggest that peripheral CD4⁺CD8⁺ ATL cells can express not only CD8α, but also CD8β and that a single ATL cell clone has the potential to change its surface phenotype in vivo as well as in vitro .