The importance of left ventricular hypertrophy in human hypertension

Hemodynamic and non-hemodynamic factors contribute to the development of left ventricular hypertrophy (LVH). The presence of LVH is an important independent risk factor for total mortality and for cardiovascular morbidity and mortality. Direct cardiac effects of LVH include an increased risk of developing of congestive heart failure, an increased risk of arrhythmic events, and a reduced coronary flow reserve, promoting myocardial ischemic episodes. In addition, hypertension may promote the development of coronary artery atherosclerosis. The prognostic implications of LVH underscore the importance of diagnostic procedures. The electrocardiogram has a high specificity to identify patients with LVH but the sensitivity is fairly low. Echocardiography provides higher sensitivity and also gives important information, such as the pattern of left ventricular geometry, which is of prognostic importance, and the presence of diastolic dysfunction, which is an early abnormality in the evolution of hypertensive LVH. Reversal of LVH appears to improve prognosis. Reduction of blood pressure is one important component in the regression of LVH. Important quantitative differences exist between drug classes in the reversal of cardiac hypertrophy despite similar antihypertensive effects, suggesting other factors to be of importance in the regression of left ventricular mass. LVH is reduced more by angiotensin-converting enzyme inhibitors than by other antihypertensive drug classes, suggesting an effect on structural myocardial changes beyond that provided by the reduction of blood pressure. Recent data suggest that angiotensin II receptor antagonists (AIIRAs) have quantitatively similar effects on left ventricular mass as do angiotensin-converting enzyme inhibitors. A comparative trial of the AIIRA irbesartan and the beta-blocker atenolol demonstrated that despite similar reductions in blood pressure, the reductions attained in left ventricular mass with irbesartan were progressive and numerically greater than those attained with atenolol. Taken together, these findings provide circumstantial evidence for an important role of angiotensin II acting on angiotensin type 1 (AT1) receptors in the development or maintenance of cardiac hypertrophy. Confirmation of the favorable effects of angiotensin-converting enzyme inhibitors and AIIRAs on left ventricular mass in larger trials, including those assessing cardiovascular morbidity and mortality, will be of major importance in the future treatment of hypertension.     

Left ventricular hypertrophy--an important, often unrecognized risk factor

Epidemiological studies both in the general population and in series of hypertensive patients have shown the presence of left ventricular hypertrophy (LVH), as determined by echocardiography, to be a powerful risk factor for cardiovascular events. Although LVH is generally associated with hypertension, less than half of hypertensive patients develop LVH. Insulin resistance, endothelial dysfunction, increased blood viscosity, decreased arterial compliance, and increased angiotensin-converting enzyme activity have all been associated with the development of LVH. Although findings in observational studies suggest LVH regression to have a beneficial effect in terms of decreased cardiovascular risk, confirmation of this awaits the results of prospective clinical trials currently being carried out.     

Single-drug therapy and reduction of left ventricular mass in hypertension

Echocardiography has provided most of what is understood today about the relationships between human hypertension, cardiac anatomic and functional responses. It has proven its value in determining the effects of antihypertensive therapy on cardiac structure and function. A growing body of research supports initial concerns that not all drugs effective for blood pressure reduction are effective for reduction of left ventricular mass and regression of LVH. It has been of interest that agents initially believed to be ineffective for left ventricular mass reduction (principally diuretics and beta blockers) on the basis of pathophysiological theory and inadequate clinical trials, may in fact be quite effective for LVH regression, as well as improved cardiac outcomes. Hence, supposed inefficacy of these agents for this purpose should no longer be used as a reason to disregard long-standing recommendations of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Hypertension supporting the use of diuretics and beta blockers for the initial pharmacotherapy of hypertension.     

The Power of Statistical Tests for Moderators in Meta-Analysis.

Calculation of the statistical power of statistical tests is important in planning and interpreting the results of research studies, including meta-analyses. It is particularly important in moderator analyses in meta-analysis, which are often used as sensitivity analyses to rule out moderator effects but also may have low statistical power. This article describes how to compute statistical power of both fixed- and mixed-effects moderator tests in meta-analysis that are analogous to the analysis of variance and multiple regression analysis for effect sizes. It also shows how to compute power of tests for goodness of fit associated with these models. Examples from a published meta-analysis demonstrate that power of moderator tests and goodness-of-fit tests is not always high. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of the reduction of colloid oncotic pressure, with and without reduction of osmolality, on post-traumatic cerebral edema

The fact that centrally acting analgesics have abuse potential commensurate with their analgesic activity raises the question of whether these effects are related. The abuse potential of drugs depends on their ability to produce reinforcing effects, which are mediated by a neural system that includes the ventral tegmental dopamine cells and their connections with the ventral striatum. Morphine and amphetamine are both powerful analgesics and have high abuse potential. Their analgesic and reinforcing effects are mediated by similar receptors, similar sites of action, and overlapping neural substrates. These coincidences suggest that reinforcers may produce analgesia by transforming the aversive affective state evoked by pain into a more positive affective state. The implications of this hypothesis and its relation to other known mechanisms of analgesia are discussed. The hypothesis predicts that drugs with reinforcing effects should produce analgesia. A survey of drugs acting through 21 classes of receptors reveals that in 13 classes there is evidence for both analgesic and reinforcing effects that are approximately equipotent. The GABA(A) agonists were found to be the only drugs with confirmed abuse potential that lack analgesic activity. The interpretation of this and several other anomalous cases is discussed.     

Can good surrogate end-points predict the prognosis of hypertensive patients?

SURROGATE END-POINTS FOR PROGNOSIS OF HYPERTENSION: The identification of surrogate measures of cardiovascular risk in patients with hypertension may allow clinicians to better estimate a patient's long-term prognosis and monitor the effects of antihypertensive therapy in reducing risk and thereby reducing the cardiovascular complications of hypertension. PROGNOSTIC LIMITATIONS OF OFFICE BLOOD PRESSURE: Previous studies have shown that office blood pressure may predict the incidence of fatal and nonfatal cardiovascular complications of hypertension. However, evidence also suggests that the predictive value of office blood pressure is limited and that it does not provide accurate estimates of the changes in the cardiovascular risk profile that can occur with antihypertensive treatment. PROGNOSTIC VALUE OF 24-H AMBULATORY BLOOD PRESSURE: Cross-sectional studies have shown that 24-h average blood pressure values are more closely correlated with hypertensive target-organ damage [e.g. left ventricular hypertrophy (LVH), retinopathy, increased serum creatinine, albuminuria, and microalbuminuria] than are office blood pressure values. Although longitudinal evidence of the clinical relevance of 24-h ambulatory blood pressure monitoring is limited, preliminary data from a recently completed trial, the Study on Ambulatory Pressure and Lisinopril Evaluation (SAMPLE), have clearly shown the superiority of 24-h blood pressure monitoring over office readings in predicting the regression of LVH in hypertensive patients following treatment to reduce blood pressure.     

Alpha 1-blocker combination therapy for hypertension

Combination therapy is a cost-effective and rational approach to treatment of severe hypertension and of mild to moderate hypertension that is refractory to monotherapy. The method has several advantages, most notably improved tolerability and enhanced antihypertensive efficacy. Long-term prospective studies are needed to confirm that such agents as calcium channel blockers, ACE inhibitors, and alpha 1 blockers reduce end-organ damage more effectively than do older antihypertensive drugs. However, scientific evidence strongly suggests that reducing risk factors for end-organ damage reduces heart, brain, kidney, and large-artery injury. Alpha 1 blockers appear to be a particularly suitable choice for use in combination regimens. The only class of agents that should be avoided in combination with alpha 1 blockers is central alpha agonists; all other agents act in an additive or synergistic fashion. Unlike diuretics and beta blockers, alpha 1 blockers do not adversely affect serum lipid, glucose, or insulin levels. In fact, alpha 1 blockers may improve these measurements and also counteract the adverse effects of other antihypertensive agents on them. Alpha1-blocker therapy may bring about regression of LVH, and it does not have deleterious effects on disorders that often coexist with hypertension (e.g., gout, chronic obstructive lung disease, peripheral ischemia).     

The Influence of Framing on Risky Decisions: A Meta-analysis

In framing studies, logically equivalent choice situations are differently described and the resulting preferences are studied. A meta-analysis of framing effects is presented for risky choice problems which are framed either as gains or as losses. This evaluates the finding that highlighting the positive aspects of formally identical problems does lead to risk aversion and that highlighting their equivalent negative aspects does lead to risk seeking. Based on a data pool of 136 empirical papers that reported framing experiments with nearly 30,000 participants, we calculated 230 effect sizes. Results show that the overall framing effect between conditions is of small to moderate size and that profound differences exist between research designs. Potentially relevant characteristics were coded for each study. The most important characteristics were whether framing is manipulated by changing reference points or by manipulating outcome salience, and response mode (choice vs. rating/judgment). Further important characteristics were whether options differ qualitatively or quantitatively in risk, whether there is one or multiple risky events, whether framing is manipulated by gain/loss or by task-responsive wording, whether dependent variables are measured between- or within- subjects, and problem domains. Sample (students vs. target populations) and unit of analysis (individual vs. group) was not influential. It is concluded that framing is a reliable phenomenon, but that outcome salience manipulations, which constitute a considerable amount of work, have to be distinguished from reference point manipulations and that procedural features of experimental settings have a considerable effect on effect sizes in framing experiments. Copyright 1998 Academic Press.     

Regression of cardiac hypertrophy by 1,4 dihydropyridines in hypertensive patients

BACKGROUND: Left ventricular hypertrophy (LVH) represents an important intermediate end-point for, for example, the progression to heart failure. The persistence or progression of LVH despite antihypertensive therapy probably reflects the persistence or activation of mechanisms that negatively affect the cardiovascular system and, consequently, long-term outcome. EFFECT OF MODERN ANTIHYPERTENSIVE AGENTS: Long-term treatment with rapid-onset (and usually short-acting) dihydropyridine calcium antagonists is significantly less effective than angiotensin converting enzyme (ACE) inhibition in reducing left ventricular mass (LVM) in hypertensive patients. Both intermittent, and probably only partial, blood pressure control and an increase in sympathetic activity resulting from rapid decreases in blood pressure following dosing with such calcium antagonists may contribute to this relative ineffectiveness. In contrast, more recent studies have demonstrated that the longer acting dihydropyridines can reduce LVM as effectively as ACE inhibitors. DISTINCTIONS AMONG DIHYDROPYRIDINE CALCIUM ANTAGONISTS: Among the 1,4-dihydropyridines, drugs such as amlodipine and nifedipine in the gastrointestinal therapeutic system (GITS) maintain good blood pressure control over the full 24-h dosing period and do not cause dose-related increases in sympathetic activity. In contrast, extended-release felodipine has been shown to provide only intermittent blood pressure control, still leading to sympathetic activation. Notably, during short periods of noncompliance, blood pressure control is maintained with intrinsically long-acting agents such as amlodipine but not with slow-release formulations of short-acting agents such as nifedipine GITS. CONCLUSIONS: It is possible that the rate of onset and duration of action of various dihydropyridines may be pivotal factors in determining their effects on cardiovascular outcomes. Thus, the least beneficial dihydropyridines may be rapid-onset, short-acting agents, such as nifedipine capsules, and the most beneficial may be the slow-onset, long-acting agents such as amlodipine.     

Meta-analysis of multiple outcomes by regression with random effects

Earlier work showed how to perform fixed-effects meta-analysis of studies or trials when each provides results on more than one outcome per patient and these multiple outcomes are correlated. That fixed-effects generalized-least-squares approach analyzes the multiple outcomes jointly within a single model, and it can include covariates, such as duration of therapy or quality of trial, that may explain observed heterogeneity of results among the trials. Sometimes the covariates explain all the heterogeneity, and the fixed-effects regression model is appropriate. However, unexplained heterogeneity may often remain, even after taking into account known or suspected covariates. Because fixed-effects models do not make allowance for this remaining unexplained heterogeneity, the potential exists for bias in estimated coefficients, standard errors and p-values. We propose two random-effects approaches for the regression meta-analysis of multiple correlated outcomes. We compare their use with fixed-effects models and with separate-outcomes models in a meta-analysis of periodontal clinical trials. A simulation study shows the advantages of the random-effects approach. These methods also facilitate meta-analysis of trials that compare more than two treatments.     

Links between physical fitness and cardiovascular reactivity and recovery to psychological stressors: A meta-analysis.

A meta-analysis of published studies with adult human participants was conducted to evaluate whether physical fitness attenuates cardiovascular reactivity and improves recovery from acute psychological stressors. Thirty-three studies met selection criteria; 18 were included in recovery analyses. Effect sizes and moderator influences were calculated by using meta-analysis software. A fixed effects model was fit initially; however, between-studies heterogeneity could not be explained even after inclusion of moderators. Therefore, to account for residual heterogeneity, a random effects model was estimated. Under this model, fit individuals showed significantly attenuated heart rate and systolic blood pressure reactivity and a trend toward attenuated diastolic blood pressure reactivity. Fit individuals also showed faster heart rate recovery, but there were no significant differences in systolic blood pressure or diastolic blood pressure recovery. No significant moderators emerged. Results have important implications for elucidating mechanisms underlying effects of fitness on cardiovascular disease and suggest that fitness may be an important confound in studies of stress reactivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Traditional treatment of obesity: does it work?

Obesity is the most important nutritional disorder in the developed world, since up to 10% of the population are obese. The place of physical activity and diet in the aetiology of obesity is discussed. The traditional treatment of obesity includes change in lifestyle, nutritional education and modification and increase in exercise. These changes are important for long-term success. There are a number of other treatment options including anorectic drugs, the use of very low calorie diets and surgical techniques which may have some clinical role. For the extremely obese patient with established complications surgery may be the most appropriate intervention and may be life-saving. Most studies of traditional treatment have demonstrated limited success. The prevention of obesity is therefore of great importance. Large-scale studies have shown that it is possible to modify behaviour and cardiovascular risk factors. The prevention of obesity requires a coordinated approach with targeting of children and their carers. Governmental involvement and legislation is essential. The future holds the promise of more imaginative and coordinated therapies for obesity using the skills of physicians, nutritionists, exercise physiologists and psychologists. Different forms of treatment may be appropriate for different groups of obese patients.     

A critical analysis of studies of state drug reimbursement policies: research in need of discipline

Concerns over pharmaceutical costs and appropriateness of medication use have led state Medicaid programs to restrict drug reimbursement. This article critically reviews 20 years of research on cost sharing, drug reimbursement limits, and administrative limitations on access to particular drugs via formularies, category exclusions, or prior authorization requirements; evaluates their methodological rigor; summarizes the state of current knowledge; and proposes future research directions. Drug reimbursement caps and modest cost sharing can reduce the use of both essential and less important drugs in Medicaid populations; severe reimbursement caps may precipitate serious unintended effects. Limitations on access to particular drugs can cause both rational and irrational drug substitution effects; it is unclear whether such limits reduce expenditures either for drugs or for overall health care.     

Association of electrocardiographic left ventricular hypertrophy with the incidence of new congestive heart failure

OBJECTIVE: To investigate the association of electrocardiographic (ECG) left ventricular hypertrophy (LVH) with the incidence of new congestive heart failure (CHF) in older people. DESIGN: In a prospective study of 2638 older people, ECGs were obtained at study entry, at 1 month after study entry, when clinically indicated, and at least yearly after study entry. ECG LVH was diagnosed if the point score of Romhilt and Estes was > or = 5. Persistent LVH was diagnosed if all of the ECGs showed LVH. New LVH was diagnosed if the baseline ECG showed no LVH but LVH was present on the last ECG. Regression of LVH was diagnosed if the baseline ECG showed LVH but no LVH was present on the last ECG. No LVH was diagnosed if all of the ECGs showed no LVH. Persistent LVH, new LVH, regression of LVH, and no LVH were correlated with the incidence of new CHF at follow-up. SETTING: A large long-term health care facility. PATIENTS: The patients included 1805 women and 833 men, mean age 81 +/- 9 years (range 60 to 103). MEASUREMENTS AND MAIN RESULTS: Of the 2,638 older persons studied, 281 (11%) had persistent ECG LVH, 31 (1%) had new ECG LVH, 12 (0.5%) had regression of ECG LVH, and 2314 (88%) had no ECG LVH. At 42 +/- 24 months (range 1 to 154 months) follow-up, new CHF developed in 168 of 281 persons (60%) with persistent LVH, in 16 of 31 persons (52%) with new LVH, in 4 of 12 persons (33%) with regression of LVH, and in 507 of 2314 persons (22%) with no LVH. Kaplan-Meier survival curves showed that the development of new CHF was higher in persons with persistent LVH versus regression of LVH (P = .013), in persons with persistent LVH versus no LVH (P = .001), in persons with new LVH versus regression of LVH (P = .039), and in persons with new LVH versus no LVH (P = .001). CONCLUSION: Older persons with persistent or new ECG LVH have a higher incidence of new CHF and an earlier time to the development of new CHF than older persons without ECG LVH.     

Left ventricular hypertrophy, blood pressure and ACE genotype in untreated hypertension

It has been suggested that the deletion polymorphism of the angiotensin-converting enzyme (ACE) genotype may be important in the development of left ventricular hypertrophy (LVH). In order to test this hypothesis we investigated the interaction between blood pressure (BP), LVH and ACE genotype in 86 previously untreated hypertensive patients. Each underwent two-dimensional and Doppler echocardiography and ACE genotyping. There were no significant differences in BP, the parameters of left ventricular structure (including left ventricular mass index) or diastolic function between the three genotype groups. Additionally, there were no significant differences in the relationship between systolic BP and left ventricular mass index among the three genotype groups (II genotype, r = 0.46, P = 0.02; ID genotype, r = 0.42, P = 0.01; DD genotype, r = 0.34, P = 0.10; F = 0.38). In contrast to some previous studies, we have found in this group of previously untreated hypertensive subjects no evidence to suggest that the deletion polymorphism of the ACE genotype is important in the development of LVH.     

Regression of left ventricular hypertrophy results in improvement of QT dispersion in patients with hypertension

OBJECTIVES: Increased QT dispersion has been considered as predisposing to ventricular arrhythmias in hypertrophic cardiomyopathy, congestive heart failure, and coronary artery disease. An increased QT dispersion has also been found in hypertensive patients with left ventricular hypertrophy (LVH). The data on the effect of LVH regression on QT dispersion are limited. METHODS AND RESULTS: To assess the relation of LVH regression and QT dispersion decrease, 68 patients (42 men and 26 women, mean age 56.3+/-9.5 years) with uncomplicated essential hypertension were studied. All underwent full electrocardiographic and echocardiographic studies at baseline and after 6 months of monotherapy, 29 with angiotensin-converting enzyme inhibitors and 39 with calcium antagonists. QT dispersion was calculated by subtracting the shortest QT from the longest QT, in absolute value (QTmax - QTmin). It was also corrected with Bazett's formula (QTc dispersion). Left ventricular mass index was assessed according to the Devereux formula. After treatment, LVH decreased with both angiotensin-converting enzyme inhibitors (from 155 to 130 g/m2, P < .001) and calcium antagonists (156 to 133/92/m2, P < .001). QT dispersion decreased both after angiotensin-converting enzyme inhibitor treatment (from 82 to 63 ms) and calcium antagonist treatment (from 77 to 63 ms, both P < .001 ). There was a significant correlation of QT dispersion and left ventricular mass after therapy (r = 0.36, P < .005). There was a correlation of the degree of LVH and QT dispersion decrease (r = 0.27, P < .05). CONCLUSIONS: It is concluded that LVH regression influences AQT favorably. Its prognostic value has yet to be determined.     

Nicotinic system involvement in Alzheimer's and Parkinson's diseases. Implications for therapeutics

Advances in our understanding of the structure, function and distribution of nicotinic acetylcholine receptors in the CNS have provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realisation that such receptors must be involved in the maintenance of cigarette smoking, and from clues provided by studies of degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease, in which the loss of nicotinic receptors has been described. Ongoing investigations of the molecular substructure of central nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioural, motor and sensory functioning. Clues from careful studies of human cognition are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Despite the promising results of acute studies, few long term studies with nicotine or nicotinic drugs have been performed in dementing disorders. Thus there is uncertainty as to whether long term nicotinic treatment will provide sustained cognitive benefit. It is even more uncertain whether such cognitive benefit will have a significant clinical impact on patients and their families. To maximise the potential benefit of long term treatment with nicotinic agonists (or other cholinergic drugs), we suggest that drug treatment should be combined with cognitive rehabilitation strategies. This will enable patients and/or their families to focus on the particular cognitive domains that may be improved.     

Electrophysiologic significance of leftward QRS axis deviation in bifascicular and trifascicular blocks

The trustworthiness of meta-analysis, a set of techniques used to quantitatively combine results from different studies, has recently been questioned. Problems with meta-analysis stem from bias in selecting studies to include in a meta-analysis and from combining study results when it is inappropriate to do so. Simple graphical techniques address these problems but are infrequently applied. Funnel plots display the relationship of effect size versus sample size and help determine whether there is likely to have been selection bias in including studies in the meta-analysis. The L'Abbé plot displays the outcomes in both the treatment and control groups of included studies and helps to decide whether the studies are too heterogeneous to appropriately combine into a single measure of effect.     

Does psi exist? Reply to Storm and Ertel (2001).

The authors recently published a nonsignificant meta-analysis of 30 extrasensory perception ganzfeld studies, all conducted after the 1986 publication of important methodological guidelines aimed at reducing sources of artifact noted in earlier studies. In response, L. Storm and S. Ertel (2001) presented a meta-analysis of 79 studies published between 1974 and 1996. They argued that the positive and highly statistically significant overall outcome indicates a replicable paranormal effect. In doing so, they ignored the well-documented and widely recognized methodological problems in the early studies, which make it impossible to interpret the results as evidence of extrasensory perception. In addition, Storm and Ertel's meta-analysis is not an accurate quantitative summary of ganzfeld research because of methodological problems such as their use of an inconsistent method for calculating study outcomes and inconsistent inclusion criteria. (PsycINFO Database Record (c) 2010 APA, all rights reserved)