Combination pharmacologic therapies for heart failure: What next after angiotensin-converting enzyme inhibitors and beta-blockers?

Although the introduction of angiotensin-converting enzyme (ACE) inhibitors and β-adrenergic blockers has resulted in significant improvements in the management of heart failure (HF), morbidity and mortality remain high. Therefore, additional approaches have been sought to discover newer agents that might add incremental benefit. Although not all of these approaches have been successful, there have been some notable new approaches to therapy that have shown benefit or may be promising in terms of additional benefit. Most of these agents are targeted to achieve a more global neurohormonal blockade aiming to reduce or potentially reverse the ventricular remodeling process that occurs in HF. Some of the newer approaches aim for targets other than neurohormonal systems, eg, effects on myocardial metabolism or the vasculature. This article reviews the latest advances in pharmacologic therapy in HF, looking at several trials that may have a significant impact on the treatment of HF. We also discuss several newer agents with promising potential in HF management.     

Changes in aortic stiffness and augmentation index after acute converting enzyme or vasopeptidase inhibition

Augmentation index (AI), a measure of enhanced wave reflection, has been proposed as a bedside measure of aortic stiffness. However, because AI is potentially sensitive to various factors other than vessel wall stiffness, the utility of AI as a stiffness indicator may be limited. To assess relations between AI and vascular properties, we used arterial tonometry and aortic Doppler flow to evaluate trough (24 hours) and peak (4 hours) pulsatile hemodynamics and pulse wave velocity in 159 individuals with systolic hypertension at the completion of a 12-week period of monotherapy with the vasopeptidase inhibitor omapatrilat (80 mg; n=75) or the converting enzyme inhibitor enalapril (40 mg; n=84). Characteristic impedance (Zc) was calculated from the ratio of change in carotid pressure and aortic flow in early systole. Systolic ejection period (SEP), timing of wave reflection, and AI were assessed from the carotid waveform. Comparable acute reductions in mean pressure were associated with greater reductions in peripheral resistance with enalapril, whereas neither drug had an acute effect on Zc. Both drugs reduced AI, but neither drug altered the timing of wave reflection. Both drugs increased heart rate and shortened SEP. Multiple regression analysis demonstrated that the acute reduction in AI was most affected by reductions in SEP and peripheral resistance. Change in AI was inversely related to change in Zc and pulse wave velocity did not enter the model. Our findings indicate that AI is a complex surrogate marker that is inversely related to changes in proximal aortic stiffness in systolic hypertension.     

Residence,income and cancer hospitalizations in British Columbia during a decade of policy change

BACKGROUND: Through the 1990s, governments across Canada shifted health care funding allocation and organizational foci toward a community-based population health model. Major concerns of reform based on this model include ensuring equitable access to health and health care, and enhancing preventive and community-based resources for care. Reforms may act differentially relative to specific conditions and services, including those geared to chronic versus acute conditions. The present study therefore focuses on health service utilization, specifically cancer hospitalizations, in British Columbia during a decade of health system reform. METHODS: Data were drawn from the British Columbia Linked Health Data resource; income measures were derived from Statistics Canada 1996 Census public use enumeration area income files. Records with a discharge (separation) date between 1 January 1991 and 31 December 1998 were selected. All hospitalizations with ICD-9 codes 140 through 208 (except skin cancer, code 173) as principal diagnosis were included. Specific cancers analyzed include lung; colorectal; female breast; and prostate. Hospitalizations were examined in total (all separations), and as divided into first and all other hospitalizations attributed to any given individual. Annual trends in age-sex adjusted rates were analyzed by joinpoint regression; longitudinal multivariate analyses assessing association of residence and income with hospitalizations utilized generalised estimating equations. Results are evaluated in relation to cancer incidence trends, health policy reform and access to care. RESULTS: Age-sex adjusted hospitalization rates for all separations for all cancers, and lung, breast and prostate cancers, decreased significantly over the study period; colorectal cancer separations did not change significantly. Rates for first and other hospitalizations remained stationary or gradually declined over the study period. Area of residence and income were not significantly associated with first hospitalizations; effects were less consistent for all and other hospitalizations. No interactions were observed for any category of separations. CONCLUSIONS: No discontinuities were observed with respect to total hospitalizations that could be associated temporally with health policy reform; observed changes were primarily gradual. These results do not indicate whether equity was present prior to health care reform. However, findings concur with previous reports indicating no change in access to health care across income or residence consequent on health care reform.     

Evaluation of landscape coverings to reduce soil lead hazards in urban residential yards: The Safer Yards Project

This study was designed primarily to evaluate the effectiveness of landscape coverings to reduce the potential for exposure to lead-contaminated soil in an urban neighborhood. Residential properties were randomized in to three groups: application of ground coverings/barriers plus placement of a raised garden bed (RB), application of ground coverings/barriers only (no raised bed, NRB), and control. Outcomes evaluated soil lead concentration (employing a weighting method to assess acute hazard soil lead [areas not fully covered] and potential hazard soil lead [all soil surfaces regardless of covering status]), density of landscape coverings (6 = heavy, > 90% covered; 1 = bare, < 10% covered), lead tracked onto carpeted entryway floor mats, and entryway floor dust lead loadings. Over 1 year, the intervention groups had significantly reduced acute hazard soil lead concentration (median change: RB, -478 ppm; NRB, -698 ppm; control, +52 ppm; Kruskal-Wallis, P = 0.02), enhanced landscape coverings (mean change in score: RB, +0.6; NRB, +1.5; control, -0.6; ANOVA, P < 0.001), and a 50% decrease in lead tracked onto the floor mats. The potential hazard soil lead concentration and the entryway floor dust lead loading did not change significantly. Techniques evaluated by this study are feasible for use by property owners but will require continued maintenance. The long-term sustainability of the method needs further examination.     

A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris

Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial with a potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.     

1alpha,25-dihydroxyvitamin D(3) (calcitriol) and its analogue, 19-nor-1alpha,25(OH)(2)D(2), potentiate the effects of ionising radiation on human prostate cancer cells

Radiotherapy with external beam radiation or brachytherapy is an established therapeutic modality for prostate cancer. Approximately 30% of patients with localised prostate cancer relapse at the irradiated site. Secondary effects of ionising radiation (IR), for example, bowel and bladder complications, are common. Thus, the search for biological response modifiers that could potentiate the therapeutic effects of radiation and limit the occurrence of serious side effects is an important task in prostate cancer therapy. 1alpha,25-Dihydroxyvitamin D(3) (calcitriol), the active metabolite of vitamin D, and its analogues are under investigation for the treatment of several malignancies including prostate cancer. Here, we report that 1alpha,25-dihydroxyvitamin D(3) and its less calcaemic analogue 19-nor-1alpha,25-(OH)(2)D(2) (Zemplar) act synergistically with IR to inhibit the growth of the human prostate cancer cells in vitro. 1alpha,25-dihydroxyvitamin D(3) potentiated IR-induced apoptosis of LNCaP cells, and nanomolar doses of 1alpha,25-dihydroxyvitamin D(3) and 19-nor-1alpha,25-(OH)(2)D(2) showed synergistic inhibition of growth of LNCaP cells at radiobiologically relevant doses of IR (1-2 Gy). At higher doses of IR, the combination of 1alpha,25-dihydroxyvitamin D(3) and IR or 19-nor-1alpha,25-(OH)(2)D(2) and IR resulted in moderate antagonism. The synergistic effect at radiobiologically relevant doses of radiation suggests that a combination of 1alpha,25-dihydroxyvitamin D(3) or 19-nor-1alpha,25-(OH)(2)D(2) with IR could permit a reduction in the dose of radiation given clinically and thus potentially reduce treatment-related morbidity.     

Id proteins in cell growth and tumorigenesis

Since the gene encoding Id1 was cloned in 1990, Id proteins have been implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation. The development of knockout and transgenic animal models for many members of the Id gene family has been particularly useful in sorting out the biologic relevance of these genes and their expression during normal development, malignant transformation, and tumor progression. Here we review the current understanding of Id gene function, the biologic consequences of Id gene expression, and the implications for Id gene regulation of cell growth and tumorigenesis.