Department of Medicine， Sahlgrenska University Hospital， Goteborg， Sweden.
BACKGROUND: Chronic heart failure (CHF) is an increasing burden to health care. Pharmacological treatment with angiotensin-converting enzyme (ACE) inhibitors and beta blockers improve survival and reduce hospitalizations in patients with low left ventricular ejection fraction (LVEF). Despite these therapies， morbidity and mortality remains problematic. Furthermore， 30% to 50% of patients with CHF have a preserved LVEF. It is not known if treatments are of benefit in this group.
DESIGN: Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) is a program designed to investigate the clinical usefulness of the long-acting angiotensin II type 1 receptor blocker， candesartan cilexetil， in a broad spectrum of patients with symptomatic heart failure. Patients with systolic dysfunction， tolerant or intolerant to an ACE-inhibitor， and patients with preserved systolic function are included. Specifically， the CHARM program consists of 3 independent， parallel， placebo-controlled studies in patients with (1) LVEF less than or equal to 40%， ACE-inhibitor treated (n = 2，300); (2) LVEF less than or equal to 40%， ACE-inhibitor intolerant (n = 1，700); (3) LVEF greater than 40%， not treated with ACE inhibitors (n = 2，500). The 3 studies will be combined to evaluate the effect of candesartan cilexetil on all-cause mortality in the broad spectrum of symptomatic heart failure. The primary objective in each trial is to evaluate the effects on the combined endpoint of cardiovascular mortality or CHF hospitalization. Other endpoints include the effects on myocardial infarction， all-cause hospitalization， and resource utilization. CHARM is intended to randomize 6，500 patients with symptomatic heart failure from 26 countries in Europe， the United States， Canada， South Africa， and Australia. The CHARM program started to enroll patients in March 1999. The follow-up period is a minimum of 2 years. The study is expected to end in the third quarter of 2002. 1: J Am Coll Cardiol. 2006 Sep 19;48(6):1277-82. Epub 2006 Aug 14. Links Aldosterone synthase promoter polymorphism predicts outcome in African Americans with heart failure: results from the A-HeFT Trial. · McNamara DM， · Tam SW， · Sabolinski ML， · Tobelmann P， · Janosko K， · Taylor AL， · Cohn JN， · Feldman AM， · Worcel M. University of Pittsburgh Medical Center， Pittsburgh， Pennsylvania， USA. mcnamaradm@upmc.edu
OBJECTIVES: We sought to evaluate the effect of the aldosterone synthase promoter polymorphism on heart failure outcomes for subjects in the African American Heart Failure Trial (A-HeFT).
BACKGROUND: Genetic heterogeneity modulates clinical outcomes in subjects with heart failure (HF); however， little data exist in African American populations. A common polymorphism exists in the promoter region of the aldosterone synthase gene (CYP11B2) at position -344 (T/C). The -344C allele， associated with higher aldosterone synthase activity， has been linked to hypertension; however， its impact on outcomes in HF is unknown.
METHODS: A total of 354 subjects from A-HeFT participated in the GRAHF (Genetic Risk Assessment of Heart Failure in African Americans) substudy and were genotyped for the aldosterone synthase polymorphism. Patients were followed prospectively， and event-free survival (freedom from death and HF hospitalization) compared by CYP11B2 genotype.
RESULTS: Of the cohort， 218 patients were TT， 114 CT， and 22 patients were CC. Baseline etiology， blood pressure， and functional class were not significantly different among the 3 cohorts. The C allele was associated with significantly poorer HF hospitalization-free survival with the best survival among TT subjects， intermediate for heterozygotes， and the poorest for CC homozygotes (p = 0.018)， and a higher rate of death (% death TT/TC/CC = 1.8/3.5/18.2， p = 0.001). The TT genotype， more prevalent in blacks， was associated with greater impact of fixed combination of isosorbide dinitrate and hydralazine on the primary composite end point (p = 0.01).
CONCLUSIONS: The aldosterone synthase promoter -344C allele linked to higher aldosterone levels is associated with poorer event-free survival in blacks with HF. The role of aldosterone receptor antagonists in diminishing this apparent genetic risk remains to be explored.