Bethesda, MD - Atorvastatin therapy appeared to improve measures of inflammation and ventricular function and structure over one year among nondiabetic patients with nonischemic systolic heart failure in a randomized trial [1]. The drug also seemed to improve symptoms but didn't cut hospitalization time or alter the risk of clinical events, observe the authors, Dr Srikanth Sola (Emory University, Atlanta, GA) and associates. As one of the few prospective explorations of statins in such a population, the study may help clarify mechanisms behind the potential benefits of drugs in heart-disease patients who don't typically receive them.

The findings support and strengthen previous research, according to Dr Gregg C Fonarow (University of California, Los Angeles), who has investigated the same issue but wasn't involved in the current study. "With a larger population and a longer-term follow-up than some of the previous studies, it seems to show, in a nice placebo-controlled fashion, the improvement in ventricular function and reduction in proinflammatory cytokines that have been seen in smaller studies," he told heartwire.

It seems to show, in a nice placebo-controlled fashion, the improvement in ventricular function and reduction in proinflammatory cytokines that have been seen in smaller studies.

People with nonischemic HF, compared with those with the ischemic syndrome, "appear to derive at least the same if not greater benefit" from statin therapy, according to Fonarow. But the evidence to date requires further exploration in more definitive randomized trials, such as several that are now under way, he observed. The study from Sola and associates, he said, "certainly gives us important information for interpreting those trials when they become available and generates additional avenues to study."

On the other hand, a separate, much smaller study concluded something quite different [2]. Dr Barry E Bleske (University of Michigan, Ann Arbor) and colleagues observed no important changes in laboratory markers of inflammation, endothelial function, and vagal tone among patients with nonischemic HF who took high-dose atorvastatin for 12 weeks.

Of this investigation, Fonarow said, "I think there are some caveats. This was a short-term study that did not have a concurrent placebo control. Instead, they used a crossover design with a washout period." Such a short follow-up, he added, may not be enough to see ventricular structural improvements, "and that may have limited its ability to discern a true effect."

Both studies appeared in the January 17, 2006 issue of the Journal of the American College of Cardiology.

Sola and associates randomized 108 predominantly NYHA class 3 patients with nonischemic HF and an LVEF <35% to a yearlong double-blind course of either 20 mg/day atorvastatin or placebo. Patients with diabetes or who were already on statins were excluded. The mean baseline levels of low-density-lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol were "below the current National Cholesterol Education Program III guidelines for the initiation of lipid-lowering therapy."

Left ventricular function climbed among actively treated patients and fell in the control group. Those on atorvastatin also showed significantly improved LV echocardiographic structural measures, NYHA functional class, and levels of HF-related biomarkers.

End points	Atorvastatin, n=46	Placebo, n=43	p
Structural-functional measures
LV mass/body surface area (g/m2)	113	118	0.1
LVEDD (mm)	53.4	60.3	0.01
LVESD (mm)	39.1	43.1	0.01
Ejection fraction (%)	37	31	0.004
NYHA functional class (mean)	2.2	2.9	0.001
Biomarkers
hs-CRP (mg/dL)	1.7	1.9	0.002
IL-6 (ng/dL)	13.3	17.3	0.001
TNF- RII (ng/dL)	24.3	34.5	0.001
Erythrocyte superoxide dismutase (µ/g Hb)	649	577	<0.0001

*Includes the 89 patients who completed the one-year trial. LVEDD=left ventricle end-diastolic diameter; LVESD=left ventricle end systolic diameter; hs-CRP=high sensitivity C-reactive protein; IL-6=interleukin-6; TNF- RII=tumor necrosis factor alpha receptor II; Hb=hemoglobin.

"This study extends previous observations by demonstrating that treatment with statins leads to reverse cardiac remodeling and suggests, but does not prove, that the antiinflammatory effects of statins may be through a reduction in oxidative stress," write Dr Kumudha Ramasubbu and Dr Douglas L Mann (Baylor College of Medicine and the Texas Heart Institute, Houston) in an accompanying editorial [3].

Bleske and colleagues randomized 15 nondiabetic, mostly NYHA class 2 patients with an LVEF <40% to receive 80 mg/day atorvastatin for 12 weeks in a double-blind fashion. The rest were given placebo. The two groups then crossed over to the other regimen after a washout period of at least eight weeks.

The patients showed the expected statin-related fall in LDL-cholesterol levels but no significant alterations in a long list of surrogate markers of HF. But even at the "aggressive" atorvastatin dosage used and with the marked LDL reductions, the authors write, "no apparent negative consequences were observed."

Fonarow disagreed that the findings argue against a statin benefit in nonischemic HF. Not only were the population small and the study duration limited, "this group of patients, despite a [mean] ejection fraction that started off at 25%, by some other measures had very mild heart failure," he observed. "Their blood pressure was 130/70 mm Hg, renal function was normal, and they weren't anemic."

Acknowledging their patients were "relatively healthy" and that the study had limitations, Bleske et al nonetheless concluded there was no short-term statin benefit according to the measures they examined. "Higher-risk patients, such as patients with ischemic cardiomyopathy or with diabetes and either ischemic or nonischemic cardiomyopathy, may show greater benefit with statin therapy," they write.

In their editorial covering both studies, Ramasubbu and Mann write that statins are appropriate for patients with HF accompanied by CAD and elevated LDL-cholesterol, as the guidelines recommend. "However, the broader question of whether statins should be routinely used in all patients with HF, including patients with ischemic HF with low or normal LDL levels and/or nonischemic HF, remains unanswered."