Long-term effect of atorvastatin on neurohumoral activation and cardiac function in patients with chronic heart failure: A prospective randomized controlled study

doi:10.1016/j.ahj.2007.03.027

American Heart Journal

Volume 153, Issue 6, June 2007, Pages 1055.e1-1055.e8

https://doi.org/10.1016/j.ahj.2007.03.027 Get rights and content

Background

Statins have pleiotropic effects, such as improvement in endothelial function and antiinflammatory, antiproliferative, and antioxidative effects, that should be beneficial for patients with chronic heart failure (CHF). The aim of this study was to investigate the long-term effect of statins on neurohumoral activation and cardiac function in patients with CHF.

Methods

We enrolled 38 outpatients with mild to moderate CHF and radionuclide left ventricular ejection fraction (LVEF) <40%. These patients were randomly assigned to receive atorvastatin (10 mg/d) or conventional treatment for heart failure and were prospectively followed up for at least 3 years. At entry, we measured plasma concentrations of brain natriuretic peptides (BNPs) and left ventricular end-diastolic dimension and LVEF by echocardiography; thereafter, these measurements were repeated at least every 6 months. The primary end point was defined as the improvement in cardiac function and BNP.

Results

There were no significant differences in age, sex, New York Heart Association class, left ventricular end-diastolic dimension, LVEF, and serum cholesterol level at entry between patients with (n = 19) and without atorvastatin (control, n = 19). After a follow-up period of 31 ± 14 months, BNP (median [25th, 75th percentile]) significantly decreased in the atorvastatin group (84 [36, 186] to 55 [37, 91] pg/mL, P = .02) but not in the control group. Left ventricular end-diastolic dimension significantly decreased (67.1 [59.9, 70.8] to 61.1 [58, 63.9] mm, P = .02), and LVEF also significantly increased in the atorvastatin group (33.3% ± 7.4% to 39.1% ± 12.1%, P = .01) but not in the control group.

Conclusion

Long-term atorvastatin therapy decreases neurohumoral activation and improves cardiac function in patients with mild to moderate CHF.

Section snippets

Study patients

We studied 38 outpatients with mild to moderate CHF with radionuclide left ventricular ejection fraction (LVEF) <40% and serum cholesterol levels from 150 to 280 mg/dL. Before study entry, these patients had at least one hospital admission for worsening heart failure and were required to be stable for at least 3 months on conventional therapy including β-blockers. Exclusion criteria included the use of lipid-lowering agents during the past 6 months, severe renal dysfunction (serum creatinine

Results

Of 38 patients, 19 were assigned to atorvastatin treatment (statin group), whereas the remaining 19 patients were assigned to placebo (control group). No patient had a cardiac event, and all patients completed the protocol for the initial double-blinded 6 months. Thereafter, we could not follow up 2 patients (one patient in each group) because of difficulty with the hospital visit, and atorvastatin was administered to 4 patients in the control group because of moderate hyperlipidemia, based on

Discussion

Recent studies showed that statins enhance nitric oxide synthesis and improve endothelial function,¹⁵ inhibit inflammatory cytokines,11, 12, 13, 16 restore impaired autonomic function,¹⁷ and attenuate pathologic myocardial remodeling in heart failure.¹⁸ The present study demonstrated that long-term statin therapy decreased neurohumoral activation and improved cardiac function and symptoms in patients with mild to moderate CHF. These results suggest that statin therapy may be a potential novel

References (29)

T. Tsutamoto et al.
Relationship between tumor necrosis factor-alpha production and oxidative stress in the failing hearts of patients with dilated cardiomyopathy
J Am Coll Cardiol
(2001)
T.B. Horwich et al.
Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure
J Am Coll Cardiol
(2004)
D. Mozaffarian et al.
Statin therapy is associated with lower mortality among patients with severe heart failure
Am J Cardiol
(2004)
S. Sola et al.
Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure
J Am Coll Cardiol
(2006)
R. Wojnicz et al.
Usefulness of atorvastatin in patients with heart failure due to inflammatory dilated cardiomyopathy and elevated cholesterol levels
Am J Cardiol
(2006)
D. Mozaffarian et al.
The effects of atorvastatin (10 mg) on systemic inflammation in heart failure
Am J Cardiol
(2005)
B.E. Bleske et al.
Neutral effect on markers of heart failure, inflammation, endothelial activation and function, and vagal tone after high-dose HMG-CoA reductase inhibition in non-diabetic patients with non-ischemic cardiomyopathy and average low-density lipoprotein level
J Am Coll Cardiol
(2006)
M. Rauchhaus et al.
The endotoxin-lipoprotein hypothesis
Lancet
(2000)
C. Antoniades et al.
Combined effects of smoking and hypercholesterolemia on inflammatory process, thrombosis/fibrinolysis system, and forearm hyperemic response
Am J Cardiol
(2004)
M. Rauchhaus et al.
The relationship between cholesterol and survival in patients with chronic heart failure
J Am Coll Cardiol
(2003)

G. Torre-Aminoe

The syndrome of heart failure: emerging concepts in the understanding of its pathogenesis and treatment

Curr Opin Cardiol

(1999)

M. Packer

Neurohumoral interactions and adaptations in congestive heart failure

Circulation

(1988)

R.S. Vasan et al.

Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study

Circulation

(2003)

J.J. Belch et al.

Oxygen free radicals and congestive heart failure

Br Heart J

(1991)

Cited by (68)

Efficacy and safety of long-term treatment with statins for coronary heart disease: A Bayesian network meta-analysis
2016, Atherosclerosis
Our study aims to evaluate the efficacy and safety of long-term treatment of statins for coronary heart disease (CHD).
Efficacy outcomes included changes in blood lipids, risk of CHD mortality and all-cause mortality. Safety outcomes were evaluated by the risk of adverse events (AE). Bayesian network meta-analysis was used to compare the direct and indirect effects between different statins.
The systematic review showed that levels of blood lipids decreased during statin treatment. High dose of atorvastatin was the most obvious treatment for the reduction of blood lipids. Network meta-analysis showed that statins were significantly more effective than the control in reducing the risk of CHD mortality (Odds Ratio (OR) 0.69, 95% CI 0.61–0.77) and all-cause mortality (OR 0.84, 95% CI 0.80–0.87). In terms of reducing the risk of CHD morality, fluvastatin (77.3%), atorvastatin (72.3%) and lovastatin (68.4%) had higher cumulative probability than other statins, which were more effective treatments for the reduction of CHD morality. In terms of reducing all-cause mortality, atorvastatin (78.6%), fluvastatin (77.1%) and pitavastatin (74.1%) had higher cumulative probability than other statins, which were more effective treatment for reducing the all-cause mortality. Compared with placebo, statins increased the incidence risk of muscle disease (OR 1.05, 95% CI 1.00–1.10) and kidney disease (OR 1.11, 95% CI 1.05–1.72).
Statins significantly reduced levels of blood lipids, with a high dose of atorvastatin being the most effective in blood-lipid level modification. Statins reduced the risk of CHD mortality and all-cause mortality, with atorvastatin and fluvastatin being the most effective in reducing the risk of CHD mortality and all-cause mortality. Statins increased the risk of muscle disease and kidney damage.
Atorvastatin improves cardiac function and remodeling in chronic non-ischemic heart failure: A clinical and pre-clinical study
2015, Egyptian Heart Journal
The aim was to evaluate the cardio-protective effect of atorvastatin in combination with standard chronic heart failure (CHF) therapy that might improve cardiac function, remodeling, and further delay the progression of CHF in patients and rats.
CHF patients (n = 20 per group) with left ventricular ejection fraction (LV-EF) <45% were randomized into: standard anti-failure treatment alone (controls) and standard anti-failure treatment plus atorvastatin (40 mg/day) for 6 weeks. After 6 weeks, the patients were assessed using echocardiography. Laboratory evaluation for lipid profiles, high sensitive C-reactive protein (hs-CRP), cardiac troponin-T (cTnT) and malondialdehyde (MDA) were performed in all patients. In parallel, rats (n = 10 per group) received treatment for 4 weeks and were divided as follows: saline treated (control, 1 ml intraperitoneal, IP), doxorubicin treated (2.5 mg/kg, IP), atorvastatin–doxorubicin treated (10 mg/kg, orally), and digoxin–doxorubicin treated (0.02 mg/kg, orally). The same laboratory analysis including histopathology of heart tissues was performed on the rats.
In patients, atorvastatin improved heart function (increased LV-EF%, LV-fraction shorting (LV-FS%), and E/A velocity ratio; decreased LV-end diastolic diameter (LV-EDD) and LV-end systolic diameter (LV-ESD)) and significantly reduced serum lipid profiles, cTnT, hs-CRP and MDA versus patient controls. In rats, atorvastatin improved signs of CHF, systolic blood pressure, reduced serum lipid profiles, cTnT, hs-CRP and tissue MDA; less cardiac necrosis and fibrosis with enhancement of neo-vascularization versus other doxorubicin-treated rats.
Atorvastatin with standard CHF therapy improved cardiac function and remodeling. Cardio-protective “pleiotropic” actions of atorvastatin are anti-inflammatory, anti-fibrotic and anti-oxidative. Thus, atorvastatin has a potential therapeutic value in the management of CHF patients.
Lower cardiovascular mortality with atorvastatin and rosuvastatin vs simvastatin: Data from "moderate-intensity" statin users in an observational registry on chronic heart failure (Daunia Heart Failure Registry)
2015, International Journal of Cardiology
Lipid-Modifying Treatments for Heart Failure. Is Their Use Justified?
2014, Heart Failure Clinics
Effects of lipophilic statins for heart failure: A meta-analysis of 13 randomised controlled trials
2014, Heart Lung and Circulation
The effects of lipophilic statins in heart failure (HF) were controversial. The goal of the present study was to systematically review all randomised controlled trials evaluating the effects of lipophilic statins in patients with HF.
We performed a comprehensive literature search to identify eligible trials that prospectively randomised patients with HF to lipophilic statins or control. Primary end points were all-cause mortality, cardiovascular mortality, hospitalisation for worsening HF, left ventricular ejection fraction (LVEF), and low-density lipoprotein cholesterol. Risk ratios (RRs) and Weighted mean differences (WMDs) were calculated using fixed-effects models or random-effects models.
A total of 13 randomised trials with 1,532 subjects were included in this analysis. Ten trials randomised patients to atorvastatin, two to simvastatin, and one to pitavastatin. Overall, lipophilic statins significantly decreased all-cause mortality (RR 0.53, P < 0.001), cardiovascular mortality (RR 0.66, P = 0.04), and hospitalisation for worsening HF (RR 0.60, P < 0.001). Subgroup analyses showed that the effects of lipophilic statins in HF were not modified by age, baseline LVEF, and cause of HF. In addition, patients randomised to lipophilic statins had a significant increase in LVEF (WMD 3.91%, P < 0.001) and decrease in low-density lipoprotein cholesterol (WMD 0.90 mmol/L, P < 0.001).
It appears that further studies are needed to determine if lipophilic statins are beneficial for HF patients.
Changes of natriuretic peptides predict hospital admissions in patients with chronic heart failure. A meta-analysis
2014, JACC: Heart Failure
Citation Excerpt :
In 10 (53%) of the 19 trials, information about the exclusion of patients was not reported in detail (27,30,33,35,37,39,40,42–44). Sample size was not calculated in 8 (42%) trials included in the analysis (30,35,37,39,40,42–44). Active treatments significantly reduced the risk of hospital stay for worsening of HF (OR: 0.678 [95% CI: 0.547 to 0.841]; comparison p = 0.000; heterogeneity p = 0.000; I2 = 62.1%; random effect) (Fig. 2).
The goal of this study was to explore the association between changes in B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) plasma levels and risk of hospital admission for heart failure (HF) worsening in patients with chronic HF.
The relationship between BNP and NT-proBNP plasma levels and risk of cardiovascular events in patients with chronic HF has been previously demonstrated. However, it is unclear whether changes in BNP and NT-proBNP levels predict morbidity in patients with chronic HF.
The MEDLINE, Cochrane, ISI Web of Science, and SCOPUS databases were searched for papers about HF treatment up to August 2013. Randomized trials enrolling patients with systolic HF, assessing BNP and/or NT-proBNP at baseline and at end of follow-up, and reporting hospital stay for HF were included in the analysis. Meta-regression analysis was performed to test the relationship between BNP and NT-proBNP changes and the clinical endpoint. Sensitivity analysis was performed to assess the influence of baseline variables on results. Egger's linear regression was used to assess publication bias.
Nineteen trials enrolling 12,891 participants were included. The median follow-up was 9.5 months (interquartile range: 6 to 18 months), and 22% of patients were women. Active treatments significantly reduced the risk of hospital stay for HF worsening. In meta-regression analysis, changes in BNP and NT-proBNP were significantly associated with risk of hospital stay for HF worsening. Results were confirmed by using sensitivity analysis. No publication bias was detected.
In patients with HF, reduction of BNP or NT-proBNP levels was associated with reduced risk of hospital stay for HF worsening.

View all citing articles on Scopus

View full text

Clinical InvestigationCongestive Heart DiseaseLong-term effect of atorvastatin on neurohumoral activation and cardiac function in patients with chronic heart failure: A prospective randomized controlled study

Background

Methods

Results

Conclusion

Section snippets

Study patients

Results

Discussion

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

Lancet

Am J Cardiol

J Am Coll Cardiol

The syndrome of heart failure: emerging concepts in the understanding of its pathogenesis and treatment

Curr Opin Cardiol

Neurohumoral interactions and adaptations in congestive heart failure

Circulation

Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study

Circulation

Oxygen free radicals and congestive heart failure

Br Heart J

Clinical Investigation
Congestive Heart Disease
Long-term effect of atorvastatin on neurohumoral activation and cardiac function in patients with chronic heart failure: A prospective randomized controlled study