Why did high-dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study
Department of Health Science, Monash University, Frankston Vic 3119, Melbourne, Australia. International journal of cardiology
(Impact Factor: 4.04).
02/2011; 146(3):404-7. DOI: 10.1016/j.ijcard.2009.12.028
Statins are often prescribed for prevention of atherosclerotic outcomes in patients who have chronic heart failure (CHF), if this has an ischaemic etiology. These agents may also possess additional properties, independent of effects on blood lipid levels, which may have an effect on cardiac remodeling. However, beneficial effects were not observed in the recent UNIVERSE trial.
We prospectively planned a sub-study of UNIVERSE to explore relevant mechanistic effects of rosuvastatin, including effects on collagen turnover and plasma coenzyme Q10 (CoQ) levels. Additionally, CoQ levels in CHF patients receiving chronic statin therapy were measured.
CoQ levels were significantly reduced after 26 weeks of rosuvastatin statin therapy (n = 32), compared to placebo (n = 37) in CHF patients in UNIVERSE trial. Patients with CHF (n = 56) matched for age, gender and severity of disease who had been taking statins for 12 months or longer had CoQ levels of 847 ± 344 nmol/L, significantly lower than 1065.4 ± 394 nmol/L in UNIVERSE patients at baseline (p = 0.0001). Serum types I and III N-terminal procollagen peptide (PINP and PIIINP), measures of collagen turnover which can contribute to cardiac fibrosis were significantly increased in the rosuvastatin group compared to baseline in UNIVERSE patients (PINP: p = 0.03, PIIINP: p = 0.001).
In conclusion putative beneficial effects of statin therapy on cardiac remodeling in UNIVERSE may have been negated by increases in collagen turnover markers as well as a reduction in plasma CoQ levels in these patients with CHF.
Available from: Maciej Banach
- "The Rosuvastatin Impact on Ventricular Remodelling Lipids and Cytokines (UNIVERSE), Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA), and Effect of rosuvastatin in patients with chronic heart failure (GISSI-HF) trials did not indicate a significant role for statins in HF patients, although the drug did reduce the number of cardiovascular (CV) hospitalizations in the CORONA trial [11-13]. Although mentioned prospective studies using hydrophilic rosuvastatin showed no beneficial effect on mortality, Vrtovec et al. reported that atorvastatin therapy reduced the incidence of sudden cardiac death in patients with advanced CHF . "
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We assessed the influence of atorvastatin on selected indicators of an inflammatory condition, left ventricular function, hospitalizations and mortality in patients with dilated cardiomyopathy (DCM).
We included 68 DCM patients with left ventricular ejection fraction (LVEF) ≤40% treated optimally in a prospective, randomized study. They were observed for 5 years. Patients were divided into two groups: patients who were commenced on atorvastatin 40 mg daily for two months followed by an individually matched dose of 10 or 20 mg/day (group A), and patients who were treated according to current recommendations without statin therapy (group B).
After 5-year follow-up we assessed 45 patients of mean age 59 ± 11 years - 22 patients in group A (77% male) and 23 patients in group B (82% male). Interleukin-6, tumor necrosis factor alpha, and uric acid concentrations were significantly lower in the statin group than in group B (14.96 ± 4.76 vs. 19.02 ± 3.94 pg/ml, p = 0.012; 19.10 ± 6.39 vs. 27.53 ± 7.39 pg/ml, p = 0.001, and 5.28 ± 0.48 vs. 6.53 ± 0.46 mg/dl, p = 0.001, respectively). In patients on statin therapy a reduction of N-terminal pro-brain natriuretic peptide concentration (from 1425.28 ± 1264.48 to 1098.01 ± 1483.86 pg/ml, p = 0.045), decrease in left ventricular diastolic (from 7.15 ± 0.90 to 6.67 ± 0.88 cm, p = 0.001) and systolic diameters (from 5.87 ± 0.92 to 5.17 ± 0.97, p = 0.001) in comparison to initial values were observed. We also showed the significant increase of LVEF in patients after statin therapy (from 32.0 ± 6.4 to 38.8 ± 8.8%, p = 0.016). Based on a comparison of curves using the log-rank test, the probability of survival to 5 years was significantly higher in patients receiving statins (p = 0.005).
Atorvastatin in a small dose significantly reduce levels of inflammatory cytokines and uric acid, improve hemodynamic parameters and improve 5-year survival in patients with DCM.
Available from: PubMed Central
- "Thus, CoQ is also important as a lipophilic regulator of oxidative stress . Inhibition of HMG-CoA reductase using statins in human causes a measurable decrease in serum levels of CoQ, which correlates with a decrease in cardiac function that can be reversed by providing CoQ as a dietary supplement [13,14]. "
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ABSTRACT: The mevalonate pathway in human is responsible for the synthesis of cholesterol and other important biomolecules such as coenzyme Q, dolichols and isoprenoids. These molecules are required in the cell for functions ranging from signaling to membrane integrity, protein prenylation and glycosylation, and energy homeostasis. The pathway consists of a main trunk followed by sub-branches that synthesize the different biomolecules. The majority of our knowledge about the mevalonate pathway is currently focused on the cholesterol synthesis branch, which is the target of the cholesterol-lowering statins; less is known about the function and regulation of the non-cholesterol-related branches. To study them, we need a biological system where it is possible to specifically modulate these metabolic branches individually or in groups. The nematode Caenorhabditis elegans (C. elegans) is a promising model to study these non-cholesterol branches since its mevalonate pathway seems very well conserved with that in human except that it has no cholesterol synthesis branch. The simple genetic makeup and tractability of C. elegans makes it relatively easy to identify and manipulate key genetic components of the mevalonate pathway, and to evaluate the consequences of tampering with their activity. This general experimental approach should lead to new insights into the physiological roles of the non-cholesterol part of the mevalonate pathway. This review will focus on the current knowledge related to the mevalonate pathway in C. elegans and its possible applications as a model organism to study the non-cholesterol functions of this pathway.
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ABSTRACT: This article focuses on the importance of ventricular function as a surrogate end point for clinical outcomes and examines the evidence base for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) as anti-remodeling agents. Overall, the published evidence strongly suggests that statins possess beneficial anti-remodeling effects in the chronic heart failure setting and that these may be additional to those observed with standard therapy, such as angiotensin-converting enzyme inhibitors and beta-blockers. The data are not universally consistent, however, and the doses of agents studied may be important in this regard. Specifically, greater benefits appear to be observed with low doses of statins.
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