Pleiotropic Effects of Long-Term Monotherapy with Rosuvastatin in Dogs with Moderate Heart Failure

A plethora of experimental and clinical data on HGM-CoA reductase inhibitors is currently available in the literature, and a stunning amount of evidence points especially to the pleiotropic effects of statins, apart from their ability to reduce cholesterol levels. The potent pleiotropic effects of statins, including potential benefits for myocardial cellular function, downregulation of tissue renin-angiotensin-aldosterone system activation, restoration of autonomic function, neoangiogenesis, and inhibition of proinflammatory cytokines, have emerged as potential influences on the natural history of cardiovascular disease, in particular cardiac heart failure (CHF). Statins possess anti-inflammatory effects and decrease vascular cell adhesion molecule-1 levels in CHF. Additionally, circulating lipids have the capacity to detoxify bacterial lipopolysaccharides, which stimulate the release of inflammatory cytokines in CHF. Taken together, this evidence strongly supports the rationale of using statin therapy in CHF [1].Recently, Zacà et al. [2] developed a model of CHF through intracoronary microembolization in dogs and chronically administered rosuvastatin. These authors could demonstrate that rosuvastatin prevented progressive left ventricular dysfunction and dilation. This beneficial effect has been associated with the reduction of tumor necrosis factor (TNF)-α expression and partly with the increased angiogenesis and enhanced mobilization of bone marrow-derived stem cells (BMSCs) [2]. The modulatory effect on the inflammatory imbalance of CHF seems to be at the root of the positive effect of statins, but this work is underpinning the role of TNF-α in this scenario. Among the many proinflammatory cytokines, TNF-α is claimed to be one of the more potent contributors to the progression of HF by inducing cardiomyocyte hypertrophy and apoptosis and promoting the induction of the fetal gene program [3]. Additionally, TNF-α may exert its effects on LV remodeling, adversely affecting the myocardial extracellular matrix turnover. Indeed, decreased expression of TNF-α results in reduced activation of the gelatinases MMP-2 and MMP-9, and reduced collagen deposition and denaturation [4]. These observations support the hypothesis that inhibition of TNF-α may represent an important determinant of the statin-mediated attenuation of myocardial fibrosis and hypertrophy that is ultimately reflected in the decrease of global LV remodeling.However, the establishment of a direct relation between rosuvastatin and the polyhedric and pleiotropic network of inflammatory cytokines would be too reductive in this context and it is preferable to talk about a general ‘permissive’ role of statins on the inflammatory balance. More importantly, the authors observed a significant increase in capillary density and in the capillary-to-cell ratio in the treated group coupled with a 7-fold increase in the number of circulating BMSCs compared to that in control animals. The authors confirmed these results in a study published in a recent issue of Cardiology [5]. They demonstrated diminished activity of the inflammatory network as by decreased expression of mediators as Nab1, PTEN, PI3K, mTOR, and IL-6 after statin treatment. Additionally, they showed positive modulation of NOS and an increase in Sca-1 and c-kit expression, indicative of stem cell mobilization, along with an increase in VEGF and FGF expression in the rosuvastatin treatment group.Statins may induce angiogenesis by activating the protein kinase Akt-signaling pathway known to promote endothelial cell survival and nitric oxide production and by the VEGF-induced differentiation and mobilization from the bone marrow, and this effect has been confirmed in clinical studies [6]. Additionally, stem cell mobilization along with their known paracrine effect could be considered a key component of statin-induced CHF clinical improvement.However, keeping a close eye on the clinical side, even if this preclinical evidence along with other in vitro experimental data are encouraging and allow to us to optimistically envisage the use of rosuvastatin in bedside CHF treatment, it is interesting to note that the potential benefits of different statins in patients with chronic heart failure remain controversial. Indeed, in a recent meta-analysis, Xu et al. [7] pointed out the effectiveness of atorvastatin treatment in CHF patients in reducing the risk of all-cause mortality and hospitalization for CHF worsening, but showed contradicting results arising from the two recent large clinical trials specifically testing the effect of rosuvastatin in the CHF population [7]. Paradoxically, in contrast to the previously mentioned reports of both the biological and clinical benefits of statin therapy, two large, prospective randomized trials with robust clinical end points present conflicting data. The CORONA trial [8] assessed the effectiveness and safety of 10 mg rosuvastatin versus placebo in addition to the optimal CHF treatment in prevalent symptomatic CHF cases with a history of myocardial infarction and not previously treated with a statin. The study reported no effect on all-cause mortality and hospitalization over the median follow-up period of 32 months, though the safety of the statin was demonstrated. The GISSI-HF trial [9] enrolled patients with symptomatic CHF of ischemic and nonischemic origin, randomly assigned them to rosuvastatin 10 mg daily or placebo, and followed them up for a median of 3.9 years. No effect was seen in all-cause mortality or combined mortality and hospital admissions. Several different reasons might underlie this conflicting result. Atorvastatin is more lipophilic than rosuvastatin and may penetrate the cell membrane more effectively, providing a theoretical advantage because of a more direct biological effect. Reduced ability to mobilize the endogenous regenerative resources could also partially explain the clinical failure of rosuvastatin. However, also functional and quantitative differences in the actual regenerative resources mobilized in the ‘aged’ population studied (mean age >65 years) might play a role. This latter point could probably explain the inadequacy of the animal model used in the study of Zacà et al. [2] as well as in the majority of the animal studies nowadays being published on the topic. Animals used are usually young, female (to reduce aggressive behavior), and sometimes immunocompromised. Clearly this situation does not reflect the clinical site and the biological response of an elderly CHF patient. More comments could be proposed in this context and regarding the possible motivations of this clinical discordance; however, the current study on rosuvastatin along with the clinical evidence reported invite both physicians and biologists to carefully think about the significance of statin treatment in cardiovascular disease and to reconsider in a more translational light the experimental findings obtained.