The Effect of Simvastatin Therapy on the Expression of Procoagulant and Inflammatory Markers in Heart Failure
Condition: Heart Failure
MeSH terms: Heart Failure
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Our proposed research will examine whether treatment with simvastatin alters expression and
      activity of monocyte TF, whether polymorphisms in the TF gene alter the therapeutic effect
      and what effect treatment has on inflammatory markers in heart failure. The results of this
      study may assist in tailoring statin therapy to specific characteristics, such as
      inflammatory state, of heart failure patients. If treatment with simvastatin significantly
      lowers TF expression, this may reduce the risk of thromboembolic events in patients with
      heart failure, thus reducing mortality and morbidity. If the treatment effect varies based on
      the TF genotype, this may define an identifiable population in whom statin therapy may be
      more beneficial than the population as a whole.
    

Detailed description: 
      Heart failure is a significant public health problem in the United States. There are more
      than five million heart failure patients in America and this number grows by over 550,000 new
      cases each year.1 Heart failure is the primary diagnosis for nearly one million hospital
      admissions each year and another two million patients are admitted with a secondary diagnosis
      of heart failure, making it the single largest expense for Medicare.1 Furthermore, heart
      failure causes or contributes to more than 300,000 deaths each year and, in spite of advances
      in treatment, 70-80% of patients with heart failure will die within 8 years.1, 2 Therefore,
      heart failure is one of, if not the most important socioeconomic health problems of the 21st
      century.

      Heart failure patients are at increased risks for thromboembolic events. Autopsy results from
      heart failure patients report a 50% to 60% incidence of thromboembolic events.3-5 Besides
      known thromboembolic risk factors associated with the heart failure state (such as blood
      stasis in a poorly contracting left ventricle, endothelial dysfunction and neuroendocrine
      activation), elevated TF expression may also contribute to enhanced thromboembolic risk.
      Recent evidence from our laboratory shows that functional TF procoagulant activity (TF-PCA)
      in monocytes is increased significantly by 2.8-fold in heart failure patients (n=48) compared
      to healthy controls (n=25) (p=0.03) (Figure 1), while the natural inhibitor tissue factor
      pathway inhibitor (TFPI) showed no significant difference.6 The heart failure subjects were
      subsequently followed to death, transplant, or clinical event (i.e. heart failure
      hospitalization, arrhythmia, acute coronary event, thromboembolic event, death or cardiac
      transplant). When TF-PCA values were divided at the median, the upper 50-percentile
      demonstrated a trend toward increased mortality (p=0.06) with a significant increase in
      clinical events (p=0.04) compared to the lower 50-percentile (Figure 2).

      Elevated TF expression is believed to play an integral role in intravascular coagulation seen
      in coronary artery disease.7-9 Human atherosclerotic plaques are highly thrombogenic, and
      exhibit high levels of TF antigen and functional TF procoagulant activity.10-15 In addition,
      TF antigen is higher in plaques from patients with myocardial infarction and unstable angina
      than in those with stable angina.15 Recent evidence also shows that local TF inhibition by
      TFPI decreases the thrombogenicity of disrupted human atherosclerotic plaques.16 These data
      support that increased TF expression may mediate an increased risk of thromboembolic events.

      Simvastatin, an antilipidemic agent of the HMG-CoA reductase inhibitor type, has been shown
      to decrease monocyte TF expression in vitro and ex vivo.17-20 In monocytes collected from
      both healthy volunteers and hyperlipidemic patients and stimulated with LPS (a potent inducer
      of TF) in vitro, simvastatin inhibits monocyte TF expression in a dose-dependent manner.17 In
      an in vivo model, hyperlipidemic patients receiving simvastatin exhibited a significant
      decrease in TF-Ag and TF-PCA from baseline (mean reduction 68% and 61%, respectively), while
      these TF parameters remained unchanged in the placebo group (p=0.0002).18 Whether simvastatin
      also decreases TF expression in heart failure is unknown.

      Clinical studies of simvastatin and other statins have mostly been confined to their
      lipid-lowering effects. However, evidence also suggests that they improve outcomes in heart
      failure. In a post-hoc analysis of the Scandinavian Simvastatin Survival Study (4S),
      simvastatin 20-40 mg daily in patients with coronary heart disease significantly reduced the
      occurrence of heart failure (relative risk reduction 21.7%, p<0.015) and heart failure
      mortality (relative risk reduction 37%, p=0.014).21 Simvastatin also showed a non-significant
      trend in decreasing heart failure hospitalizations. An analysis of data from the PRAISE trial
      showed a 62% decrease in the risk of death in patients treated with statins, independent of
      their on-treatment cholesterol levels.22 The OMPTIMAAL trial also showed an improvement in
      survival of heart failure patients with statin therapy.23 In a cohort study by Horwich et al,
      statin use was associated with a reduction in the risk of heart transplant or death, again
      without regard to cholesterol levels.24 These results suggest that treatment with HMG-CoA
      reductase inhibitors have a beneficial effect, beyond that which would be expected from their
      ability to alter plasma lipid levels.

      Two distinct common alleles of the tissue factor gene, designated - 1208 D and - 1208 I, have
      been identified.25 The two haplotypes had roughly equal frequencies in a sample of 2354
      individuals.25 There are conflicting data on the effect of the alleles on TF expression, with
      one study showing lowered plasma TF and a decreased risk of venous thrombosis when the - 1208
      D haplotype is present.25 Other studies have shown that the presence of the - 1208 D
      haplotype results in higher cellular expression of TF.26, 27 The effect of polymorphisms on
      the efficacy of statins in lowering TF is unknown, as are their clinical impact in heart
      failure.

      A number of pro-inflammatory cytokines are elevated in heart failure. Evidence from our
      laboratory showed that Interleukin-6 (IL-6) levels were 75 pg/mL in NYHA class II-IV heart
      failure patients, compared to 0.4 pg/mL in healthy volunteers (p=0.002).28 Others have found
      similar elevations and have shown elevated IL-6 concentrations to be an independent predictor
      of worsening heart failure and adverse events.29-34 Statins have been shown to decrease
      expression of IL-6 in vitro, in coronary artery disease patients and in diabetes.35-40 Other
      inflammatory cytokines, such as IL-1/10 ratio and tissue necrosis factor (TNF), have also
      been implicated in procoagulant states and are potential targets of statin therapy.29, 31, 33
      What effect statins have on the elevation of IL-6 and other cytokines in heart failure and
      what impact reduction of them with statins has on outcomes is unknown.

      Our proposed research will examine whether treatment with simvastatin alters expression and
      activity of monocyte TF, whether polymorphisms in the TF gene alter the therapeutic effect
      and what effect treatment has on inflammatory markers in heart failure. The results of this
      study may assist in tailoring statin therapy to specific characteristics, such as
      inflammatory state, of heart failure patients. If treatment with simvastatin significantly
      lowers TF expression, this may reduce the risk of thromboembolic events in patients with
      heart failure, thus reducing mortality and morbidity. If the treatment effect varies based on
      the TF genotype, this may define an identifiable population in whom statin therapy may be
      more beneficial than the population as a whole.
    

Intervention name(s): Simvastatin
Intervention type(s): Drug
Intervention description(s): Simvastatin 40 mg tablet
Other intervention name(s): Zocor
Intervention MeSH terms: Simvastatin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science