Targeting Sympathetic Overactivity in Heart Failure Patients With Statins
Condition: Heart Failure
MeSH terms: Heart Failure
Study type: Interventional

Summary: 
      Heart failure (HF) is a leading cause of morbidity and mortality in the United States with
      the incidence and prevalence of the disease on a continual rise. An overactive sympathetic
      nervous system has become a hallmark characteristic of HF. Although sympathetic activation is
      initially beneficial to maintain cardiac output, blood pressure and perfusion to vital
      organs, over the long term it becomes deleterious contributing to the worsening of HF and
      sudden cardiac death. Indeed, recent findings in HF patients suggest that the sympathetic
      overactivity is not just a marker of poor prognosis but it plays a causative role in the
      development of the disease. Thus, the sympathetic nervous system constitutes a putative drug
      target in the treatment of HF. However, despite aggressive medical management, including
      conventional anti-adrenergic strategies, sympathetic nerve activity (SNA) has been shown to
      remain abnormally high in HF patients and improvements in survival have been limited. Thus,
      other treatment strategies that include reducing SNA and its deleterious consequences are
      warranted. Recent findings from clinical trials indicate that 3-hydroxy-3-methyl-glutaryl
      coenzyme A reductase inhibitors (statins) improve survival irrespective of cholesterol
      lowering bringing the pleiotropic (i.e., cholesterol independent) effects of statins to the
      forefront. An important pleiotropic effect recently reported in experimental HF, that has yet
      to be directly tested in human HF, is the ability of statins to reduce resting sympathetic
      outflow. Several studies in pacing-induced HF rabbits have demonstrated that statins
      normalize the excessive sympathetic activation in the HF state. Thus, the goal of this
      project is to determine whether these findings in experimental HF can be translated to the
      clinical setting of human HF. Our central hypothesis is that statins reduce sympathetic
      overactivity in HF patients. To test this hypothesis we will directly measure muscle SNA and
      perform a randomized crossover placebo control study. Subjects will come to the research
      laboratory before and after the administration of Simvastatin at a standard therapeutic
      dosage of 40 mg. per day or placebo for 1 month
    

Detailed description: 
      Heart failure (HF) is a leading cause of morbidity and mortality in the United States with
      the incidence and prevalence of the disease on a continual rise. An overactive sympathetic
      nervous system has become a hallmark characteristic of HF. Although sympathetic activation is
      initially beneficial to maintain cardiac output, blood pressure and perfusion to vital
      organs, over the long term it becomes deleterious contributing to the worsening of HF and
      sudden cardiac death. Indeed, recent findings in HF patients suggest that the sympathetic
      overactivity is not just a marker of poor prognosis but it plays a causative role in the
      development of the disease. Thus, the sympathetic nervous system constitutes a putative drug
      target in the treatment of HF. However, despite aggressive medical management, including
      conventional anti-adrenergic strategies, sympathetic nerve activity (SNA) has been shown to
      remain abnormally high in HF patients and improvements in survival have been limited. Thus,
      other treatment strategies that include reducing SNA and its deleterious consequences are
      warranted. Recent findings from clinical trials indicate that 3-hydroxy-3-methyl-glutaryl
      coenzyme A reductase inhibitors (statins) improve survival irrespective of cholesterol
      lowering bringing the pleiotropic (i.e., cholesterol independent) effects of statins to the
      forefront. An important pleiotropic effect recently reported in experimental HF, that has yet
      to be directly tested in human HF, is the ability of statins to reduce resting sympathetic
      outflow. Several studies in pacing-induced HF rabbits have demonstrated that statins
      normalize the excessive sympathetic activation in the HF state. Thus, the goal of this
      proposal is to determine whether these findings in experimental HF can be translated to the
      clinical setting of human HF. Our central hypothesis is that statins reduce sympathetic
      overactivity in HF patients. To test this hypothesis we will directly measure muscle SNA
      before and after one month of statin therapy. In addition, to begin to elucidate the
      potential mechanism(s) involved in statin-induced reductions in SNA we will use the technique
      of partial autospectral analysis to assess the baroreflex-independent (i.e., central)
      component of SNA and the application of neck pressure and neck suction to assess the
      baroreflex-dependent control of SNA. The significance of the proposed experiments is the
      potential of statin therapy to reduce SNA in HF patients providing a novel therapeutic
      strategy to target the heightened resting sympathetic drive present in HF.

      The study will utilize a randomized crossover placebo-controlled study design. Subjects will
      come to the research laboratory before, during and after the administration of either a
      placebo or Simvastatin for one month at a standard therapeutic dosage of 40 mg per day.
      Subjects will be carefully monitored for any adverse effects by examining blood samples at
      baseline and 4 weeks for markers of liver, kidney, or muscle damage. If the subject's
      responses to one month of Simvastatin therapy are minimal, such that the decrease in LDL
      cholesterol is less than 25%, we will ask them to participate in an additional 2 weeks of
      Simvastatin administration at a dosage of 80 mg per day. During the baseline, the visit at 4
      wks, and during the additional visit (if necessary) subjects will undergo the following
      experimental measurements and procedures, which will take approximately four hours. All
      measurements and procedures will be performed by the principal investigator and trained
      research personnel.

      To completely obtain all the data necessary for this project, it would be expected to take 5
      years. This is based on the goal of initially collecting additional data to add to the
      preliminary data of a recent American Heart Association (AHA) grant submission and then
      submitting the project for an NIH grant. Based on power calculations and previous experience
      using these experimental measures, it will take approximately 30 heart failure patients to
      determine the influence of statins on sympathetic nerve activity. This will permit
      statistical comparisons and takes into account the technical difficulties of obtaining repeat
      quality sympathetic nerve recordings in the same patient as well as the data collection
      necessary to determine the potential contribution of baroreflex-dependent and -independent
      mechanisms. Healthy control subjects matched to each HF patients for age, sex, and body mass
      index, all of which are known factors that influence resting SNA, will also be studied. These
      studies are important for comparison to determine whether these statin-induced reductions in
      SNA specific to HF or a general overall effect of statin therapy. It is anticipated that
      identifying patients not already on statin therapy may take some time as this therapy is
      standard in this patients group. We chose Simvastatin for our studies because this was the
      statin of choice in the pacing-induced HF rabbit studies that have reported a normalization
      of resting SNA after statin therapy. We anticipate that future studies identifying the
      efficacy of different statins in reducing SNA, the impact of different dosages, and different
      durations of treatment will be warranted.
    

Intervention name(s): Simvastatin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 40 mg, P.O.,daily for 30 days; 1 capsule daily for 30 days
Other intervention name(s): Zocor
Intervention MeSH terms: Simvastatin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science