Targeting Sympathetic Overactivity in Heart Failure Patients With Statins

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 (HMG-CoA) 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 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.

Inclusion Criteria:

- Male and females of all ethnic backgrounds ranging aged 18 to 70

- Ages 18-70 yrs

- Patients with congestive heart failure diagnosed on clinical history, a routine
exercise test, echocardiography and/or routine cardiac catheterization, in functional
class I-III

- Patients with heart failure due to ischemic and non-ischemic etiologies

- Normotensive and not taking blood pressure controlling medications

Exclusion Criteria:

- Low blood pressure (<100/60)

- End stage renal disease

- COPD with concurrent daily use of inhalers

- Peripheral neuropathy

- Pregnant women