Targeting Sympathetic Overactivity in Heart Failure Patients With Statins

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

Conditions

• Heart Failure

Interventions

DRUG

Simvastatin

40 mg, P.O.,daily for 30 days

DRUG

Placebo

1 capsule daily for 30 days

Sponsors & Collaborators

• University of Nebraska

  collaborator OTHER

• University of Missouri-Columbia

  lead OTHER

Principal Investigators

• Paul J Fadel, PhD · University of Missouri-Columbia

• Anand Chockalingam, M.D. · University of Missouri-Columbia

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2009-03-31

Primary Completion

2014-07-31

Completion

2014-07-31

Countries

• United States

Study Locations