Statin Therapy in Heart Failure: Potential Mechanisms of Benefit

• Left Ventricular Ejection Fraction (by echocardiography) [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
• Muscle Sympathetic Nerve Activity (by sympathetic microneurography [ Time Frame: 3 months ] [ Designated as safety issue: No ]

• Left Ventricular Ejection Fraction (by echocardiography)
• Muscle Sympathetic Nerve Activity (by sympathetic microneurography

• Circulating cytokine and chemokine levels, as well as cytokine and chemokine receptor expression [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Secondary indices of autonomic nervous system function: [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• echocardiography (all patients):LV mass, MPI, diastolic and systolic volume index, wall thickness [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• cardiac MRI (subgroup without pacemaker or ICD): LV mass, diastolic and systolic volume index, wall thickness, sphericity index, pulmonary arteriovenous transit time, cardiac output/index, regional wall motion, and subendocardial scar [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Established cardiac biomarkers: BNP, cTnI, hs-CRP [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Symptoms: NYHA class (assessed by blinded physician or nurse), QOL questionnaire [ Time Frame: 3 months ] [ Designated as safety issue: No ]
• Arrhythmia frequency on 24 hour Holter: ventricular ectopy, non-sustained ventricular tachycardia, sustained ventricular tachycardia, atrial fibrillation. [ Time Frame: 3 months ] [ Designated as safety issue: No ]

• Circulating cytokine and chemokine levels, as well as cytokine and chemokine receptor expression
• Secondary indices of autonomic nervous system function:
• -MSNA (bursts/100 heart beats)
• -HRV scores (time and frequency domains
• Secondary indices of cardiac remodeling
• -echocardiography (all patients):LV mass, MPI, diastolic and systolic volume index, wall thickness
• -cardiac MRI (subgroup without pacemaker or ICD): LV mass, diastolic and systolic volume index, wall thickness, sphericity index, pulmonary arteriovenous transit time, cardiac output/index, regional wall motion, and subendocardial scar
• Established cardiac biomarkers: BNP, cTnI, hs-CRP
• Symptoms: NYHA class (assessed by blinded physician or nurse), QOL questionnaire
• Arrhythmia frequency on 24 hour Holter: ventricular ectopy, non-sustained ventricular tachycardia, sustained ventricular tachycardia, atrial fibrillation.

The goal of the investigators' study is to further understand the potentially beneficial effects of statin therapy in patients with heart failure. It is hypothesized that statins will 1) increase the heart's pumping ability 2) improve functioning of the sympathetic nervous system and 3) decrease immune activation in heart failure.

Recent evidence suggests that HMG-Coenzyme A (statin) therapy may be associated with improved survival in both ischemic and non-ischemic heart failure (HF). Large, randomized outcome studies of statins in HF are currently underway, but these trials will not address underlying mechanisms. The aim of the study is to investigate statins' potentially beneficial mechanisms of action in HF, focusing on: 1) sympathetic nervous system activation and 2) myocardial remodeling, and 3) immune activation in heart failure.

Fifty patients with systolic HF of non-ischemic etiology from a single center will be randomized in a double-blinded fashion to 3 months of atorvastatin 10mg QD (25 subjects) vs matching placebo QD (25 subjects). The following exams will be performed at baseline (pre-treatment) and at end of study (post-treatment): sympathetic microneurography, echocardiography, and peripheral blood chemokine analysis. Sympathetic microneurography at the peroneal nerve will directly quantify changes in sympathetic nerve activity (bursts/minute). Echocardiography (with the addition of MRI in a subset of subjects without pacemakers or implantable defibrillators) will be used to track changes in cardiac structure and function; indices of remodeling will include measurement of left ventricular mass index, left ventricular volume indices, left ventricular ejection fraction, and subendocardial scar quantification (MRI only). Immune activation will be characterized by circulating cytokines and chemokines. Additionally, quantification of established cardiac biomarkers (cardiac troponin, B-type natriuretic peptide, and C-reactive Protein), Holter monitor/heart rate variability studies, and quality of life and global clinical assessment will be performed pre- and post- treatment.

Neither sympathetic microneurography nor MRI have been previously utilized to assess statins' effects in humans with HF. The impact of statin therapy on inflammatory chemokine activation in HF also has not been studied. The knowledge gained from our proposed investigations may serve as a basis for understanding how statin therapy has potential to improve clinical outcomes in HF, and may ultimately lead to new therapeutic strategies for HF.

• Drug: atorvastatin
  atorvastatin 10mg PO QD
  Other Name: lipitor
• Drug: placebo
  matched placebo Qd x 3 months

• Experimental: active treatment
  atorvastatin 10mg QD x 3 months
  Intervention: Drug: atorvastatin
• Placebo Comparator: placebo
  matched placebo QD x 3 months
  Intervention: Drug: placebo

• Horwich TB, Middlekauff HR. Potential autonomic nervous system effects of statins in heart failure. Heart Fail Clin. 2008 Apr;4(2):163-70.
• Horwich TB, MacLellan WR. Atorvastatin and statins in the treatment of heart failure. Expert Opin Pharmacother. 2007 Dec;8(17):3061-8. Review.
• Horwich TB, Middlekauff HR, Maclellan WR, Fonarow GC. Statins do not significantly affect muscle sympathetic nerve activity in humans with nonischemic heart failure: a double-blind placebo-controlled trial. J Card Fail. 2011 Nov;17(11):879-86. Epub 2011 Sep 3.

Inclusion Criteria:

• Age≥18 years old
• LVEF ≤ 35%, as documented by echocardiography, radionuclide ventriculography, gated SPECT, or contrast ventriculography within past 6 months
• Symptomatic HF (NYHA II-IV) or current NYHA I with history of symptomatic HF within the last year
• Stable doses of optimal HF medical therapy, unless documented contraindication.

Exclusion Criteria:

• Ischemic etiology of HF, defined as the presence of at least one of the following four criteria; angiographic evidence of > 50% lesion in 1 or more of the 3 major epicardial vessels; history of myocardial infarction; history of revascularization procedure; evidence of significant perfusion defect in the setting of ischemic symptoms.
• Clinical indication for statin treatment - coronary artery, cerebrovascular, or peripheral vascular disease
• Major cardiovascular event or surgical procedure within past 8 weeks
• LDL<70 mg/dL
• HF secondary to congenital heart disease or uncorrected valvular disease
• Treatment with statin within past 2 months
• Pregnancy
• Contraindication to statin: moderate liver disease, AST/ALT > 150 U/ L, known hypersensitivity
• Likely to receive heart transplant within 3 months
• Known peripheral or autonomic neuropathy