Regression of Myocardial Steatosis by Nebivolol
Condition: Cardiac Steatosis and Lipotoxicity
MeSH terms: Fatty Liver
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Within large number of patients with obesity, it is crucial to determine who is at the
      greatest risk for development of chronic heart disease. The investigators previous studies
      suggest that an excessive accumulation of fat in heart cells precedes the development of
      obesity-related pathologies and may serve as a biomarker of heart disease in high-risk
      population. Until now, the evaluation of fat in the human heart was possible postmortem or by
      biopsy. The investigators novel magnetic resonance spectroscopy technique enables the
      quantification of intracellular lipid content non-invasively and repeatedly in humans in
      vivo. It could be used to better screen and treat obese patients at risk for the development
      of metabolic disease. The investigators hypothesize that in obese humans with elevated
      myocardial triglycerides, treatment with Nebivolol will reduce myocardial fat and will
      improve heart function.
    

Detailed description: 
      Background:

      Epidemiological data have provided abundant evidence showing that obesity is a major risk
      factor for cardiovascular morbidity and mortality, although the exact mechanisms remain
      incompletely understood. Traditionally, obesity is thought to indirectly increase
      cardiovascular risk by means of its intermediary effects; obesity increases the risk of
      hypertension, dyslipidemia, and diabetes mellitus, thereby increasing one's overall risk for
      cardiovascular disease. In contrast to this traditional view, a growing body of research from
      our group and others advanced the novel hypothesis that ectopic myocardial fat deposition
      directly damages the heart. Lipid deposition and overload in the myocardium, termed "cardiac
      steatosis", is directly toxic to cardiac myocytes.

      Deposition of lipid droplets in non-adipocytes (Steatosis): Normally, most of the
      triglycerides in the body are stored in adipose tissue with little to no lipid accumulation
      in non-adipocytes (e.g. parenchymal cells of the liver, pancreas, and muscle) due to a
      balance between fatty acid uptake and oxidation. When this mechanism is defective, fat
      accumulates in non-adipocytes. This abnormal retention of lipid within non-adipose tissues
      such as heart, liver, pancrease, and skeletal muscle is known as "steatosis" and reflects an
      impairment of the normal synthesis and elimination of triglyceride. This was first
      demonstrated in pancreatic β-cells of obese Zucker rats, a genetic model of obesity.

      The intracellular accumulation of long chain free fatty acids (FFA) is hypothesized to engage
      an adverse signaling cascade in which conversion to Ceramide stimulates inducible nitric
      oxide synthase (iNOS), eventually leading to apoptosis. Progressive apoptosis of lipid-laden
      pancreatic β-cells over time eventually leads to insulin deficiency. A combination of β-cell
      failure and insulin resistance has produced diabetes in this animal model. More importantly,
      the pancreatic steatosis in pre-diabetic Zucker rats and the accompanying metabolic
      abnormalities were shown to be effectively reversed by the PPAR-Ƴ antagonist, Troglitazone.

      The next logical step was to ask if similar mechanisms lead to deposition of lipid droplets
      within cardiomyocytes. Indeed, prediabetic obese Zucker rats deposit fat into cardiomyocytes;
      whereas, lean rats do not deposit fat in cardiomyocytes. Furthermore, the obese Zucker rats
      have progressive left ventricular systolic dysfunction, presumably due to excessive lipid
      deposition and toxicity, as dysfunction occurs before the onset of frank diabetes. In human
      studies, MR spectroscopy allows non-invasive evaluation of the number and size of lipid
      droplets in cardiomyocytes. Similar to the rodent studies, our group has demonstrated a
      strong linear relationship between triglyceride deposition in the myocardium and LV
      concentricity and function.

      Nebivolol and its role in myocardial steatosis regression: Nebivolol (Bystolic® by
      Forest/Mylan)through its various modes of action has an exquisite ability to regress cardiac
      steatosis on many different levels. We propose a novel mechanism of Nebivolol action that
      results in reduction of myocardial steatosis.

      Specific aims: This investigation will study whether: 1) cardiac steatosis plays a pivotal
      role in the early pathogenesis of obesity-related adverse cardiac remodeling in humans, 2)
      Nebivolol improves cardiac remodeling via its unique metabolic ability to reduce cardiac
      steatosis above and beyond its effect on hemodynamic cardiac remodeling due to blood pressure
      reduction.

      Study Design and Hypotheses: Before and after six months of low dose (10 mg daily) Nebivolol
      treatment, localized proton MR spectroscopy (to measure triglyceride content in myocytes, as
      well as liver, pancreas and skeletal muscle) and cardiac MRI (for structural and functional
      measurements of the left ventricle) will be performed. Additionally, we will study abdominal
      subcutaneous fat levels over the six month period (MRI and Bioimpedance).
    

Intervention name(s): Nebivolol
Intervention type(s): Drug
Intervention description(s): Day 1 - Patients will start Nebivolol 5 mg PO daily; after one month, if the subject has tolerated 5 mg PO Nebivolol, the dose will be increased to 10 mg PO daily. If the patients is unable to tolerate 5 mg PO Nebivolol, he/she will be discontinued from the study. After six months, medication will be tapered to 5 mg PO daily for two weeks. Medication will then be tapered to 2.5 mg PO daily for two additional weeks.
Other intervention name(s): Bystolic® by Forest/Mylan
Intervention MeSH terms: Nebivolol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: steatosis; MR spectroscopy; Nebivolol; cardiac MRI