Regression of Myocardial Steatosis by Nebivolol
| Status: | Completed |
|---|---|
| Conditions: | Gastrointestinal |
| Therapuetic Areas: | Gastroenterology |
| Healthy: | No |
| Age Range: | 18 - 59 |
| Updated: | 4/2/2016 |
| Start Date: | June 2011 |
| End Date: | June 2013 |
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.
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.
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).
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).
Inclusion Criteria:
- Mexican American men and women
- Age 18 - 59
- Metabolic Syndrome*
- Myocardial TG > or = to 0.5% by localized MR spectroscopy
*Metabolic syndrome in our study will follow the NCEP ATP III (National Cholesterol
Education Program Adult Treatment Panel III) Guidelines which include > or = to 3 of
the following:
- Fasting blood glucose > or = to 100 mg/dL
- Waist circumference: Men > 102 cm, Women > 88 cm
- Triglycerides > or = to 150 mg/dL
- BP > 130/85
Exclusion Criteria:
- Current use of a beta-blocker
- HR < 50 beats/min or BP < 130/85
- Contraindication to beta-blocker therapy such as asthma, reactive airway disease,
heart block, or depression
- CHF (any NYHA class) by history, physical examination, or current use of CHF
medication including beta-blockers, ACE inhibitors, angiotensin receptor blockers
(ARBs), diuretics, calcium channel blockers, digitoxin, hydralazine, nitrates
(including sublingual nitroglycerin), and inotropic agents
- LVEF < 50% by cardiac MRI
- Hepatic insufficiency or current use of another medication that is also metabolized
by the CYP2D6 isozyme (paroxetine, fluoxetine, quinidine, propafenone).
- Any contraindication to MRI, e.g. metallic implants, metallic tattoos,
claustrophobia, weight > 350 pounds (the MRI weight limit)
- Pregnancy at any time during the study
- A recent weight loss (>10% of body weight within the past year) or plans to undergo
significant weight reduction (>10% of body weight) during the experimental protocol.
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