ENERGY METABOLISM IN HYPERTROPHIED HEART

  • Taegtmeyer, Heinrich, (PI)

Project: Research projectResearch Project

Description

The general morphological and functional derangement of hypertensive
cardiac hypertrophy (HCH) are defined, both in humans and in experimental
animals, and biochemical investigations at the subcellular level have
brought to light an almost confusing number of abnormalities. Since the
natural history of HCH is one of eventual deterioration of contractility,
we propose to examine the possibility that the functional decline stems
from an abnormality or limiting factor in myocardial energy metabolism.
The purpose of this project is to assess in sequence functional and
metabolic alterations concomitant with early, stable and advanced HCH in
the one-kidney-one-clip hypertensive rabbit model. Recovery will also be
assessed in hearts from animals whose pressure is normalized by
nifedipine. Intrinsic cardiac performance will be determined during each
stage of hypertrophy by measuring pressure-volume relationships in a
flexible perfusion system of the isolated working heart. Immediately
thereafter, the effects of work load on fuel selection and external
efficiency at each stage of HCH and regression will be measured. To
achieve this goal cardiac work will be recorded together with oxygen
consumption and the rate of substrate utilization (uptake of glucose and
oleate). Our primary hypothesis is that, as energy requirements increase,
there is a need for the provision of citric acid cyle intermediates which
may become limiting in situations of high cardiac stress. Thus, the role
of glucose in providing citric acid cycle intermedates for energy
production in normal and overloaded heart will be studied. In order to
identify potential regulatory sites of intermediary metabolism, key
metabolites will be measured in freeze-clamped hearts during an acute
increase in work load. Because in skeletal muscle the purine nucleotide
cycle is thought to be a major source of citric acid cycle intermediates
during increased work, the activity of this pathway will be assessed by
measuring release of ammonia into the perfusate and by determining key
tissue metabolites during acute work stress. Lastly, oxidation of the
amino acid leucine by hypertrophied heart will be measured, because leucine
is not only an energy-providing substrate for the normal heart, but also
acts as a signal for protein turnover. One hypothesis is that leucine
oxidation is decreased in hypertrophied heart due to decreased transminase
activity. The overall importance of these studies is to provide a
metabolic basis for abnormal cardiac function at defined stages of HCH.
StatusFinished
Effective start/end date9/30/8312/31/86

Funding

  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Energy Metabolism
Hypertrophy
Citric Acid Cycle
Workload
Pressure
Glucose
Ammonia
Surgical Instruments
Citric Acid
Leucine
Skeletal Muscle
Perfusion
Rabbits
Kidney
Light
Acids
Proteins

Keywords

  • Medicine(all)