Transcript Slide 1

New Discoveries in Heart Failure
Kirkwood F. Adams Jr., MD
Director, UNC Heart Failure Program
Associate Professor of Medicine and Radiology
Division of Cardiology
Department of Medicine
University of North Carolina
Chapel Hill, North Carolina
Definition of History
Many Different Types of Stories
• Chronological Description of Events
• Tales of Individuals
• Delineation of Patterns in Events
• Lives of Ideas
Meaning of Idea
Greek - An Image
Modern - A Concept - Abstraction
• Feminine Form of Eidos - which means
“to see or to know” - image remains
linked to knowing
• Evolved in modern language usage
from a purely mental image to a concept
History of Ideas
Focused on the
identification
of unit ideas
My interpretation
Ideas are rooted in
the conceptual ways
in which we think
Lefkowitz - History of Receptor Concept
However, even into the 1970s
the receptors themselves
remained elusive. In fact,
a considerable body of opinion
held that receptors, as we now
understand them, did not exist
as discrete molecular entities.
Exemplary of this skepticism is the
following quotation from the early
1970s by the distinguished American
pharmacologist Raymond Ahlquist
who, ironically, some 25 years before
had pioneered the concept of distinct
 and -adrenergic receptors for
catecholamines.
Raymond Ahlquist
Lefkowitz RJ. Acta Physiol. 2007;190:9-19.
Lefkowitz - History of Receptor Concept
He wrote “…This would be true
if I were so presumptuous as
to believe that - and -receptors
really did exist. There are those that
think so and even propose to describe
their intimate structure. To me they
are an abstract concept conceived
to explain observed responses
of tissues produced by chemicals
of various structure.” (Ahlquist 1973)
Raymond Ahlquist
Lefkowitz RJ. Acta Physiol. 2007;190:9-19.
Lefkowitz - The Molecular Era Radioligand Binding
As is often the case, the key
to moving forward was the
development of novel technologies,
the absence of which had previously
stymied progress. The initial technique
that was needed was a means of
identifying and studying the receptors
directly by radioligand binding so that
their properties no longer needed
to be inferred from downstream
signaling events. We were successful
in developing such radioligand binding
methods, initially for the β-adrenergic
receptors, and then for the α-adrenergic
receptors (Mukherjee C et al.1975).
Lefkowitz RJ. Acta Physiol. 2007;190:9-19.
Lefkowitz - The Molecular Era Radioligand Binding
Another important consequence
of the development of radioligand
binding techniques was that
they permitted, for the first time,
an approach for isolation and
characterization of the receptors.
Lefkowitz RJ. Acta Physiol. 2007;190:9-19.
Sir James W. Black - The Nobel Prize
in Physiology or Medicine 1988
I chose to study Medicine mainly under
the influence of an elder brother, William,
a graduate in Medicine at St. Andrews
some years earlier. In the cold, forbidding,
grayness of St Andrews - with its dedication
to "causes purely spiritual and intellectual,
to religion and learning" (Andrew Lang)
- I learned, for the first time, the joys
of substituting hard, disciplined study
for the indulgence of day-dreaming.
Undergraduate prizes seemed to confirm
that I was working harder than my
colleagues in a new-found love affair
with knowledge.
Sir James W. Black
Black, James (1988 Nobel recipient). Autobiography. Nobelprize.org.
Stuff of Nobel Prizes
Work with George Smith, concerned
with finding ways of increasing the
supply of oxygen to the heart in patients
with narrowed coronary arteries, led me
to propose that reducing myocardial
demand for oxygen by annulling cardiac
sympathetic drive might be equally
effective.
By 1956, I had clearly formulated the aim,
based on Ahlquist's dual adrenoceptor
hypothesis, of finding a specific
adrenaline receptor antagonist.
Sir James W. Black
Black, James (1988 Nobel recipient). Autobiography. Nobelprize.org.
Stuff of Nobel Prizes
Linear Conceptualization Drug Effect
HR Peak Ex Rest
Higher HR - Greater MVO2 - More angina
Lower HR - Less MVO2 - Less angina
Increasing Beta Blocker Dose
Sir James W. Black
Academic Working With Industry
Egged on by their local representative,
I successfully approached the I.C.I.
Pharmaceuticals Division for help and
ended up being employed by them at their
exciting new laboratories at Alderley Park,
Cheshire.
During my six years with them,
Dr. Garnet Davey (subsequently
Research Director) constantly
supported me and, I have no doubt,
fought many battles on my behalf
to keep the initially controversial
programme going. All I ever promised
was that I was sure I could develop
a new pharmacological agent which
might answer a physiological question.
Any utility would be implicit in that answer.
Sir James W. Black
Black, James (1988 Nobel recipient). Autobiography. Nobelprize.org.
Not Surprising That Sympathetic Activation
Occurs in CHF - circa 1970’s
Sympathetic Activation = Short-term
Improvement of All Aspects of Cardiac Function
• Heart rate = more beats per minute
• Contractility = improved – increased systolic function
• Hypertrophy = more contractile units = increased function
• Frank-Starling relationship – myocardial stretch =
improved diastolic function
Paradox of Beta-Receptor
Antagonists in Heart Failure
Why should blocking the activity of the
sympathetic nervous system, which is
known to increase myocardial contraction
and heart rate, be of benefit in heart failure,
a condition whose primary mechanism
is a deficiency of myocardial contraction
and cardiac output?
Going from Angina to CHF
Concept That May Resolve Paradox
Sympathetic nervous system designed
for acute regulation of the cardiovascular
system - rapid on-off action not for sustained
day after day, week after week, month after
month activation as is seen in CHF
Acute benefit - not equal - chronic benefit
Time the ravisher of all things - Ovid
Clinical Wellness
Non-Linear Conceptualization
of Drug Effect
Time Dependent Clinical and Functional Improvement
Passage of Time and Generally Higher BB Dose
MERIT-HF: Total Mortality
Percentage of patients
20
Risk reduction: 34%
P = 0.006
15
Placebo
Metoprolol
CR-XL
10
5
0
0
3
6
9
12 15 18
Months of follow-up
21
MERIT-HF Study Group. Lancet.1999;353(9169):2001-7.
LVEF: Mean Changes from Baseline
0.08
* **
* **
Ejection Fraction
0.07
0.06
* **
0.06
0.05
Placebo
50 mg
200 mg
0.06
*
0.04
0.04
0.03
0.03
0.02
0.01
0.01
0.00
0.00
Month 6
Month 12
* P-value < 0.05 vs. baseline
** P-value < 0.05 vs. placebo
Based upon repeated ANOVA model with terms for treatment group,
time, and the interaction between treatment group and time.
The Truth Will Out