New Discoveries in Heart Failure

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New Discoveries in Heart Failure
Kirkwood F. Adams Jr., MD Director, UNC Heart
Failure ProgramAssociate Professor of Medicine
and Radiology Division of CardiologyDepartment
of MedicineUniversity of North CarolinaChapel
Hill, North Carolina
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Definition of History

• Many Different Types of Stories
• Chronological Description of Events
• Tales of Individuals
• Delineation of Patterns in Events
• Lives of Ideas

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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

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History of IdeasFocused on the identification
of unit ideasMy interpretation Ideas are
rooted in the conceptual ways in which we think
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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.
Lefkowitz RJ. Acta Physiol. 20071909-19.
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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)
Lefkowitz RJ. Acta Physiol. 20071909-19.
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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 ß-adrenergic
receptors, and then for the a-adrenergic
receptors (Mukherjee C et al.1975).
Lefkowitz RJ. Acta Physiol. 20071909-19.
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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. 20071909-19.
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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.

Black, James (1988 Nobel recipient).
Autobiography. Nobelprize.org.
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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.

Black, James (1988 Nobel recipient).
Autobiography. Nobelprize.org.
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Stuff of Nobel PrizesLinear Conceptualization
Drug Effect
Higher HR - Greater MVO2 - More angina
HR Peak Ex Rest
Lower HR - Less MVO2 - Less angina
Increasing Beta Blocker Dose
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Sir James W. BlackAcademic 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.

Black, James (1988 Nobel recipient).
Autobiography. Nobelprize.org.
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Not Surprising That Sympathetic Activation
Occurs in CHF - circa 1970s

Sympathetic Activation Short-term Improvement
of All Aspects of Cardiac Function
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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?
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Going from Angina to CHF
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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

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Non-Linear Conceptualization of Drug Effect
Clinical Wellness
Time Dependent Clinical and Functional Improvement
Passage of Time and Generally Higher BB Dose
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MERIT-HF Total Mortality
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Placebo
P 0.006
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Metoprolol CR-XL
Percentage of patients
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5
0
0
3
6
9
12
15
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Months of follow-up
MERIT-HF Study Group. Lancet.1999353(9169)2001-7
.
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LVEF Mean Changes from Baseline
0.08


Placebo 50 mg 200 mg
0.07
0.06

0.06
0.06
0.05

Ejection Fraction
0.04
0.04
0.03
0.03
0.02
0.01
0.01
0.00
0.00
Month 6
Month 12
P-value lt 0.05 vs. baseline P-value lt 0.05
vs. placebo Based upon repeated ANOVA model with
terms for treatment group, time, and the
interaction between treatment group and time.
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The Truth Will Out