New Discoveries in Heart Failure Kirkwood F. Adams Jr., MD Director, UNC Heart Failure Program...
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Transcript of New Discoveries in Heart Failure Kirkwood F. Adams Jr., MD Director, UNC Heart Failure Program...
New Discoveries in Heart Failure
Kirkwood F. Adams Jr., MDDirector, UNC Heart Failure Program
Associate Professor of Medicine and Radiology Division of Cardiology
Department of MedicineUniversity of North CarolinaChapel 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 ImageModern - 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.
Lefkowitz RJ. Acta Physiol. 2007;190:9-19.
Raymond Ahlquist
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. 2007;190:9-19.
Raymond Ahlquist
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 PrizesLinear Conceptualization Drug Effect
Lower HR - Less MVO2 - Less angina
Higher HR - Greater MVO2 - More angina
Increasing Beta Blocker Dose
HR
Pe
ak
Ex
Res
t
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.
Sir James W. Black
Black, James (1988 Nobel recipient). Autobiography. Nobelprize.org.
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
Not Surprising That Sympathetic Activation Occurs in CHF - circa 1970’s
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?
Paradox of Beta-Receptor Antagonists in Heart Failure
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
Non-Linear Conceptualization of Drug Effect
Time Dependent Clinical and Functional Improvement
Passage of Time and Generally Higher BB Dose
Clin
ica
l We
llne
ss
20
Months of follow-up
0 3 6 9 12 15 18 21
5
0
10
Per
cen
tag
e o
f p
atie
nts
15P = 0.006
Risk reduction: 34%Placebo
Metoprolol
CR-XL
MERIT-HF: Total Mortality
MERIT-HF Study Group. Lancet.1999;353(9169):2001-7.
0.000.01
Placebo50 mg200 mg
LVEF: Mean Changes from Baseline
* 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.
* ** * **
* **
*
Month 6 Month 12
0.06
0.03
0.06
0.04
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0.00
Eje
ctio
n F
ract
ion
The Truth Will Out