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)


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 - 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.


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


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


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

new discoveries in heart failure kirkwood f. adams jr., md director, unc heart failure program...

Documents