New Discoveries in Heart Failure

2. 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

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

4. 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

5. History of IdeasFocused on the identification of unit ideasMy interpretation Ideas are rooted in the conceptual ways in which we think

6. Raymond Ahlquist 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.

7. 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.

8. Lefkowitz - The Molecular Era - Radioligand Binding As is often the case, the key to moving forward was the development ofnovel 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 byradioligand bindingso 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.

9. 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.

10. Sir James W. Black 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.

11. Sir James W. Black 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.

12. 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

13. Sir James W. Black 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.

14. • 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 Sympathetic Activation = Short-term Improvement of All Aspects of Cardiac Function

15. 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?

16. Going from Angina to CHF

17. 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

18. Non-Linear Conceptualization of Drug Effect Clinical Wellness Time Dependent Clinical and Functional Improvement Passage of Time and Generally Higher BB Dose

19. MERIT-HF: Total Mortality Risk reduction: 34% 20 Placebo P = 0.006 15 Metoprolol CR-XL Percentage of patients 10 5 0 0 3 6 9 12 15 18 21 Months of follow-up MERIT-HF Study Group. Lancet.1999;353(9169):2001-7.

20. 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 12 Month 6 * 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.

21. The Truth Will Out