Dr. Peter Liu to present 2009 Ronnie Campbell Memorial Lecture at ACCLL
Dr. Peter Liu is the Scientific Director of the Institute of Circulatory and Respiratory Health at the Canadian Institutes of Health Research.
He is also the Heart & Stroke/Polo Chair Professor of Medicine and Physiology at the Toronto General Hospital, University Health Network, and till recently, the Director of the Heart & Stroke Richard/Lewar Centre of Excellence for Cardiovascular Research at the University of Toronto.
He completed his MD degree at the University of Toronto, and did his postgraduate training at Harvard University.
Dr. Liu has focused his research on the causes of heart failure from bench to bedside, and the condition afflicts one in five Canadians. His team has identified the role of inflammation in changing heart structure and function, and identified potential new biomarkers through system biology approaches and novel treatment targets. His laboratory has also identified how viruses and bacteria can accelerate heart failure and coronary artery disease, and is developing novel vaccines to prevent these complications.
He has published over 250 peer reviewed articles in high impact journals, including Nature, Nature Medicine, and the New England Journal of Medicine. He has received numerous awards in recognition of his accomplishments, including the
- Rick Gallop Research Award from the Heart & Stroke Foundation (2003)
- Research Achievement Award from the Canadian Cardiovascular Society (2003)
- Extramural Award of Merit from the American College of Cardiology (2005)
- Postgraduate Mentorship Award from the University of Toronto (2006)
- Award of Merit from the Federation of Chinese Canadian Professionals (2006).
He has been the scientific program chair of the Canadian Cardiovascular Society, Heart Failure Society of America and International Society of Heart Research Scientific Sessions. He is the President-Elect of the International Society of Cardiomyopathy and Heart Failure of the World Heart Federation. He co-chaired a series of Canadian Cardiovascular Society Consensus Guideline Recommendations for heart failure care. He also chaired several CIHR and NIH scientific review panels. He is also the co-chair the 6th International Initiative on Global Cardiovascular Proteomics for HUPO (Human Proteome Organization), and will be co-hosting the 2009 International HUPO Meeting in Canada.
At the Canadian Institute of Health Research (CIHR), he coordinates research in heart, lung, blood and critical care and establishes strategic directions for the Canadian research community, and liaises with national and international partners. He is also the champion of the CIHR’s Clinical Research Initiative, promoting excellence and building capacity to maximize the opportunity in translating fundamental discoveries to the bedside and fostering excellence in evidence-based health care delivery to Canadians.
Ronnie Campbell Memorial Lecture: Heart Failure Lost and Found — Discoveries over 25 Years
Sunday, March 1, 2009
6:00 PM
Download Dr. Liu’s slide set [PDF].
Retrospectives on Heart Failure Research on the ACC Lake Louise 25th Year Anniversary – Many Hits, More Misses
On this auspicious occasion of the 200th birthday of Charles Darwin, the 25th anniversary of the ACC Lake Louise conferences, and the 10th anniversary of the passing of Professor Ronald W.F. Campbell, it is inspirational for us to look back how the understanding and treatment of heart failure has been completely transformed. We are reminded that through evolution, the shape and function of the heart have not changed. Heart failure, on the other hand, is a modern human disease, a consequence of ageing and acute and chronic injury to the heart. Keep in mind that the original textbook of medicine by Sir William Osler, heart failure occupied only couple pages in the end of the section on valvular disease, and digitalis with bed rest were the only treatments. In the current Braunwald’s textbook, heart failure occupies multiple sections of the book, and we are now spoiled for choices of therapy for systolic heart failure.
1984 - Vasodilators to Rattle Snake Venoms - Orwellian Prophecy?
Back in 1984, the patients with heart failure were treated with digoxin, diuretics and bedrest. Beta blockers were contraindicated. An innovative discovery at the time was the use of vasodilators in the acute heart failure setting. This started a new trend in the use of vasodilators such as nitrates or hydralazine in patients with heart failure, lowering peripheral vascular resistance, and improving peripheral muscle blood flow, with the first indication of improvement in outcomes1. The focus of heart failure shifted away from the heart to the peripheral musculature. Much controversy ensued as to whether the heart or the periphery is more important in heart failure2. The support for the role of the periphery is only evident 2 decades later with the A-HeFT and HF-ACTION trials, where combination of nitrates and hydralazine was able to reduce mortality and hospitalization in patients who are unresponsive to ACE inhibitors3, and exercise training was beneficial in reducing heart failure hospitalization.
CONSENSUS on ACE inhibitors - But how do they really work?
The most dramatic turnaround point for thinking about heart failure occurred in 1987 on the release of the CONSENSUS trial results, in which only 253 patients with severe heart failure were randomized to the ACE inhibitor enalapril or placebo4. The patients receiving enalapril showed a 31% reduction in one year mortality, and had smaller hearts and less heart failure progression. This was confirmed by the SOLVD trials, and ushered in the era of renin-angiotensin blockade in the setting of heart failure5,6. This protection was subsequently expanded to the post-myocardial infarction (MI) patients7,8. This also began an era in which neurohormones are regarded as culprits in heart failure, and that the more we blocked the neurohormones the better should be the outcome.
But, how did the ACE inhibitors really work in the setting of heart failure? Was it a vasodilator, or blocker of a harmful chemical that was regarded as “toxic” in heart failure? Much of this was elucidated by the team of Marc and Janet Pfeffer, in whose laboratory discovered that ACE inhibitors were potent inhibitors of cardiac dilation and functional deterioration, a process called “cardiac remodeling”9,10. The focus of heart failure research has finally returned to the heart.
PROMISE no more Inotropes in Chronic Heart Failure
Short term observations in basic laboratory and coronary care unit have continued to identify the lack of contractile reserve as the fundamental flaw in heart failure, and investigators extolled the virtues of increasing inotropy. However, intrope after inotrope have failed to prolong survival or even improve quality of life. This included the classic digoxin in the DIG trial, where no survival benefit was observed despite 200 years of experience since William Wuthering11. Worse, trials such as PROMISE evaluating the potential efficacy of milrinone, a phosphodiesterase inhibitor that putatively did not raise intracellular calcium, increased mortality and complications, despite the fact that patient may temporarily feel better12. With the limited efficacy seen with levosimendan ten years later, the future of inotropic agents will need to change an entirely different paradigm for approach13.
Constellation of Rediscovered Beta and Aldosterone Blockers, with the Birth of Molecular Cardiology
Again due to the extrapolation of acute heart failure experience to chronic heart failure, beta blockers were long contraindicated in the textbooks of medicine for heart failure. Fortunately, the treatment of heart failure has taken a major forward leap after a cluster of clinical trials evaluated beta blockade in the 1990s in a more formal setting than Fenn Waggstein’s original momentous experiment in which he showed the efficacy of beta blockade in patients with heart failure for which he was reprimanded14. The “modern” beta blocker trials were all conducted on the background of ACE inhibition, yet the trials were all terminated early because of overwhelming efficacy of beta blockade in reducing mortality and hospitalization15, 16. This included the COPERNICUS trial, in which patients with class III-IV heart failure benefited surprisingly and dramatically to graduated doses of carvedilol17. This has transformed the treatment of heart failure, and the challenge for the next 5 years is to undo the teachings of the last 2 decades on the role of beta blockers in heart failure. The subsequent negative results of more potential neurohormonal blockers such as moxonidine and omapatrilat suggested that it is not neurohormonal blockade per se, but more likely the biology of these specific agents on reverse remodeling of the damaged heart cells that made the difference.
A parallel set of studies uncovered the surprising efficacy of aldosterone antagonist such as spironolactone in the RALES trial18, more recently eplerenone in the EPHESUS trial in heart failure post-myocardial infarction19. The efficacy is as great if not greater than ACE inhibitors or beta blockers. The EPHESUS study is the only major trial in modern era of reperfusion post myocardial infarction (MI) to show such a dramatic reduction in all cause mortality, sudden deaths and prevention of heart failure. Fast forward to the present, we anticipate the potential approval of eplerenone for patients with cardiac dysfunction post MI in Canada later this year.
Better CARE with Devices rather than Antiarrhythmics
The triumph with pharmacological therapy was matched only by the innovations in electrical devices that appear to also reverse remodel the heart. The concept of multi-sited pacing in diseased hearts really took a firm step forward in patients with heart failure and conduction abnormalities. The initial results of cardiac resynchronization therapy (CRT) improved quality of life and exercise tolerance, but CARE trial with its impact on survival and reduction in heart size and mitral regurgitation suggested reverse remodeling using electrical signals became a reality20. This together with ICDs have secured the electrical devices as part of the treatment repertoire in the appropriate patients with heart failure.
Lessons Learned and Challenges Ahead for the Next 25 Years
It is indeed gratifying to look back at the major advances in heart failure research over the last 25 years. Now patients with heart failure in Canada are enjoying improved survival and less hospital stay. For decades, we have seen the inexorable rise of the heart failure epidemic in our population21. But in the past year for the first time, we are witnessing a plateau in the incidence of heart failure, a direct results of innovations in research.
This is changing the epidemiology of cardiovascular disease, and transformed the lives of many of these patients. However, while one type of heart failure has been tamed, the rising tide in heart failure now turns to diastolic heart failure or heart failure with preserved systolic function22. The failure of the recent I-PRESERVE trial underscores the plight and the absence of any evidence based therapy for this rising population. Equally challenging are the patients with acute heart failure, where the table has been turned around - chronic therapy does not work for acute decompensated heart failure. The failure of recent tirals such as EVEREST and SURVIVE put the focus back on understanding the underlying pathophysiology of these “new conditions”. The agenda promises that the next 25 years of heart failure will be just as challenging, paradigm shifting and I am sure as fruitful.
Selected References
1. Cohn J, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Loeb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. New England Journal of Medicine. 1986;314:1547-1552.
2. Cohn JN. Nitrates are effective in the treatment of chronic congestive heart failure: The protagonist’s view. American Journal of Cardiology. 1990;66:444-446.
3. Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R, Jr., Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-57.
4. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. New England Journal of Medicine. 1987;316:1429-1435.
5. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New England Journal of Medicine. 1991;325:293-302.
6. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. New England Journal of Medicine. 1992;327:685-691.
7. The AIRE Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-828.
8. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM, Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. New England Journal of Medicine. 2003;349:1893-906.
9. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation. 1990;81:1161-1172.
10. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilation after anterior myocardial infarction. New England Journal of Medicine. 1988;319:80-86.
11. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. New England Journal of Medicine. 1997;336:525-533.
12. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, Mallis GE, Sollano JA, Shannon J, Tandon PK, DeMets DL, Group PSR. Effect of oral milrinone on mortality in severe chronic heart failure. New England Journal of Medicine. 1991;325:1468-1475.
13. Mebazaa A, Nieminen MS, Packer M, Cohen-Solal A, Kleber FX, Pocock SJ, Thakkar R, Padley RJ, Poder P, Kivikko M. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. Jama. 2007;297:1883-91.
14. Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I. Effect of chronic beta-adrenergic blockade in congestive cardiomyopathy. British Heart Journal. 1975;37:1022-1036.
15. MERIT-HF Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-7.
16. The CIBIS-II Group. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13.
17. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL, Group. CPRCSS. Effect of carvedilol on survival in severe chronic heart failure. New England Journal of Medicine. 2001;344:1651-8.
18. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, Investigators. R. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. New England Journal of Medicine. 1999;341:709-17.
19. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-21.
20. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. New England Journal of Medicine. 2005;352:1539-49.
21. Johansen H, Strauss B, Walsh P, Moe G, Liu PP. Congestive Heart Failure: the Coming Epidemic. Canadian Journal of Cardiology. 2003;19:430-435.
22. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006;355:260-9.
Looking Forward: Are We Ready for Cardiovascular Vaccines?
Monday, March 2, 2009
9:00 AM
Protecting the Population against Environmental Challenges to Health - the Efficacy of Vaccines
The British Medical Journal conducted a poll in 2007 for its readers to rank the most important medical milestones that impacted on health since 1840. Amongst the top 10 milestones was the discovery of vaccines that was ranked #41. Certainly, as effective preventive measures for major public health problems, very few discoveries rival vaccines in their ability to transform the nature of health burden, and even eliminate diseases from human populations altogether.
The vaccines we have today are grounded in the innovation that Louis Pasteur introduced with his rabies vaccine. Pasteur’s breakthrough in 1885 represented the medical solution of an otherwise untreatable disease. In the 21st century we have witnessed the elimination of diseases such as smallpox from all countries in the world. The most recent awarding of the Nobel Prize to Professor Harald zur Hausen for discoveries that led up to the development of the HPV vaccine is another example2. The influenza and pneumococcal vaccines annually save many lives in the vulnerable populations3. One of the major goals of global funding agencies such as the Gates Foundation in improving the global health challenge is the development of effective vaccines. As the focus of chronic diseases such as cardiovascular disease move towards prevention in the new millennium, an intriguing concept is the possibility of cardiovascular preventive vaccines.
The Concept of a Cardiovascular Vaccine
The development of cardiovascular vaccines is however much more challenging, as the most successful vaccines to date are against infectious agents. In chronic conditions that constitute risk factors for cardiovascular disease, such as atherosclerosis, hypertension, and diabetes, there are not always infectious triggers that could be readily identified as antigens for vaccination. However, it is well known that the progression of cardiovascular disease, whether atherosclerosis, diabetes, hypertension and cardiovascular remodelling all involve the activation of inflammatory systems. The recent identification of high sensitivity C-reactive protein (hsCRP), a biomarker indicative of inflammation, as a potential new risk factor for atherosclerotic complications underscores this concept.
Work from our and other laboratories suggest that modifying the immune system can significantly change the outcomes of chronic diseases such as atherosclerosis and cardiac hypertrophy4. Vaccination thus may be a strategy to modify our immune system such that the excessive inflammatory reaction towards the environmental insult could be attenuated to protect the host. In this case, the pro-inflammatory cytokines, macrophages or T-cells against oxidized lipoprotein, shared vascular antigen, angiotensin receptor or other targets could be modulated to avoid the complications.
Developing Potential Candidates for Cardiovascular Vaccines
How do we approach the concept of the cardiovascular vaccine? The current approach is to take conditions where some of the immunogenic triggers may be identifiable. This included atherosclerosis where oxidized lipoproteins have been used as a vaccine candidate. Other candidates included the potential chlamydial outer wall antigen, which crosses react with the vessel wall components to promote inflammatory response, underscoring the association of chlamydial infections with atherosclerosis5,6. Similarly, the utilization of angiotensin and its receptor as potential immunogens help to block the function of angiotensin with its receptor. This can be applied also to aldosterone, and beta adrenergic receptors as targets for blockade. Finally, for myocarditis and diabetes, the shared trigger of enteroviruses such as coxsackievirus made the viral coat antigen another ideal target7.
Preclinical studies for infectious agents such as coxsackievirus in myocarditis has indicated that combinatorial approaches using coxsackieviral receptor engaging viral coat protein is effective in protecting the host against exposure to the virus. A combination of molecularly generated DNA vaccine together with protein based vaccine appears to be most efficacious. Similarly, the utilization of chlamydial based antigen in a LDL-receptor knockout animal fed with high fat western diet was able to reduce the burden of atherosclerosis, particularly if the animals also were exposed the infectious agents. Other strategies include the use of heat shock protein (HSP-60) which is shared between chlamydia and vascular atherosclerotic lesions appear to be also efficacious8. The various combinations of these type of strategies will likely result in several clinical vaccine candidates.
Secondary Prevention of Cardiovascular Complications with Influenza Vaccines
Evidence from cohort studies and a randomized clinical trial indicates that annual vaccination against seasonal influenza prevents cardiovascular morbidity and all-cause mortality in patients with identified cardiovascular conditions. The American Heart Association and American College of Cardiology recommended influenza immunization with inactivated vaccine as part of comprehensive secondary prevention in persons with coronary and other atherosclerotic vascular disease (Class I, Level B)9. The Canadian Cardiovascular Society Heart Failure guidelines also recommend influenza and pneumococcal vaccination in patients with heart failure or post-myocardial infarction10. The efficacy likely arise from at least 2 different mechanisms of action: (1) patients with cardiovascular conditions are prone to infections such as influenza, and the consequences are more severe including deaths; and (2) infection with influenza virus induces an overall inflammatory response in the host that can trigger cardiovascular events such as myocardial infarction or heart failure. Therefore, vaccination with the influenza vaccine has already been shown to be effective in preventing cardiovascular complications.
Clinical Trial of a Potential Anti-Hypertensive Vaccine
Most recently, the development of clinical vaccines targeted towards angiotensin II/receptor interaction in a hypertensive population has reached phase II trial11. The result was encouraging in that the patients with mild to moderate hypertension had a magnitude of blood pressure reduction similar to that of standard antihypertensive medication. The patient showed an average of 9/4 mmHg reduction at week 14 following immunization. There were only minor side effects related to local immunization injection site similar to other vaccines. This is an important proof of concept that gave hypertension treatment a “new shot in the arm”.
The Future of CV Vaccines - Promises and Challenges
The shift of focus from treating complications to prevention in chronic diseases such as cardiovascular disease demands innovations in prevention. While pharmacological therapies are currently most efficacious in achieving broad patient protection, the challenges of compliance and side effects make it relatively ineffective over the long run. Vaccination while still in its infancy, does offer some attractive alternatives to the traditional lifestyle modifications and pharmacological treatments. Further research will shed light on better antigenic targets, better immunological interventions, and better means of delivering vaccines and combinations with other preventive strategies. There may come one day all children get a combination vaccine together with their DPTP to prevent heart disease, Alzheimer’s disease and other health problems before they ever occur.
Selected References
1. Worboys M. Vaccines: conquering untreatable diseases. Bmj. 2007;334 Suppl 1:s19.
2. Weiss RA. On viruses, discovery, and recognition. Cell. 2008;135:983-6.
3. Nichol KL, Nordin JD, Nelson DB, Mullooly JP, Hak E. Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med. 2007;357:1373-81.
4. Nian M, Lee P, Khaper N, Liu P. Inflammation and cytokines in post-myocardial infarction remodeling. Circulation Research. 2004;94:1543-53.
5. Bachmaier K, Neu N, de la Maza L, Pal S, Hessel A, Penninger J. Chlamydia infections and heart disease linked through antigenic mimicry. Science. 1999;283:1335-39.
6. Saren A, Pascolo S, Stevanovic S, Dumrese T, Puolakkainen M, Sarvas M, Rammensee HG, Vuola JM. Identification of Chlamydia pneumoniae-derived mouse CD8 epitopes. Infections and Immunity. 2002;70:3336-43.
7. Scheerlinck. Genetic adjuvants for DNA vaccines. Vaccine. 2001;19:2647-2656.
8. Benagiano M, D’Elios MM, Amedei A, Azzurri A, van der Zee R, Ciervo A, Rombola G, Romagnani S, Cassone A, Del Prete G. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques. J Immunol. 2005;174:6509-17.
9. Davis MM, Taubert K, Benin AL, Brown DW, Mensah GA, Baddour LM, Dunbar S, Krumholz HM. Influenza vaccination as secondary prevention for cardiovascular disease: a science advisory from the American Heart Association/American College of Cardiology. Circulation. 2006;114:1549-53.
10. Liu P, Arnold M, Belenkie I, Howlett J, Huckell V, Ignazewski A, al. e. The 2003 Update of the Canadian Cardiovascular Society Heart Failure Practice Guidelines. Canadian Journal of Cardiology. 2003;19:347-356.
11. Tissot AC, Maurer P, Nussberger J, Sabat R, Pfister T, Ignatenko S, Volk HD, Stocker H, Muller P, Jennings GT, Wagner F, Bachmann MF. Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study. Lancet. 2008;371:821-7.
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