Peter Liu, MD FRCPC FACC

Filed under: 2008 Presentations on March 6, 2008

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.

Cardiac Stem Cell Therapy for Regeneration: Re-Building a Castle in the Air or True Homecoming?

Monday, March 17, 2008
5:00 PM

Cell Based Therapy: Promise of the Fountain of Youth?
The problem of heart failure is partially driven by the inability of the myocardium to regenerate adequately during aging or following injury such as myocardial infarction. The advances in stem cell biology bring forth the exciting premise of potentially unlimited supply of myocytes and vascular cells to replenish those lost during ageing or following injury (1, 2). This has stimulated a flurry of activities both in the basic laboratory and the clinical arena to realize this golden opportunity, but also identified the potential barriers of translating this into reality.

The past year has been particularly exciting because progress has also been made in the past year – the ability to reprogram human skin cells to become embryonic stem cells, the identification of new stem cells that can form myocytes, and the repopulation of the matrix skeleton of the heart with stem cells to form a beating heart are astounding advances.

However, when these concepts are translated into clinical studies, the original promise of regenerating the heart in situ does not appear to readily feasible. Along the way, it appears that instillation of the cells can assist significantly the remodelling process. However, many challenges remain in the progress towards the goal of regenerating the heart.

Cell Based Therapy: Whence We Have Arrived in Clinical Trials
Currently there are a number of small sized studies using a variety of cell sources ventricular remodelling post-infarction, with reductions of LVEF as measured by ventriculogram or MRI (3). However, the results are rather mixed, depending on the cell type, cell number and type of patients studied. In the largest study to date, the REPAIR-AMI trial studied 199 patients randomized to intracoronary bone marrow cell infusion vs. placebo in patients undergoing intervention post MI (4). There was an absolute increase of 2.5% in LVEF at 4 months post procedure. There was a reduction in combined adverse clinical events in the bone marrow treated group at one year. Overall, the largest cluster of trials involving proper randomization and placebo control used bone marrow derived cells delivered intracoronarily. Overall, these studies showed a small benefit of 3-4% of LVEF increase, followed up on the average of 6 months (2). The However, the studies are all small in size, and not powered for clinical outcomes.

A concerning issue is whether this effect is sustained or not with time. The major randomized controlled trials was the BOOST trial from Germany, which in 60 patients demonstrated an early ejection fraction improvement of 6% (absolute) in the bone marrow cell treated arm, compared to placebo at 6 months of follow up (5). However, by 18 months of follow-up, the difference has reduced to 2.8% and no longer statically significant (6).

The mechanisms of these functional improvements are unknown, but it is unlikely that the improvements result from differentiation of the injected cells into cardio myocytes. Growth factor and cytokine release by injected cells is frequently suggested as a potential mechanism of action, and improved microvascular function has been shown in the REPAIR-AMI study.

Cell Based Therapy – Developments in the Cell Source
A large number of potential cell sources have been tried in experimental models of myocardial injury, such as myocardial infarction. While bone marrow derived cells or endothelial progenitor cells have been shown to improve angiogenesis and remodelling, convincing evidence of significant differentiation of these cells into myocytes has been lacking. Much of the benefits seen to date appear to be due to paracrine effects of the injected cells. Endogenous cardiac stem cells do exist, but their numbers are extremely low, and they are difficult to isolate and proliferate. Embryonic stem cells, from abandoned embryos with survival factors (7), or more recently, reprogramming of adult cells such as skin cells, provide the most promising potential of being a true source of cells for repairing the heart (8). However, allowing these cells to survive in the hostile environment of the injured adult heart has been the major challenge, with most cells dying a very short time after implantation.

An additional factor that appears to be important in the cell survival is the matrix environment of the heart. Artificial membranes or matrix with embedded stem cells appear to have greater efficacy in allowing the cells to survive. Alternatively, the cells may be embedded in a gel capsule to trigger less immunological activation and killing. Most dramatically, Taylor and colleagues have used an entire cardiac matrix skeleton as a framework to grow stem cells, and showed the ability to regenerate a contracting heart successfully using this approach (9).

Advances in Understanding of Homing and Niche
Another important factor to consider is the innate host repair and regeneration mechanism post MI. These involve locally produced homing factors for mobilization of stem cells and repair cells from other sites, and can be enhanced following local instillation of cells (1, 10).

We have found for example that following infarction, the endogenous production of stem cell factor help to mobilize c-kit+ cells to produce local angiogenesis and improved cell survival. Similarly, we have also identified that innate immune signalling pathways, such as IRAK-4 can help to mobilize dendritic cells that contributes to excessive fibrosis (11). The inhibition of the latter pathways helps to achieve much better repair and improved survival.

Cell Based Therapy – Barriers that Need to be Overcome
Many questions still remain unanswered – what are the cells actually doing in mediating repair and remodelling following instillation? What source of cells will be most appropriate, and what is the best time and route of delivery of the cells? How do we reprogram the cells to strike the delicate balance of appropriate cell proliferation vs. the risk of cancerous transformation? Can we harness the endogenous stem cells in the heart, or do we need to use embryonic stem cells, or can we reprogram our skin cells? We are still very far off from the original goal of regenerating the lost myocyte, but we have learned tremendously along the way, and have understood much better the process of cardiac repair and regeneration.

References

Wollert KC, Drexler H. “Clinical applications of stem cells for the heart.” Circ Res. 2005;96:151-63.
Segers VF, Lee RT. “Stem-cell therapy for cardiac disease.” Nature 2008;451:937-42.
Rosenzweig A. “Cardiac cell therapy—mixed results from mixed cells.” N Engl J Med. 2006;355:1274-7.
Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM. “Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction.” N Engl J Med. 2006;355:1210-21.
Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H. “Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial.” Lancet 2004;364:141-8.
Meyer GP, Wollert KC, Lotz J, Steffens J, Lippolt P, Fichtner S, Hecker H, Schaefer A, Arseniev L, Hertenstein B, Ganser A, Drexler H. “Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial.” Circulation 2006;113:1287-94.
Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, Reinecke H, Xu C, Hassanipour M, Police S, O’Sullivan C, Collins L, Chen Y, Minami E, Gill EA, Ueno S, Yuan C, Gold J, Murry CE. “Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts.” Nat Biotechnol. 2007;25:1015-1024.
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. “Induction of pluripotent stem cells from adult human fibroblasts by defined factors.” Cell. 2007;131:861-72.
Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA. “Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart.” Nat Med. 2008;14:213-21.
Ayach BB, Yoshimitsu M, Dawood F, Sun M, Arab S, Chen M, Higuchi K, Siatskas C, Lee P, Lim H, Zhang J, Cukerman E, Stanford WL, Medin JA, Liu PP. “Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction.” Proc Natl Acad Sci USA. 2006;103:2304-9.
Maekawa Y, Mizue N, Chan A, Dawood S, Chen M, Dawood F, Suzuki N, Yeh WC, Medin JA, Liu PP. “Survival and cardiac remodeling after myocardial infarction are critically dependent on the host innate immune interleukin-1 receptor associated kinase-4 (IRAK-4) signaling: A regulator of bone marrow-derived dendritic cells.” Circulation 2008;(in press).

Renin Angiotensin System In Cardiovascular Disease: Are We at the End or the Beginning?

Tuesday, March 18, 2008
9:00 AM

Renin-Angiotensin System – Foundation of CV Therapy, but Are We at the End of the Road?
Over the past 2 decades, the renin-angiotensin system (RAS) has become the foundation of CV therapy. We are all familiar with the paradigm of angiotensinogen being converted to angiotensin-I by renin in the kidneys. The circulating angiotensin-I in turn is cleaved by the angiotensin converting enzyme (ACE or ACE1) in the lungs, into angiotensin-II (AII). Angiotensin-II, a simple octapeptide acting on the AT-1 receptor, mediates vasoconstriction, myocyte hypertrophy and cardiovascular fibrosis and remodeling. It is also important to realize that while there is a systemic processing of the RAS, that is present in all cardiovascular system cells (1).

Blockade of RAS, whether at the ACE level with ACE inhibitors, or at the receptor level with AT-1 receptor blockers (ARBs), has been practically uniformly protective in the injured or stressed heart. This applies to hypertension, diabetes, myocardial infarction or congestive heart failure (2, 3).

With so many ACE inhibitors and ARBs to choose from, and many of them becoming generic, is there anything left to learn in RAS? Would the ONTARGET trial, for example, be the last study that we will ever learn about RAS?

Renin Inhibition – Redundancy or New Opportunity?
Attempts at renin inhibitions have had a long history. However, stable inhibitors of renin or plasma renin activity have not become a reality until recently. It is known that in hypertension or heart failure, plasma renin activity can be elevated. This is further aggravated by the use of ACEi or ARBs, as the feedback inhibition stimulates further the renin activity.

The availability and recent approval of renin inhibitor, Aliskiren, have provided a wonderful new tool to answer the question – inhibiting renin: Is it a new opportunity, or completely redundant in view of blockade of ACE or AT-1 receptor (4)?

With the clinical trial results of Aliskiren now available, the result is an overwhelming positive one. Despite full level of ACE inhibition or ARB utilization, the additional Aliskiren is always additive, or at time synergistic. Despite full dose of ACEi or ARB usage, patients with hypertension will be able to double their blood pressure lowering by the use of Aliskiren. Furthermore, there is also added benefit on top of ACEi or ARB in reducing left ventricular hypertrophy. Even in heart failure, the addition of renin inhibition on top of existing state of art therapy can further reduce BNP, a useful marker of cardiovascular hemodynamic stress, and an important marker of prognosis.

Aliskiren has also been shown now to significantly reduce proteinuria in patients with diabetes and renal dysfunction. An unexplained phenomenon but reflected in a number of clinical studies, is the fact that combination of ACEi with Aliskiren actually reduces the cough side effects of ACEi. Even harder to understand is the observation that in combination with long acting calcium channel blockers, Aliskiren not only increases the efficacy, offers organ protection, but also reduces significantly the nuisance side effect of peripheral edema.

More Angiotensin-Converting Enzyme – ACE2?
Major questions also remain – how does nature control this important stress activated pro-inflammatory system? In the absence of ACEi or ARBs, how did our ancestors survive angiotensin elevation?

The advances in genome sciences afforded the opportunity to identify additional candidates in the renin-angiotensin system. ACE2 turns out to be similar structurally to ACE1, is located on the X-chromosome, and converts AII to A1-7, which is a vasodilator (5). In addition, ACE2 processes another vasodilator hormone, apelin, which will be covered later. Therefore, it appears that nature has indeed designed a counter regulatory system to angiotensin.

A human equivalent situation of ACE2 removal is in the infectious disease epidemic of SARS. The coronavirus responsible for SARS in fact uses the ACE2 in the lungs as a receptor (6). This leads to tremendous inflammatory response, elevations of angiotensin and other cytokines, and accompanied by pulmonary edema and heart failure. Infusion of recombinant ACE2 is very useful in treating pulmonary edema (7).

More recently, there are also reports that ACE2 is decreased in conditions such as heart failure and atrial fibrillation (8). Therefore, it appears that ACE2-Angiotensin1-7 axis is a potential novel target for regulating the cardiovascular homeostasis. There are already early candidates to stimulate the angiotensin1-7 receptor, or stimulate ACE2 production. The opportunity is now open to explore this system, and other related members for future therapeutic application.

Apelin – a Counter Regulator of Angiotensin?
As mentioned earlier, apelin is a novel endogenous peptide that is converted to active form by ACE2 enzyme into a vasodilator. Apelin is also important in heart development, fluid homeostasis and obesity. Infusion of apelin can reduce blood pressure, induce diuresis, and reduce body fat content. Recently, we have investigated apelin function through a transgenic knockout mice model, and found that absence of apelin raised baseline blood pressure, increased risk of ventricular hypertrophy, and induced much more heart failure (9).

RAS – Stay Tuned
With these above examples, and many other new opportunities involving additional ACE enzymes, and aldosterone modulating pathways, many new diagnostic and therapeutic tools will emerge. These will add further to our understanding of the RAS, and open up new opportunities for its modulation.

References

Dzau VJ. “Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis.” Hypertension 2001;37:1047-52.
Dzau VJ, Antman EM, Black HR, Hayes DL, Manson JE, Plutzky J, Popma JJ, Stevenson W. “The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part I: Pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease).” Circulation 2006;114:2850-70.
Jong P, Demers C, McKelvie R, Liu P. “Angiotensin receptor blockers in heart failure: Meta-Analysis of randomizd controlled trial.” Journal of American College of Cardiology 2002;39:463-470.
Gradman AH, Kad R. “Renin inhibition in hypertension.” J Am Coll Cardiol. 2008;51:519-28.
Crackower M, Oudit GY, Backx P, Penninger J. “Functional analysis of a novel angiotensin converting enzyme - ACE2.” Nature 2002;417:822-8.
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. “Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.” Nature” 2003;426:450-4.
Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM. “Angiotensin-converting enzyme 2 protects from severe acute lung failure.” Nature 2005;436:112-6.
Pan CH, Lin JL, Lai LP, Chen CL, Stephen Huang SK, Lin CS. “Downregulation of angiotensin converting enzyme II is associated with pacing-induced sustained atrial fibrillation.” FEBS Lett. 2007;581:526-34.
Kuba K, Zhang L, Imai Y, Arab S, Chen M, Maekawa Y, Leschnik M, Leibbrandt A, Makovic M, Schwaighofer J, Beetz N, Musialek R, Neely GG, Komnenovic V, Kolm U, Metzler B, Ricci R, Hara H, Meixner A, Nghiem M, Chen X, Dawood F, Wong KM, Sarao R, Cukerman E, Kimura A, Hein L, Thalhammer J, Liu PP, Penninger JM. “Impaired Heart Contractility in Apelin Gene Deficient Mice Associated With Aging and Pressure Overload.” Circ Res. 2007; 101:e32-e42.