Textbook of Interventional Cardiovascular Pharmacology - part 8 doc

who were not candidates for traditional revascularization owing to the diffuse nature of their disease (38,39). The studies failed to account for a strong placebo effect observed in this group and the follow-up studies failed to show efficacy (40). The idea of using ABMSCs as potential sources of angiogenic factors has now been tested in several trials (41–44). Given that patients are not candidates for revascularization injection of the cells has to be accomplished via a transendocardial route with the guidance of electromechanical mapping (EMM) using a NOGA catheter or other intramyocardial injection catheters. The first feasibility study to assess this new methodology enrolled eight patients with angina refractory to medical therapy (42). They were assessed with functional cardiac MRI at three months after the treatment. The EF was 57% at baseline and did not increase significantly. There was an improvement in the wall thickening (11%; P ϭ 0.004) and wall motion (5.5%; P ϭ 0.008) of the target wall, in addition to a decrease in hypoperfused myocardium (3.9%; P ϭ 0.004). The EMM times approached 200 minutes. Fuchs et al. study (2003) (41) was a second feasibility pilot trial of 10 patients with chronic angina secondary to nonintervenable coronary disease but with EF above 30% (mean of 47%). Patients received 12 injections of ABMSCs via a transendocardial approach using EMM into the ischemic territory as determined by single photon emission computer tomography (SPECT). The outcomes assessed were EF change by echocardiography at three months after the procedure, and a change in the size of reversible ischemia on SPECT, in addition to a change in the angina score. The EFs did not change. However, there was a decrease in the semi-quantitative stress scores on SPECT imaging within the injected segments (P Ͻ 0.0001). Angina score also improved in 8/10 patients. Importantly, there were no arrhythmic or procedural complications. The EMM time was 30 minutes. The largest study to date of 21 patients was an open-label study with 14 patients who received treatment and seven who served as controls (44). Unlike in the pilot studies, the patients had to have an EF of less than 40% (both pilot studies enrolled patients with EFs Ͼ 40%). All patients had a demonstrable reversible defect by SPECT imaging. The group therefore represented a high mortality and morbidity patient population. The mean of 25 million cells were injected (split into 15 aliquots) into the area of viability and reversible defect as determined by unipolar voltage with NOGA catheter and by prior SPECT imaging, respectively. Notably control group patients did not undergo a sham procedure. The outcomes assessed were the change in cardiopulmonary exercise tolerance, echocardiographic EF and viability on SPECT at two months after treatment, in addition to angiographic LV function and EMM at four months. Again, the control group did not undergo the EMM assessment at four months. There was a significant decrease in the brain natriuretic peptide (BNP) levels and improvement 444 Clinical trials in cellular therapy Trial N N Cell dose Delivery Time post Outcome MI (days) Strauer 10 Tx ϩ 10 Ctrl 28 million IC 5–9 Decreased infarct size; improved perfusion; improved wall motion TOPCARE-AMI 59 Tx ϩ 11 Ctrl 200 million IC 4 Increased EF, coronary flow, regional wall motion and decreased infarct size Fernander-Aviles 20 Tx ϩ 13 Ctrl 78 million IC 14 Increased EF and wall motion BOOST 30 Tx and 30 Ctrl 2.5 billion of IC 6 Increased EF and regional nucleated bone wall motion; no change marrow cells in infarct size Kuethe 5 Tx 40 million IC 6 No effect REPAIR-AMI 204 236 million IC 4 Increased EF (5%) and less repeat revascularization ASTAMI 100 IC 5–8 No effect Abbreviations : ASTAMI, autologous stem cell transplantation in acute myocardial infarction; BOOST, bone marrow transfer to enhance ST-elevation infarct regeneration; Ctrl, control; EF, ejection fraction; IC, intracoronary; N , number; Tx, treated; REPAIR-AMI, reinfusion of enriched progenitor cells and infarct remodeling in acute myocardial infarction; TOPCARE-AMI, transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction. Table 1 Clinical trials of cellular therapy in acute myocardial infarction 1180 Chap37 3/14/07 11:42 AM Page 444 in creatinine in the treated group at two months (BNP 282 vs. 565; P ϭ 0.06; cr 1.1 vs. 1.62; P ϭ 0.03). Patients in the treatment group had less anginal symptoms and increased exercise capacity [metabolic equivalent units (METs) went up from 5 to 6.7 in the treatment group and did not change in the control group; P ϭ 0.0085]. There was a 6% increase in EF by echocardiography (P ϭ 0.027). There was a reduction in the reversible defect by SPECT from 15% to 4.5% (P ϭ 0.022) without a concomitant change in fixed defect percentage (ruling out the possibility that a decrease in the reversible defect was attributed to scar formation at the site of the injection). There was an increase in the ischemic area in the control group although the difference was not statisti- cally significant. The improvement in the LV function was sustained at four months. The EMM also showed increased contractility in the injected regions (change in linear shortening 5.7 to 10.8; P Ͻ 0.0005). The authors hypothesized that the effect of ABMSCs injections was to the result of angiogenic properties of cells and hence better contractility of the hibernating myocardium. The use of EMM to guide the procedure was particularly useful to determine the viability of the tissue treated. The procedures were not associated with arrhythmia or myocardial injury or high incidence of perfora- tion. The major limitation was the lack of sham procedure control, which raises the issue of placebo effect in interpret- ing the subjective NYHA class and exercise tolerance data. Improvement in SPECT imaging is reassuring, however. More recently, the same authors extended their patient follow up to six and 12 months and attempted to stratify the magnitude of improvement by progenitor cell characteristics, that is, elucidate the potential mechanism of improvement (43). The BNP levels increased in both groups but not as markedly in the treatment group (BNP 507 vs. 740 at 12 months; P ϭ 0.08). There was a persistent favorable difference in the NYHA class (2.7 vs. 1.4; P ϭ 0.01) and exercise tolerance (METs 7.2 vs. 5.1; P ϭ 0.02). There was no longer a difference in the EF between the two groups; however, the size of the reversible defect on repeat SPECT scans at 12 months was markedly smaller in the treated group (11% vs. 34%; P ϭ 0.01). Monocyte and early hematopoietic cell phenotype correlated with better perfusion at six months by SPECT, particularly the monocyte lineage, suggesting their possible role in angiogenic factor secretion. Similar to the experience in the acute MI setting, cellular therapy use in chronic angina patients needs validation in larger randomized trials that would allow for sham procedures to control for the placebo effect. In addition, although transendocardial administration with NOGA catheter appears to be an effective method of administration of cells, both preclinical and clinical studies are needed to establish the best approach that would allow for maximal cell survival and retention. As recently reviewed by Thompson (45), endoventricular catheters can be subject to motion owing to cardiac cycle, interference from the subvalvular apparatus or inadequate tract formation within the myocardium by the needle. One of the possible solutions to some of these limi- tations may be a use of the injections via the coronary sinus and the great cardiac vein using the guidance of intravascular ultrasound (IVUS) and an extendable nitinol needle (46). This approach may also shorten the procedure times (80–90 minutes as reported by Perin for EMM mapping). The results of the trials are summarized in Table 2. Skeletal myoblast intramyocardial injection for ischemic myocardial dysfunction In acute or chronic ischemia patients, angiogenic potential of transplanted cells is of the greatest importance. The patients with chronic nonviable scar and myocardial dysfunction are more likely to benefit from the cells that, either directly or indirectly (via paracrine effect) (47), improve the contractility of the treated myocardium (9). Autologous skeletal myoblasts have been successfully expanded in vitro and implanted in the myocardia of animals. Although they do not contract synchro- nously with the rest of the myocardium and do not integrate into it, they have been shown to improve contractility Clinical trials 445 Trial N Baseline EF Cell dose Delivery Outcome Tse 8 Tx 58% 40 ml TEN-EMM Decreased angina, increased perfusion, and regional wall motion Fuchs 10 Tx 47% 78 million TEN-EMM Decreased angina and increased perfusion Perin 14 Tx ϩ 7 Ctrl 30% 30 million TEN-EMM Decreased angina and heart failure; increased perfusion, EF and regional wall motion Abbreviations : Ctrl, control; N , number; TEN-EMM, transendocardial-electromechanical mapping; Tx, treated. Table 2 Clinical trials in cell therapy for chronic angina without revascularization options 1180 Chap37 3/14/07 11:42 AM Page 445 (48,49). The major drawback has been a need for manipula- tion in culture, need for epicardial implantation during an open surgical procedure, and most importantly, arrhythmogenic potential of these cell islands (50). The first clinical study enrolled 10 patients with LVEF Ͻ35% and nonviable scar owing to past MI on FDG-PET and indication for coronary artery bypass grafting (CABG) (51). Myocytes were cultured from the patient’s autologous vastus lateralis biopsy obtained two to three weeks before CABG. Eight hundred million myoblasts were injected via a 27-gauge needle epicardially during CABG into a scar supplied by a nongraftable diseased vessel. All patients were given prednisone postoperatively. Primary outcomes were patient safety and ability to obtain myocytes after culture. Left ventricular EF at one, three, and six months postprocedure was the secondary outcome. Sixty percent of the expanded cells were myogenic and 90% of them were viable. The patients had no major complications of the surgery but four of them developed inducible VT within 11–22 days and required automatic internal cardioverter-defibrillator (AICD). The LVEF increased from 23% to 32% (P ϭ 0.002); however, this increase may have been to the result of revascularization alone. Both nonrevascularized segments that were transplanted with cells and those that were revascularized, improved their contractility, suggesting that myoblasts indeed improved contractility locally. Another small pilot of 12 patients undergoing CABG with EFs between 25% and 45% and nonviable scar showed no need for AICD implantation and improvement in EF from mean of 35–53% at three months (P ϭ 0.002) (52). It is unclear what contributed to this lower incidence of inducible VT, although the use of autologous patient plasma for muscle culture may have decreased the degree of inflammation around skeletal myoblasts, potentially caused by culture in fetal bovine serum. The suggestion that the risk of VT can be reduced by the use of autologous plasma is also shown in another more recent study by Chachques et al. of 20 patients (53). A smaller number of myoblasts (200 million) were injected than in Menasche study, and appeared equally effective. In contrast to the Menasche study, the scar area was also revascularized making it more difficult to dissect the contribution of revascularization from myoblast transplant effect. The myoblast-treated areas had larger semi-quantitative improvement in wall motion than revascularized areas (wall motion score index 2.6 down to 1.6; P ϭ 0.0001). The FDG-PET showed increase in the uptake in transplanted scar areas (from 0.126 to 0.231; P ϭ 0.01). Similar change was observed in the revascularized areas (0.170–0.284; P ϭ 0.014). Again, although this may imply the presence of viable myoblasts in the scar area, a definitive proof is lacking. It is possible that this improvement simply represents the effect of revascularization on hibernating myocardium that was previously undetected by FDG-PET and thought to be nonviable. A small five-patient study (54) used a catheter-based transendocardial injection of skeletal myoblasts with EMM guidance and no concomitant revascularization. One of the patients developed long nonsustained ventricular tachycardia (NSVT), and an AICD was placed. There was a trend toward improvement in EF by echocardiography and LV angiography but not by MRI. Wall thickening in the injected areas showed significant improvement over untreated segments 0.9–1.8 mm; P ϭ 0.008). The longest follow up to date of patients status postskele- tal myoblast implantation was 12 months (55). Ten patients undergoing CABG with low EFs were treated. Two patients developed NSVT in the postoperative period, necessitating amiodarone infusion, and all subsequent patients were placed on prophylactic amiodarone. Improvement in EF was similar to other studies and was sustained at 12 months. In conclusion, skeletal myoblast implantations require better investigation into the efficacy of implantation and the viability of injected myocytes by possibly obtaining the biopsy data from 446 Clinical trials in cellular therapy Trial N (Tx) EF ( %) Dose Delivery Outcomes Menasche 10 25 870 million TEP-CABG Increased EF and wall motion; Complications of VT (arrhythmia) Herreros 11 36 190 million TEP-CABG Increased EF and wall (in human serum) motion and increased viability; no arrhythmias observed Siminiak 10 25–40 50 million TEP-CABG Increased EF and wall motion Chachques 20 28 300 million TEP-CABG Increased EF and wall motion and (in human serum) viability; no arrhythmias Smits 5 36 200 million TEN-EMM Increased EF and wall motion Abbreviations : Ctrl, control; EF, ejection fraction; N , number; TEP-CABG, transepicardial coronary artery bypass grafting; VT, ventricular tachycardia; TEN-EMM, transendocardial-electromechanical mapping; Tx, treated. Table 3 Clinical trials of cell therapy in ischemic cardiomyopathy 1180 Chap37 3/14/07 11:42 AM Page 446 patients. It appears that the risk of arrhythmia is substantial and its etiology is still unclear. It may be prudent that the patients enrolled in further studies receive prophylactic AICDs which would offer not only treatment, but also potentially better recording and monitoring capabilities for different arrhythmias. The new EMM-guided catheters for epicardial implantation may offer less-invasive option for implantation than open-heart surgery. One such CellFix catheter allows for possible repeat administration of cells (56) and coadministration with angiogenic factors to improve survival. Larger safety and efficacy randomized trials are also needed to separate the effect of myoblast transplant from that of revascularization. Another option not yet investigated in human trials would be the use of adult cardiac myocytes for transplantation (57) or fetal cardiomyocytes, the supply of which is rather scarce (58). These cells may have a better chance of integrating with the rest of the myocardium and being less arrhythmogenic, potentially provide enhanced contractility. The results of cell therapy trials in ischemic myocardial dysfunction are summarized in Table 3. Angiogenesis and cytokine clinical trials The results of preclinical and clinical trials of angiogenic factor protein and gene therapy were recently reviewed by Losordo et al. (59,60), and are reviewed in detail elsewhere in this textbook. Here we will discuss the issues of synergistic coadministration of angiogenic factors and cytokine with cellular therapy. Fibroblast growth factor (FGF) Initiating RevaScularization Trial (FIRST) of intracoronary FGF-2 protein administration in 300 patients with coronary artery disease (CAD) did not show any advantage over placebo and demonstrated a substantial placebo effect (61). Similarly, a phase I trial of VEGF-2 gene therapy by direct myocardial injection showed no evidence of angiogenic effect by angiography (62). It is possible that the extracellular matrix or cellular vehicle is needed for sustained and effective administration of angiogenic factors. It is also possible that the angiogenic network elaborated after an MI is so elaborate that the administration of a single cytokine cannot replicate it. In addition, the endogenous endothelium may be too diseased to respond to angiogenic proteins, and new endothelial progenitor mobilization is needed for the process of angiogenesis and vasculogenesis to take place. Conversely, transplanted cells may also demonstrate better survival and retention when administered in their natural humoral and struc- tural milieu rather than a suspension of cultured cells. Skeletal myoblast survival was demonstrated to be improved when fibrin biodegradable scaffold was used (63). Other tissue-engineering approaches to myocardial regeneration were recently reviewed by Nugent and Edelman (64). Our own laboratory is conducting preclinical trials of cardiomyoplasty for acute and chronic MI with myotissue transplantation. This technology would provide the ultimate preservation of structure and angiogenic milieu of the transplanted cardiomyocytes (Fig. 3). Another possibility for combining cytokine treatment and cell therapy was recently tested in the Myoblast Autologous Graft in Ischemic Cardiomyopathy (MAGIC) trial (65). In this prospective randomized trial of 27 patients undergoing stenting for acute MI effects of combining intracoronary infusion of unselected peripheral blood stem cells with the administration of intravenous granulocyte-colony stimulating factor (G-CSF). The hypothesis was that G-CSF would increase endothelial progenitor/stem cell mobilization from the bone marrow that usually occurs in the acute setting of MI (66), and that peripheral blood could be used instead of bone marrow for infusion. The trial was stopped prematurely, however, owing to increased incidence of in-stent restenosis in the patients treated with G-CSF. This safety concern outweighed the benefits on LVEF and exercise tolerance, in addition to recent evidence that G-CSF is capable of preventing the unfa- vorable ventricular remodeling (67). Conclusions and future directions Cellular therapy holds great promise, especially for patients with limited options, such as those with end-stage ischemic cardiomyopathy or refractory angina. It has the potential to reduce the incidence of LV dysfunction and heart failure. The results of small phase I trials conducted to date and summarized here are somewhat encouraging, but they clearly show the need for perfecting this technology before it can be widely applied. Similar to the early angiogenesis trials where small phase I studies showed some promise, but larger randomized phase II and III trials proved disappointing, we run a danger of disappointment with cellular therapy unless the mechanistic foundation is elucidated first, and the technology perfected based on this work (68). We need more research into the mechanisms of cellular therapy effects on ventricular performance, before embarking on larger randomized and appropriately controlled clinical trials. One of the fundamental issues that remains unresolved is the viability and survival of the injected cells that remain rather poor calling into question their direct contribution to the improvement in contractility, and suggesting that possibly the paracrine effect of apoptosis of these cells leads to the improvement in function. Many preclinical studies to date, including our own work, have shown this poor viability (Fig. 2). Cell delivery catheter technologies need to be developed further. Tissue-engineering technologies to construct matrix scaffolds, which would allow for better cell survival, need to be developed. The imaging techniques to allow for cell tracking and monitoring of their viability need to be developed further. Magnetic resonance imaging technology, allowing for gene and protein expression Conclusions and future directions 447 1180 Chap37 3/14/07 11:42 AM Page 447 imaging (69,70), would seem ideal for this purpose, in addition to being the most sensitive and specific technique of assessing the LV performance (wall motion, wall thickening, EF) and perfusion in addition to viability (late enhancement). References 1 American Heart Association. Heart Disease and Stroke Statistics—Update 2004. 2004. 2 Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114(6):763–776. 3 Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regen- erate infarcted myocardium. Nature 2001; 410(6829):701–705. 4 Nadal-Ginard B, Kajstura J, Anversa P, Leri A. A matter of life and death: cardiac myocyte apoptosis and regeneration. J Clin Invest 2003; 111(10):1457–1459. 5 Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004; 364(9429):141–148. 6 Niam S, Cheung W, Sullivan PE, Kent S, Gu X. Balance and physical impairments after stroke. Arch Phys Med Rehabil 1999; 80(10):1227–1233. 7 Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003; 108(4):457–463. 8 Zhang H, Fazel S, Tian H, et al. Increasing donor age adversely impacts beneficial effects of bone marrow but not smooth muscle myocardial cell therapy. Am J Physiol Heart Circ Physiol 2005; 289(5):H2089–2096. 448 Clinical trials in cellular therapy 0 02 04 06 08 1 12 14 0 1 2 3 4 5 6 7 8 Control Control Treatment Treatment Control Treatment Ant/septal perfusion ratio Infarct Volume (% of LV) P < 0.01 P = 0.04 MRI outcomes measures: perfusion and infarct volume Autologous myotissue viability at 4 weeks post implantation (A) (B) Figure 3 ( See color plate .) ( AA ) Viability of myotissue (autologous myocardial septal biopsy tissue) implanted into anterior wall scar at four weeks postimplantation in a porcine model of myocardial infarction (MI). Twelve Yorkshire pigs underwent an anterior MI by balloon occlusion of the lactate dehydrogenase (LAD) and were randomized to the implantation of six to nine septal intact myocardial biopsy tissues into the anterior infarct area versus sham operation. Animals underwent cardiac magnetic resonance imaging (MRI) for anterior-wall perfusion and delayed enhancement imaging for infarct volume at four weeks postimplant and were subsequently sacrificed. Tissues were harvested for histology. ( BB ) Bar graph showing the results of cardiac MRI showing increased perfusion in the anterior wall of treated animals as compared with the septal (nonimplanted) wall perfusion, and decreased infarction volume after myotissue implantation, as measured by delayed enhancement cardiac MRI in the same porcine model of MI. 1180 Chap37 3/14/07 11:42 AM Page 448 9 Taylor DA. Cell-based myocardial repair: how should we proceed? Int J Cardiol 2004; 95(suppl 1):S8–12. 10 Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275(5302):964–967. 11 Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411):143–147. 12 Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 1999; 103(5):697–705. 13 Shintani S, Murohara T, Ikeda H, et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 2001; 103(23):2776–2779. 14 Jackson KA, Majka SM, Wang H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 2001; 107(11):1395–1402. 15 Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 2002; 105(1):93–98. 16 Mauro A. Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol 1961; 9:493–495. 17 Eckert P, Schnackerz K. Ischemic tolerance of human skeletal muscle. Ann Plast Surg 1991; 26(1):77–84. 18 Reinecke H, MacDonald GH, Hauschka SD, Murry CE. Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair. J Cell Biol 2000; 149(3):731–740. 19 Ghostine S, Carrion C, Souza LC, et al. Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation 2002; 106(12 suppl 1): I131–136. 20 Fan Y, Maley M, Beilharz M, Grounds M. Rapid death of injected myoblasts in myoblast transfer therapy. Muscle Nerve 1996; 19(7):853–860. 21 Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest 2005; 115(3):572–583. 22 Murry CE, Soonpaa MH, Reinecke H, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004; 428(6983):664–668. 23 Fuchs S, Baffour R, Zhou YF, et al. Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol 2001; 37(6):1726–1732. 24 Kamihata H, Matsubara H, Nishiue T, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 2001; 104(9):1046–1052. 25 Kobayashi T, Hamano K, Li TS, et al. Enhancement of angiogenesis by the implantation of self bone marrow cells in a rat ischemic heart model. J Surg Res 2000; 89(2):189–195. 26 Ikenaga S, Hamano K, Nishida M, et al. Autologous bone marrow implantation induced angiogenesis and improved deteriorated exercise capacity in a rat ischemic hindlimb model. J Surg Res 2001; 96(2):277–283. 27 Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106(15):1913–1918. 28 Lee SH, Wolf PL, Escudero R, Deutsch R, Jamieson SW, Thistlethwaite PA. Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med 2000; 342(9):626–633. 29 Assmus B, Schachinger V, Teupe C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002; 106(24):3009–3017. 30 Schachinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE- AMI Trial. J Am Coll Cardiol 2004; 44(8):1690–1699. 31 Stone GW, Grines CL, Cox DA, et al. Comparison of angio- plasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002; 346(13):957–966. 32 Britten MB, Abolmaali ND, Assmus B, et al. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003; 108(18):2212–2218. 33 Kim RJ, Manning WJ. Viability assessment by delayed enhancement cardiovascular magnetic resonance: will low-dose dobutamine dull the shine? Circulation 2004; 109(21):2476–2479. 34 Fernandez-Aviles F, San Roman JA, Garcia-Frade J, et al. Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction. Circ Res 2004; 95(7):742–748. 35 Nian M, Lee P, Khaper N, Liu P. Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 2004; 94(12):1543–1553. 36 Kuethe F, Richartz BM, Sayer HG, et al. Lack of regeneration of myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans with large anterior myocardial infarctions. Int J Cardiol 2004; 97(1):123–127. 37 Cleland JG, Freemantle N, Coletta AP, Clark AL. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROAC- TIVE. Eur J Heart Fail 2006; 8(1):105–110. 38 Frazier OH, March RJ, Horvath KA. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med 1999; 341(14):1021–1028. 39 Allen KB, Dowling RD, Fudge TL, et al. Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina. N Engl J Med 1999; 341(14):1029–1036. 40 Saririan M, Eisenberg MJ. Myocardial laser revascularization for the treatment of end-stage coronary artery disease. J Am Coll Cardiol 2003; 41(2):173–183. 41 Fuchs S, Satler LF, Kornowski R, et al. Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study. J Am Coll Cardiol 2003; 41(10):1721–1724. 42 Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003; 361(9351):47–49. 43 Perin EC, Dohmann HF, Borojevic R, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial References 449 1180 Chap37 3/14/07 11:42 AM Page 449 injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation 2004; 110(11 suppl 1): II213–218. 44 Perin EC, Dohmann HF, Borojevic R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003; 107(18):2294–2302. 45 Thompson CA. Transvascular cellular cardiomyoplasty. Int J Cardiol 2004; 95(suppl 1):S47–49. 46 Thompson CA, Nasseri BA, Makower J, et al. Percutaneous transvenous cellular cardiomyoplasty. A novel nonsurgical approach for myocardial cell transplantation. J Am Coll Cardiol 2003; 41(11):1964–1971. 47 Leobon B, Garcin I, Menasche P, Vilquin JT, Audinat E, Charpak S. Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host. Proc Natl Acad Sci USA 2003; 100(13):7808–7811. 48 Taylor DA, Atkins BZ, Hungspreugs P, et al. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 1998; 4(8):929–933. 49 Jain M, DerSimonian H, Brenner DA, et al. Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction. Circulation 2001; 103(14):1920–1927. 50 Makkar RR, Lill M, Chen PS. Stem cell therapy for myocardial repair: is it arrhythmogenic? J Am Coll Cardiol 2003; 42(12):2070–2072. 51 Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003; 41(7):1078–1083. 52 Herreros J, Prosper F, Perez A, et al. Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Eur Heart J 2003; 24(22):2012–2020. 53 Chachques JC, Herreros J, Trainini J, et al. Autologous human serum for cell culture avoids the implantation of cardioverter- defibrillators in cellular cardiomyoplasty. Int J Cardiol 2004; 95(suppl 1):S29–33. 54 Smits PC, van Geuns RJ, Poldermans D, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol 2003; 42(12):2063–2069. 55 Siminiak T, Kalawski R, Fiszer D, et al. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J 2004; 148(3):531–537. 56 Chachques JC, Acar C, Herreros J, et al. Cellular cardiomyoplasty: clinical application. Ann Thorac Surg 2004; 77(3):1121–1130. 57 Koh GY, Soonpaa MH, Klug MG, Field LJ. Long-term survival of AT-1 cardiomyocyte grafts in syngeneic myocardium. Am J Physiol 1993; 264(5 Pt 2):H1727–733. 58 Soonpaa MH, Koh GY, Klug MG, Field LJ. Formation of nascent intercalated disks between grafted fetal cardiomyocytes and host myocardium. Science 1994; 264(5155):98–101. 59 Losordo DW, Dimmeler S. Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based thera- pies. Circulation 2004; 109(22):2692–2697. 60 Losordo DW, Dimmeler S. Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part I: angiogenic cytokines. Circulation 2004; 109(21):2487–2491. 61 Simons M, Annex BH, Laham RJ, et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 2002; 105(7):788–793. 62 Fortuin FD, Vale P, Losordo DW, et al. One-year follow-up of direct myocardial gene transfer of vascular endothelial growth factor-2 using naked plasmid deoxyribonucleic acid by way of thoracotomy in no-option patients. Am J Cardiol 2003; 92(4):436–439. 63 Christman KL, Vardanian AJ, Fang Q, Sievers RE, Fok HH, Lee RJ. Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. J Am Coll Cardiol 2004; 44(3): 654–660. 64 Nugent HM, Edelman ER. Tissue engineering therapy for cardiovascular disease. Circ Res 2003; 92(10):1068–1078. 65 Kang HJ, Kim HS, Zhang SY, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 2004; 363(9411):751–756. 66 Wojakowski W, Tendera M, Michalowska A, et al. Mobilization of CD34/CXCR4 ϩ , CD34/CD117 ϩ , c-met ϩ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation 2004; 110(20):3213–3220. 67 Harada M, Qin Y, Takano H, et al. G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 2005; 11(3):305–311. 68 Lee SU, Wykrzykowska JJ, Laham RJ. Angiogenesis: bench to bedside, have we learned anything? Toxicol Pathol 2006; 34(1):3–10. 69 Pearlman JD, Laham RJ, Post M, Leiner T, Simons M. Medical imaging techniques in the evaluation of strategies for therapeutic angiogenesis. Curr Pharm Des 2002; 8(16):1467–1496. 70 Jaffer FA, Weissleder R. Seeing within: molecular imaging of the cardiovascular system. Circ Res 2004; 94(4):433–445. 450 Clinical trials in cellular therapy 1180 Chap37 3/14/07 11:42 AM Page 450 Introduction Management of the heart failure (HF) patient presents a number of challenges to the interventional cardiologist. These include the pharmacologic management of heart failure and special considerations regarding the practical aspects of intervention, including the risk of intervention and the need for the preparation before intervention (HF management, hemodynamic support, renal function). Clinical decision-making regarding further treatment options may be different in the patient with HF. Pharmacotherapy in the heart failure patient Heart failure is a progressive syndrome, and optimal pharmacologic management is based on a detailed diagnosis, determination of the etiology, characterization of the clinical syndrome (systolic vs. diastolic) and careful monitoring of the response to pharmacologic therapy. There is a need to modify treatment in accordance with the patient’s response to therapy. Patients with left ventricular systolic dysfunction Angiotensin-converting enzyme inhibitors Pathophysiology Drugs acting on the renin–angiotensin– aldosterone system (RAAS) are the cornerstone of treatment in the management of the HF patient with systolic dysfunction. Angiotensin-converting enzyme (ACE) inhibitors interfere with the formation of angiotensin II, both at systemic and tissue level. In chronic HF, activation of the renin–angiotensin system has negative effects on the myocardium and on cardiovascular hemodynamics so that the preload and afterload are increased, and sodium and water are retained (1). The increased production of angiotensin II leads to ventricular hypertrophy, increased myocardial fibrosis, and apoptosis (2). Angiotensin-converting enzyme inhibitors stop the deleterious effects of angiotensin II, and lead to an improvement in the hemodynamic profile and a decrease in cardiac remodeling. They also increase the plasma concentrations of inflammatory cytokines (e.g., bradykinin), nitric oxide, and vasodilating prostaglandins (3). Hemodynamic effects During treatment with ACE inhibitors, systemic vascular resistance is decreased along with the pulmonary capillary wedge pressure and right atrial pressure (4). End-diastolic and end-systolic dimensions are reduced. Long-term ACE inhibition decreases echocardiographic left ventricle (LV) dimensions and increases the shortening fraction (5). Clinical effects Angiotensin-converting enzyme inhibitors improve symptoms, New York Heart Association (NYHA) functional class, and exercise capacity in patients with HF. The Captopril Multicenter Research Group (6) showed that captopril treatment improved the NYHA class in 61% of patients compared with only 24% of patients taking placebo over a 12-week period. Treadmill exercise time improved throughout the 12 weeks of the study in 24% of captopril-treated patients, but in none of the placebo-treated patients. Therapy with ACE inhibitors is associated with a dramatic increase in survival in patients with NYHA class II–IV and in all 38 The heart failure patient Basil S. Lewis and Mihai Gheorghiade 1180 Chap38 3/14/07 11:43 AM Page 451 patients with LV systolic dysfunction after an acute myocardial infarction, even those without the signs or symptoms of HF (Table 1) (7–9). After myocardial infarction, ACE inhibition attenuates ventricular dilation, reduces the incidence and hospitalization for HF, prevents recurrent ischemic events, and increase survival. The decreased recurrence of acute coronary events or stroke (10) with ACE-inhibitor therapy means that these drugs are an essential part of the therapeutic armamentarium in patients undergoing intervention in the circumstances of an acute coronary syndrome, and hence, perhaps in more than half the patients treated in a modern interventional center. Practical use of ACE inhibitors Based on the data from published trials, the 2005 American College of Cardiology/ American Heart Association (ACC/AHA) guidelines (11) recommend ACE inhibitors as first-line therapy for symptomatic HF with reduced systolic function and for asymptomatic LV dysfunction. In stage C HF, they should be used in conjunction with a diuretic to maintain the sodium balance and prevent the development of fluid overload. The ACC/AHA recommendations specify that ACE inhibitors should be initiated at very low dose and gradually uptitrated. Patients with HF should not generally be maintained on very low doses of an ACE inhibitor unless these are the only doses 452 The heart failure patient Study Selection criteria Patients, n Drug, dosage Results Chronic heart failure CONSENSUS (7) NYHA IV cardiomegaly 253 Enalapril , 20-mg 40% Reduction of overall twice/day, mortality; significant vs. placebo improvement of NYHA class SOLVD treatment (8) NYHA I-IV LVEF Ͻ 35% 2569 Enalapril , 10-mg 16% Reduction of overall twice/day, mortality; fewer vs. placebo rehospitalizations for worsening HF SOLVD prevention (9) Asymptomatic LV 4228 Enalapril , 10 -mg No differences on dysfunction LVEF Ͻ 35% twice/day, mortality; significant vs. placebo reduction of worsening HF and hospitalizations Postmyocardial infarction SAVE (86) Acute MI within 3–16 days 2231 Captopril , 50-mg/ 19% Reduction of overall LVEF Ͻ 40% no overt HF three times a day, mortality; significant vs. placebo reduction of death, hospitalization, and recurrent myocardial infarction AIRE (87) Acute MI within 3–10 days 2006 Ramipril , 5-mg 27% Reduction of overall Clinical evidence of HF twice a day mortality; significant vs. placebo reduction of severe heart failure, myocardial infarction, and stroke TRACE (88) Acute MI within 3–7 days 2606 Trandolapril , 4-mg 22% Reduction of overall LVEF Ͻ 35% once per day, mortality; lower risk of vs. placebo cardiovascular death, severe HF, and sudden death SMILE (89) Acute MI within 24 hrs 1556 Zofenopril 26% Reduction of overall vs. placebo mortality Abbreviations : AIRE, acute Infarction ramipril efficacy; CONSENSUS, cooperative north scandinavian enalapril survival study; HF, heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SAVE, survival and ventricular enlargement; SMILE, survival of myocardial infarction long-term evaluation; SOLVD, studies of left ventricular dysfunction; TRACE, trandolapril cardiac evaluation study group. Table 1 Angiotensin-converting enzyme inhibitor trials 1180 Chap38 3/14/07 11:43 AM Page 452 that can be tolerated. Once the appropriate dose has been achieved, patients can be maintained on long-term therapy with an ACE inhibitor with little difficulty. Renal function and serum potassium should be assessed within one to two weeks of initiating therapy and every two to three months thereafter. Adverse effects The adverse effects of ACE-inhibitor use are related to angiotensin suppression (hypotension, increase in serum creatinine and potassium) and bradykinin potentiation (cough and angioedema). Initial hypotension would usually respond to a decrease in the dose of diuretic agent or the lowering of the ACE-inhibitor dose. If hypotension persists, the assessment of orthostatic changes in order to properly administer ACE inhibitors may be useful. Treatment should be reassessed if the levels of creatinine are Ͼ3.0 mg/dL or if serum potassium is Ͼ5.5 mEq/L. The development of a cough is a major reason for the discontinuation of the therapy, but ACE inhibitors should be stopped only if cough is persistent, and should be replaced with an angiotensin II receptor blocker. Pregnant patients should not be administered ACE inhibitors because of the danger of teratogenic effects. A history of angioedema or renal failure during previous exposure to this class of drugs, or severe hypotension with an immediate risk of cardiogenic shock, are contraindications to the prescription of this class of drug. Beta blockers Pathophysiology Long-term and sustained activation of the sympathetic nervous system in the HF patient has detrimental effects on the cardiac function, and on the peripheral circulation, causing vasoconstriction (12) and possibly impairing sodium excretion by the kidney (13). Increased levels of plasma catecholamines cause myocyte hypertrophy and apoptosis (14–16). In the failing heart, there is a ␤-receptor downsensitizing and uncoupling with the intracellular signaling. Sympathetic activation has shown to be related to arrhythmogenesis and sudden death (17). ␤ blockers act by inhibiting the adverse effects of sympathetic nervous system activation in patients with HF. Hemodynamic effects Shortly after the administration of this class of drugs, ␤-adrenergic blockade can decrease the ventricular contractility and impair sodium excretion, particularly in patients whose cardiac function is already compromised. These early adverse effects may be minimized by the use of ␤ blockers with ␣ -blocking properties; inversely, during long-term treatment, ␤ blockers can improve cardiac performance (17,18). The administration of a ␤ blocker for a longer period of time (three to six months) is associated with an increase in the stroke volume and cardiac output and decreased pulmonary wedge pressure, right atrial pressure, heart rate, and systemic vascular resistance (19). Cardiac output, initially reduced by short-term treatment, was restored or increased during long-term treatment (20,21). Left ventricular ejection fraction (LVEF) increases during long-term ␤-adrenergic blockade, and the magnitude of increase is larger than that with other treatments for HF. This improvement is particularly evident in HF patients who have viable but noncontractile myocardium and has generally been associated with a reduction in LV systolic and diastolic dimensions, suggesting a favorable effect on the process of ventricular remodeling. Clinical effects A large number of randomized, double- blind, placebo-controlled trials have shown that the long- term use of ␤ blockers improves the clinical status in patients with HF (22–32) (Table 2) and the ACC/AHA guidelines (11) recommend that ␤ blockers should be routinely prescribed to all patients with asymptomatic LV dysfunction or stable HF caused by LV systolic dysfunction (unless they have a contraindication or have been shown to be intolerant to treatment with these drugs). ␤ blockers should also be used in patients with HF and preserved LV systolic function, particularly when those patients have hypertension, coronary artery disease (CAD) and/or atrial fibrillation. ␤ Blockers should be initiated at very low doses and increased at two-week intervals to achieve the target doses. Once the target dose is achieved, patients can generally be maintained on long-term treatment with little difficulty. Abrupt withdrawal of ␤ blockers can lead to clinical deterioration and should be avoided, even in hospitalized patients who do not require inotropic support (11). Safe and feasible administration ␤ blockers can be initiated in all classes of HF patients before hospital discharge, as proved in the Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial (33). Adverse effects The adverse events associated with ␤ blockers may be avoided by starting treatment at very low doses. However, treatment can be associated with complaints of fatigue and weakness, which usually resolve in a few weeks. Sometimes it is necessary to decrease the dose of the ␤ blocker or diuretic. Symptomatic bradycardia is another serious adverse effect of ␤ blockers, and requires a decrease in the dose or sometimes cardiac pacing to allow the use of this vital medication. Hypotension is another potential side effect; however, it is rarely seen as the therapy is started with a very low dose (3.25 mg twice a day for carvedilol, 1 mg for bisoprolol and 12.5 mg for extended release metoprolol). The administration of ACE inhibitor and diuretic at a different time of day than the ␤ blocker can Pharmacotherapy in the heart failure patient 453 1180 Chap38 3/14/07 11:43 AM Page 453 [...]... effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators N Engl J Med 1995; 332 :80 85 CIBIS-II-Investigators-and-Committees The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial Lancet 1999; 353:9–13 Beta-Blocker-Evaluation -of- Survival-Trial-Investigators... analysis of the experience in the MERIT-HF study J Am Coll Cardiol 2001; 38: 932–9 38 The-Beta-Blocker-Evaluation -of- Survival-Trial-Investigators A Trial of the beta-blocker bucindolol in patients with advanced chronic heart failure N Engl J Med 2001; 344:1659–1667 Packer M, Coats AJ, Fowler MB, et al Effect of carvedilol on survival in severe chronic heart failure N Engl J Med 2001; 344:1651–16 58 Dargie... Kronenberg MW, Rousseau MF, et al Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction SOLVD (Studies of Left Ventricular Dysfunction) Investigators Circulation 1993; 88 :2277–2 283 The-Captopril-Multicenter-Research-Group A placebocontrolled trial of captopril in refractory chronic congestive... The Cardiac Arrhythmia Suppression Trial N Engl J Med 1991; 324: 781 – 788 The-Cardiac-Arrhythmia-Suppression-Trial-II-Investigators Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction N Engl J Med 1992; 327:227–233 Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R Randomised trial of low-dose amiodarone in severe congestive heart failure Grupo de Estudio... radiographic-contrast-agent-induced reductions in renal function by acetylcysteine N Engl J Med 2000; 343: 180 – 184 1 180 Chap 38 3/14/07 464 84 85 86 87 88 11:43 AM Page 464 The heart failure patient Nallamothu BK, Shojania KG, Saint S, et al Is acetylcysteine effective in preventing contrast-related nephropathy? A metaanalysis Am J Med 2004; 117:9 38 947 Nawaz S, Cleveland T, Gaines PA, Chan P Clinical risk associ ated with contrast... effects of beta-blockers in patients with heart failure: a prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol Circulation 2000; 102:546–551 Waagstein F, Caidahl K, Wallentin I, Bergh CH, Hjalmarson A Long-term beta-blockade in dilated cardiomyopathy Effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol... stress (13) In this study, N-terminal pro-BNP (NT-pro-BNP), circulating BNP and N-terminal pro- atrial natriuretic peptide , (NT-pro-ANP) were measured before and after exercise The BNP levels are as given earlier The BNP levels differed across the ischemic categories at all three time points They 467 shared an approximate 25% change from the baseline Both NT-pro-BNP and NT-pro-ANP rose with ischemia but... group of prospective, randomized, double-blind trials, provided a large body of 1 180 Chap40 3/14/07 11:44 AM Page 475 Pharmacology evidence supporting the use of platelet IIb/IIIa inhibitors during PCI in NSTE-ACS (non-ST-elevation acute coronary syndrome) (33–37) EPILOG (Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade), EPIC (The Evaluation of c7E3 for Prevention of. .. taking statins to either fenofibrate or placebo Fenofibrates are currently an area of interest and will eventually need evaluation in the diabetic PCI setting Contrast-induced nephropathy Contrast-induced nephropathy (CIN), defined as a serum creatinine increase of Ͼ25% relative to baseline, is associated 1 180 Chap40 3/14/07 4 78 11:44 AM Page 4 78 Cardiovascular interventional pharmacology in the diabetic... double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure Circulation 1990; 82 :1954–1961 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 463 Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S Diltiazem increases late-onset congestive heart failure in postinfarction patients . failure: analysis of the experience in the MERIT-HF study. J Am Coll Cardiol 2001; 38: 932–9 38. 29 The-Beta-Blocker-Evaluation -of- Survival-Trial-Investigators. A Trial of the beta-blocker bucindolol. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324: 781 – 788 . 71 The-Cardiac-Arrhythmia-Suppression-Trial-II-Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial. Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 2000; 283 :1295–302. 25 CIBIS-Investigators-and-Committees. A randomized trial of beta-blockade in heart failure.

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