JUNE 2011

ADVANCES IN HEART & HEART SURGERY

CONTENTSTranscatheter Aortic Valve ImplantationRaj Makkar, MDHasan Jilaihawi, MDGregory P. Fontana, MD

CMV Infection in Heart TransplantationLawrence S.C. Czer, MD

Rupture-Prone Coronary Artery Plaque and CCTAVictor Y. Cheng, MD

Cedars-Sinai Heart InstituteEduardo Marbán, MD, PhDDirector(310) 423-7557Eduardo.Marban@csmc.edu

Transcatheter Aortic Valve Implantation Raj Makkar, MD; Hasan Jilaihawi, MD; Gregory P. Fontana, MD

A 97-year-old man was referred for assessment to our transcather aortic valve implantation (TAVI) team. He had suffered multiple hospitalizations for heart failure with a signifi cantly elevated BNP at 1830 pg/mL. At the time of assessment, he had grade IV New York Heart Association (NYHA) symptoms. Until recently, he had been working actively, but this had subsequently been severely limited by his progressive symptoms. He had a history of bladder cancer and hypothyroidism. He had paroxysmal atrial fi brillation and a low ejection fraction of 23 percent. There was severe aortic stenosis with aortic valve area 0.58 cm2 and a peak gradient of 68 mmHg, mean gradient of 40 mmHg. His logistic EuroSCORE was 37 with an STS score of 11.5. He was declined for conventional surgery on the basis of age, risk scores and low ejection fraction.

The patient’s symptoms had little improvement after implantation of a biventricular pacemaker defi brillator. The aortic annulus measured 22 mm and iliofemoral vasculature measured 8–9 mm at minimal dimension. He was anatomically and clinically suitable for the Edwards SAPIEN™ trans-catheter aortic valve implantation (TAVI) device. Following randomization to TAVI as part of cohort B of the PARTNER trial, this was implanted by trans-femoral route in the cardiac cath lab (Fig. 1). His hemodynamics immediately improved, a result we consistently observe after TAVI (Fig. 2). The proce-dure was uncomplicated and he had a short three-day post-procedural stay. At two weeks’ follow-up, he had a mean gradient of 11 mmHg and an early

improvement in ejection fraction to 35 percent. He reported a rapid return to activity with only minor limitation. He continues to be well and enjoys an excellent quality of life more than six months post-procedure.

TAVI offers new hope to patients who cannot be treated by conventional surgery. Recent data from the fi rst randomized controlled trial to assess this technology, the PARTNER trial, has shown both a survival and a quality of life benefi t in such patients when compared to conservative management.1 Cedars-Sinai Heart Institute continues to treat patients by this procedure as part of a post-study continued access registry.

The fi rst-in-man TAVI procedure was performed by a former Cedars-Sinai fellow, Alain Cribier, MD, in Rouen, France, in 2002.2 It was a much more com-plex procedure than it is today, performed by trans-venous route and employing a transseptal puncture to deliver the catheter-mounted valve across the mitral valve to the aortic position.

Subsequent iterations to the technology and reduction in device size have facilitated a trans-femoral retrograde approach, performed without the need for cardiopulmonary assistance.3 Patients with peripheral vascular disease may be treated by a similarly off-pump antegrade transapical route, or, in selected cases, by alternative innovative ap-proaches such as transaxillary or direct thoracic aortic access.4

Figure 1: Deployed TAVI device.

Continued on page 4 (see “TAVI”)

Figure 2: Transcatheter hemodynamics pre- and post-TAVI.

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2 JUNE 2011 • CEDARS-SINAI ADVANCES IN HEART AND HEART SURGERY

Cytomegalovirus (CMV) infection is the major cause of infectious morbidity and mortal-ity after solid organ transplantation. CMV transmission can occur with transplantation of a seropositive donor organ or can result from blood product transfusion during trans-plantation. CMV disease can also result from reactivation of a dormant virus in a previously infected recipient. The use of antilymphocyte preparations for induction immunosuppres-sion after transplantation may increase the risk of CMV infection. CMV infection in heart transplant recipients is associated with an increased incidence of allograft rejection, graft atherosclerosis (allograft vasculopathy) and death.1 CMV infection can also lead to host immunosuppression and predispose the pa-tient to opportunistic infections such as fungal and parasitic infections. In one study, CMV disease was associated with signifi cantly de-creased survival, with a fi ve-year survival of 68 percent in the non-CMV group compared to 32 percent in the CMV group. The predomi-nant causes of death in the CMV group were infection and graft atherosclerosis.2

Stratifi cation and diagnosisRisk stratifi cation for CMV infection is based on the CMV serology of the donor and re-cipient. The CMV seronegative recipients of a seropositive donor are at greatest risk for developing CMV disease. Patients who are CMV-seropositive prior to transplantation, regardless of donor serology, are also at in-creased risk of virus reactivation with immu-nosuppression. However, secondary infection due to reactivation of latent virus usually runs a milder course than primary CMV infection.3

With immunosuppression, CMV infection usu-ally manifests during the fi rst few months after transplantation. CMV infection can result in various clinical syndromes, including gastro-enteritis, gastrointestinal ulcers, pneumonia, fever with leukopenia and hepatitis. The clini-cal diagnosis of CMV disease is diffi cult. CMV viremia may occur in asymptomatic patients. CMV surveillance can be carried out through detection of CMV in blood or in tissues, in-cluding bronchoalveolar lavage specimens. In one study of 501 heart transplant patients, 88 patients had CMV antigenemia, but only 30 patients had clinical manifestations of CMV in-fection.4 High antigenemia, defi ned as greater than 100 CMV positive cells per 50,000 leu-kocytes, was found to correlate with clinical manifestation of CMV infection (p < 0.001).4 More recently, detection of CMV has focused on using a CMV antigen assay or the poly-merase chain reaction (PCR).

ImmunizationMany strategies to prevent CMV infection in transplanted patients have evolved, including active and passive immunization. Attempts to actively immunize kidney transplant candi-dates with the immunogenic live attenuated CMV Towne strain vaccine resulted in posi-tive seroconversion, but did not lower the incidence of CMV disease in the patients after transplantation.5-7 However, the vaccinated patients tended to run a milder course of CMV disease than did their non-vaccinated controls.5

Antiviral therapiesGanciclovir has an important role in the pre-vention of CMV infection and disease after solid organ transplantation. Ganciclovir has excellent in vitro activity against all members of the herpes family of viruses. Ganciclovir inhibits DNA polymerase and competes with deoxyguanosine triphosphate to terminate the biosynthesis of the viral DNA strand.

In randomized, prospective, double-blind clinical trials, intravenous ganciclovir reduced the incidence of CMV disease to a variable degree in both seropositive and seronegative recipients who were transplanted with hearts from seropositive donors, including recipients treated with antilymphocyte therapy.8,9 Gan-ciclovir has also been shown to decrease the severity of CMV disease and delay its onset.

Oral ganciclovir has been shown to be supe-rior to oral acyclovir in providing CMV prophy-laxis after solid organ transplantation.10 Other studies have also shown that sequential pro-phylaxis with intravenous then oral ganciclovir was more effective than sequential intrave-nous ganciclovir followed by oral acyclovir in heart transplant recipients.11 However, a disadvantage of oral ganciclovir is its low bio-availability (6%).

Oral valganciclovir is a valine ester prodrug of ganciclovir with a bioavailability of 60 percent. Valganciclovir has replaced oral ganciclovir for prophylaxis and pre-emptive therapy, and has been demonstrated to be as effective as in-travenous ganciclovir in the treatment of CMV disease. Oral prophylaxis with valganciclovir is recommended for at least 100 days after heart transplantation.12-15 Recent data sug-gests 200 days may be superior to 100 days for prophylaxis.

Intravenous immunoglobulinIntravenous immunoglobulin (IVIG) has been shown to reduce the development of donor-

specifi c anti-HLA alloantibodies and appears to be effi cacious in the treatment of antibody-mediated allograft rejection.16 In addition to preventing humoral rejection, IVIG has also been used for CMV prophylaxis. IVIG has led to signifi cant reduction of CMV disease and infection in bone marrow and kidney trans-plant patients.17-19

Furthermore, CMV-specifi c immune globulin (CMV-IVIG, also known as CMV hyperimmune globulin) has been developed as a means to prevent CMV disease. CMV-IVIG is obtained from fractionation and ultrafi ltration of pooled plasma from CMV seropositive donors and standardized for a high titer of CMV antibody. Thus, it has 4- to 8-fold anti-CMV titer com-pared to unselective immune globulin.20 Pos-sible mechanisms of action for CMV-IVIG in-clude the potentiation of antibody-dependent cell-mediated cytotoxicity response, blockage of cytotoxic T-cell recognition of virus-infected cells and neutralization of CMV.2,21

The use of CMV-IVIG has been shown to reduce the incidence of serious CMV disease associated with solid organ transplantation. The incidence of virologically confi rmed CMV-associated syndromes was reduced to 21 percent in renal transplant patients who were treated with CMV immune globulin versus 60 percent in controls without specifi c anti-CMV therapy (p<0.01).22 Another study showed that CMV prophylaxis with CMV-specifi c hy-perimmune globulin did not decrease the in-cidence of CMV infection, but did reduce the severity of subsequent CMV disease.23

In several studies of CMV hyperimmune globulin in heart transplant recipients, the incidence of CMV disease was reduced signifi cantly in the highest risk group of patients.24-26 Variable dosing regimens have been proposed.2

Combining antivirals and IVIGDespite the successes with CMV-IVIG, this therapy alone was inferior to antiviral therapy alone in the prophylaxis of CMV disease. Therefore, the role of combined immune globulin and antiviral therapy has been inves-tigated, with benefi t initially shown for com-bined therapy versus antiviral therapy alone in extrathoracic organ recipients.27,28 Combined CMV-IVIG and ganciclovir was demonstrated to reduce CMV disease and allograft vascu-lopathy in seronegative recipients with sero-positive heart donors.29 Whether CMV-IVIG provides additional benefi t in combination with oral valganciclovir is not yet known.

Cytomegalovirus Infection in Heart TransplantationLawrence S.C. Czer, MD

Continued on page 4 (see “CMV”)

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Until quite recently, supporters of contrast-enhanced coronary computed tomographic angiography (CCTA) wrestled with the utility of its primary use: detection of anatomically signifi cant coronary artery stenoses. In 2004, mainstream introduction of the 64-detector row scanner made achievement of high-quality coronary artery imaging much more routine, sparking a fl ood of subsequent ac-curacy studies that established CCTA as a trustworthy tool for identifying coronary artery stenoses.1-4 With the question regarding diagnostic accuracy mostly answered, in-vestigators in the fi eld have redirected atten-tion to novel applications of CCTA that may enhance identifi cation of clinically important coronary artery disease.

Among the most exciting of these new direc-tions is the detailed examination of plaque appearance by CT with the goal of uncover-ing unique, noninvasively detectable features that typify rupture-prone, or vulnerable, coronary artery plaque. Intravascular ultra-sound (IVUS)-based research has implicated specifi c patterns in plaque appearance as markers for vulnerability. The seminal IVUS-based study by Mariko Ehara, MD, et al. in patients with acute myocardial infarction, unstable angina and stable angina found that plaques responsible for acute myocardial infarction exhibited small calcium inclusions (“spotty calcifi cation”), greater fi bro-fatty content and outward vessel wall expansion (“positive remodeling”).5 These morphologic features may represent increased cellular turnover or metabolic activity within plaque. Dr. Ehara’s fi ndings have been extended by the recently published PROSPECT study, which also found thin-capped fi broatheroma (corresponding in part to a lipid core or high fatty content) and high plaque burden to be predictive of plaques that rupture.6 While results from Dr. Ehara and PROSPECT have been enlightening, the invasive nature of IVUS leaves its use for risk detection in large populations impractical.

Application of CCTA in large populations is certainly feasible, but can it act as an ac-ceptable substitute for IVUS in detailing plaque? Compared to IVUS, CCTA in expert hands has demonstrated excellent promise in detecting spotty calcifi cation, lipid core (determined on CT by the presence of very low attenuation within the plaque) and posi-tive remodeling (Fig. 1). CCTA also has ac-ceptable performance in quantifying plaque volume.7-9 Furthermore, longitudinal studies conducted by Sadako Motoyama, MD, PhD, et al. have shown that plaques displaying

lipid core, positive remodeling and large noncalcifi ed plaque volume on CCTA have substantially increased risk of subsequently becoming culprit plaques for acute coronary syndrome.10,11 The imaging community has approached these results with controlled enthusiasm, since reproducibility of plaque characterization on CCTA has not been satisfactorily established, and quantifi cation of plaque volume, an important predictor of rupture-prone plaque in PROSPECT, remains labor-intensive. Despite these limitations, it is not likely that CCTA needs to exactly replicate IVUS fi ndings to maintain value in detecting vulnerable plaque.

Concurrent to the excitement for CCTA plaque visualization is the growing interest in radionuclide-based detection of coronary plaque metabolic activity. For most of the research to date, the choice radionuclide has been fl uorodeoxyglucose, uptake of which in the coronary artery is seen as evidence of increased macrophage concentration and intra-plaque infl ammation. In this experimen-tal application, CCTA takes on the comple-mentary role of creating a precise whole-volume map of the coronary arteries. Fusion of this map to fl uorodeoxyglucose positron emission tomography images has been es-sential in determining whether each detected fl uorodeoxyglucose signal truly localizes to a coronary artery.12

Detailed coronary plaque imaging pushes the technical boundaries of existing CCTA tech-nology, and challenges await its application in practice. Nevertheless, the opportunity afforded by CCTA to visualize morphologic characteristics of coronary artery plaque in vivo is unique among widely applicable non-invasive tests for coronary atherosclerosis. Early results of this use to identify rupture-

prone plaque have been encouraging. Within the cardiac CT community, there is grow-ing optimism that cardiologists may fi nally have an accessible picture into live coronary plaque biology, one that will ultimately help capture patients at truly elevated risk for myocardial infarction and its dreaded conse-quences.

References1. Abdulla J, Abildstrom SZ, Gotzsche O, et al.

Eur Heart J. Dec 2007;28(24):3042-3050.2. Budoff MJ, Dowe D, Jollis JG, et al.

J Am Coll Cardiol. Nov 18 2008;52(21):1724-1732.3. Meijboom WB, Meijs MF, Schuijf JD, et al.

J Am Coll Cardiol. Dec 16 2008;52(25):2135-2144.4. Miller JM, Rochitte CE, Dewey M, et al.

N Engl J Med. Nov 27 2008;359(22):2324-2336.5. Ehara S, Kobayashi Y, Yoshiyama M, et al.

Circulation. Nov 30 2004;110(22):3424-3429.6. Stone GW, Maehara A, Lansky AJ, et al.

N Engl J Med. Jan 20 2011;364(3):226-235.7. Choi BJ, Kang DK, Tahk SJ, et al.

Am J Cardiol. Oct 15 2008;102(8):988-993.8. Leber AW, Knez A, Becker A, et al.

J Am Coll Cardiol. Apr 7 2004;43(7):1241-1247.9. Pundziute G, Schuijf JD, Jukema JW, et al.

Eur Heart J. Oct 2008;29(19):2373-2381.10. Motoyama S, Kondo T, Sarai M, et al.

J Am Coll Cardiol. Jul 24 2007;50(4):319-326.11. Motoyama S, Sarai M, Harigaya H, et al.

J Am Coll Cardiol. Jun 30 2009;54(1):49-57.12. Rogers IS, Nasir K, Figueroa AL, et al.

JACC Cardiovasc Imaging. Apr 2010;3(4):388-397.

Dr. Cheng is a cardiologist at the Cedars-Sinai Heart Institute.Victor.Cheng@cshs.org

CEDARS-SINAI ADVANCES IN HEART AND HEART SURGERY • JUNE 2011 3

Continued on page 4 (see “CMV”)

Visualizing Rupture-Prone Coronary Artery Plaque with Cardiac Computed TomographyVictor Y. Cheng, MD

Figure 1: Appearance of lipid core (left), spotty calcifi cation (middle) and positive remodeling (right) on coro-nary CT angiography. The plaques of interest have been traced out with thin, dashed white lines.

Lipid core (low “dark” attenuation in the white circle)

Spotty calcifi cation (bright intra-plaque inclusions marked by white arrows)

Positive remodeling (length of solid straight white line exceeds dashed white reference line)

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Fundamental to the success of the TAVI procedure is careful patient selection. This comprises a detailed assessment of clinical and anatomical suitability. The patient must have severe symptomatic aortic stenosis and must be evaluated as being at high risk for conventional surgery as assessed by both cardiologists and surgeons. This often employs objective risk scores that have been validated in conventional surgery pa-tients, such as the Society of Thoracic Sur-geons score and Logistic EuroSCORE.

The anatomical selection includes a care-ful measurement of the aortic annulus to appropriately size the TAVI device; this is generally performed by transthoracic echo-cardiographic screening, with clarifi cation by transesophageal echocardiography if needed. Angiography and CT are used to assess the peripheral vasculature for mini-mal dimension, extent of calcifi cation and tortuosity for a transfemoral approach. Simi-lar imaging assesses the left ventricular apex for scarring and adhesions in the setting of previous myocardial infarction for a transapi-cal approach.

The PARTNER trial of TAVI employed the Edwards SAPIEN device and had two treat-ment arms, an inoperable cohort (B) ran-domized to TAVI or conservative manage-ment and a high-risk cohort (A) randomized to conventional surgery or TAVI. Cohort B

demonstrated a 30-day mortality for TAVI of 5 percent. Early stroke/TIA was higher with TAVI (6.7% vs. 1.7%) but overall the rate of death or stroke was signifi cantly lower with TAVI at one year (33% vs. 53.3%). The number needed to treat (NNT) for one-year mortality benefi t over conservative therapy was fi ve4 and NNT for mortality or quality of life benefi t was only three.5 Cohort A data was reported in March 2011 at the Ameri-can College of Cardiology meeting.

The imminent randomized controlled PART-NER II study will compare TAVI to surgery using a smaller profi le Sapien XT balloon ex-pandable device in intermediate risk groups, and TAVI using this newer device and the already tested Edwards SAPIEN in higher risk patients. Also planned is an international randomized controlled trial evaluating one of the fi rst fully retrievable and repositionable TAVI devices.

References1. Leon MB et al. N Engl J Med. 2010 Oct 21;363(17):

1597-607.2. Cribier A et al. Circulation 2002; 106(24):3006-3008.3. Webb JG et al. Circulation 2006; 113(6):842-850.4. Petronio AS et al. Circ Cardiovasc Interv 2010;

3(4):359-366.5. Cohen D et al. American Heart Association’s Scientifi c

Sessions 2010. Health-Related Quality of Life after Transcatheter Aortic Valve Implantation vs. Non-Surgical Therapy among Inoperable Patients with Severe Aortic Stenosis: Results from the PARTNER Trial (Cohort B). http://circ.ahajournals.org/cgi/content/full/122/21/2215. Abstract #21785.

Dr. Makkar is Director of Catheterization Laboratories and an Associate Director of the Cedars-Sinai Heart Institute. He is also the Stephen R. Corday, MD, Chair in Interventional Cardiology.Raj.Makkar@cshs.org

Dr. Jilaihawi is an interventional cardiology fellow atthe Cedars-SinaiHeart Institute.Hasanian.Al-Jilaihawi@cshs.org

Dr. Fontana is a cardiac surgeon at the Cedars-Sinai Heart Institute and Vice-Chair, Strategic Planning and Development in the Department of Surgery at Cedars-Sinai.Gregory.Fontana@cshs.org

Cedars-Sinai Heart Institute • 8700 Beverly Blvd. • Los Angeles, CA 90048(310) 423-7557 • Fax (310) 423-7637 • www.cedars-sinai.edu/heart • heartinstitute@cshs.org

TAVI: continued from page 1

Surveillance for CMV infectionAn alternative approach to preventing CMV disease in transplant patients involves pe-riodic surveillance for CMV infection prior to the onset of CMV disease. Pre-emptive treatment of heart and lung transplant pa-tients with ganciclovir, based on routine surveillance of CMV antigenemia, has been examined.30 This study argued that if the risk of CMV disease can be predicted by surveil-lance of antigenemia, then some patients may not require a mandatory CMV prophy-laxis regimen. Cedars-Sinai investigators Stanley Jordan, MD, and Mieko Toyoda, PhD, reported the use of CMV-PCR for monitoring of CMV viremia in renal and car-diac transplant recipients.31-32 This appears to be most useful in asymptomatic high-risk patients (seronegative recipients with hearts from seropositive donors), and in patients who have symptoms suggestive of CMV disease after appropriate prophylaxis.

Monitoring with CMV-PCR continues to be useful in detecting CMV viremia, which may

occur despite appropriate prophylaxis or treatment, especially in high-risk patients.

Since CMV infection remains a major cause of infectious morbidity and mortality after solid organ transplantation33, the early and accurate diagnosis of CMV infection and the development of effective antiviral therapeutic regimens are important to the success of future transplantation.References1. Grattan MT et al. JAMA 1989;262:3561-3566.2. Valantine HA. Transplant Proc 1995;27:49-57.3. Weimar W et al. Transplantation 1991;52:162-163.4. Koskinen PK et al. Transplantation 1993;55: 547-551. 5. Weimar W et al. Transplant Proc 1990;22:229-32.6. Balfour HH et al. Transplant Proc 1985;17:81.7. Plotkin SA et al. Ann Intern Med 1991;114:525.8. Merigan TC et al. N Engl J Med 1992;326:1182-6.9. Macdonald PS et al. J Heart Lung Transplant

1995;14:32-8.10. Flechner SM et al. Transplantation 1998;66: 1682-8.11. Mullen GM et al. J Am Coll Cardiol 1998;31:157.12. Lefeuvre S et al. Transpl Infect Dis 2010; 12: 213-219.13. Paya C et al. Am J Transplant 2004; 4: 611-620.14. Wiltshire H et al. Transplantation 2005; 79:1477-1483.15. Asberg A et al. Am J Transplant 2007; 7: 2106-2113.16. Jordan SC et al. Transplantation 1998;66:800-805.17. Winston DJ et al. Ann Intern Med 1987;106:12-18.18. Elfenbein G et al. Transplant Proc 1987;19:138-43.

19. Steinmuller DR et al. Transplant Proc 1989;21:2069-71.20. Patel R et al. Transplantation 1996;61:1279-89.21. Snydman DR. Transplant Proc 1991;23:131-5. 22. Snydman DR, et al. N Engl J Med 1987;317:1049-54.23. Freeman R, et al. J Clin Pathol 1990;43:373-6. 24. Laske A et al. Transplant Proc 1993;25:1427-8.25. Metselaar HJ et al. Chest 1990;97:396-9. 26. Martin M. Transplant Proc 1995;27:23-27.27. Nicol DL et al. Transplantation 1993;55:841.28. Carrieri G et al. Transplant Proc 1995;27:961.29. Bonaros NE et al. Transplantation 2004;77: 890-897.30. Egan JJ et al. Transplantation 1998;65:747-52.31. Toyoda M, et al. Transplantation 1997;63:957-63.32. Toyoda M, et al. Transplant Proc 1995;27:1272-3.33. Delgado JF et al. Transpl Infect Dis 2011;13:136-44.

Dr. Czer is Medical Director of the Heart Transplant Program, Director of Transplantation Cardiology and Co-Director of the Mechanical Support Program at the Cedars-SinaiHeart Institute.Lawrence.Czer@cshs.org

CMV: continued from page 2

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