Imaging in patients after cardiac transplantation and in patients with ventricular assist devices.

REVIEW ARTICLE Imaging in patients after cardiac transplantation and in patients with ventricular assist devices Bhanu Gupta, MD, MSc,a,b Dany Jacob, MD,b and Randall Thompson, MD, FASNCa,b a b

Department of Cardiology, St. Luke’s Mid America Heart Institute, Kansas City, MO The University of Missouri - Kansas City, Kansas City, MO

Received Dec 8, 2014; accepted Jan 29, 2015 doi:10.1007/s12350-015-0115-6

The field of cardiac imaging and the management of patients with severe heart failure have advanced substantially during the past 10 years. Cardiac transplantation offers the best longterm survival with high quality of life for the patients with end stage heart failure. However, acute cardiac rejection and cardiac allograft vasculopathy (CAV) can occur post cardiac transplantation and these problems necessitate regular surveillance. The short-term success of mechanical circulatory support devices (MCSD), such as ventricular assist devices (VADs), in improving survival and quality of life has led to a dramatic growth of the patient population with these devices. The development of optimal imaging techniques and algorithms to evaluate these advanced heart failure patients is evolving and multimodality non-invasive imaging approaches and invasive techniques are commonly employed. Most of the published studies done in the transplant and VAD population are small, and biased based on the strength of the particular program, and there is a relative lack of published protocols to evaluate these patient groups. Moreover, the techniques of echocardiography, computed tomography (CT), magnetic resonance imaging, and nuclear cardiology have all progressed rapidly in recent years. There is thus a knowledge gap for cardiologists, radiologists, and clinicians, especially regarding surveillance for CAV and ideal imaging approaches for patients with VADs. The purpose of this review article is to provide an overview of different noninvasive imaging modalities used to evaluate patients after cardiac transplantation and for patients with VADs. The review focuses on the role of echocardiography, CT, and nuclear imaging in surveillance for CAV and rejection and on the assessment of ventricular structure and function, myocardial remodeling and complications for VAD patients.

See related editorial, doi:10.1007/s12350015-0111-x.

Electronic supplementary material The online version of this article (doi:10.1007/s12350-015-0115-6) contains supplementary material, which is available to authorized users. Reprint requests: Randall Thompson, MD, FASNC, Department of Cardiology, St. Luke s Mid America Heart Institute, 4330 Wornall Rd, Suite 2000, Kansas City, MO; [email protected] J Nucl Cardiol 1071-3581/$34.00 Copyright Ó 2015 American Society of Nuclear Cardiology.

CARDIAC ALLOGRAFT VASCULOPATHY Traditional coronary artery disease (CAD) has a long latency period and patients with chronic CAD are often very stable for many years. However, this long course and relative stability are not observed in cardiac allograft vasculopathy (CAV), which is characterized by rapid progression and diffuse disease due to an underlying inflammatory process as a spectrum of chronic rejection. Early diagnosis is very important for CAV. In addition to judicious percutaneous intervention of focal stenosis, the early detection of CAV may effectively allow treatment with institution of modified immunosuppressive therapy. This alternation in the immunosuppressive pharmacotherapy in CAV may not only arrest the rapid

Gupta et al Imaging in patients after cardiac transplantation

acceleration of CAV, but also may facilitate regression and reduce the future need for revascularization.1-4 Invasive coronary angiography (ICA) remains commonly employed for routine surveillance of CAV, but of course is invasive and has inherent risks.5 It also is imperfect for detection of CAV due to the diffuse nature of this disease. During coronary angiography, either intravascular ultrasound (IVUS) or optical coherence tomography (OCT) may be performed to further increase the sensitivity of ICA. However, IVUS and OCT have several limitations and are not utilized for routine surveillance in most centers. Limitations of IVUS include incomplete visualization of small-caliber vasculature (due to large caliber of IVUS catheters currently available) and additional procedural complications related to ICA. IVUS is not able to provide information regarding intramyocardial arteries (20-50 lm) or arterioles (10-20 lm). In addition to increased cost with IVUS, the complication rate of multivessel IVUS is about reported to be 1.6%.6 OCT is emerging as a promising intracoronary imaging technique due to its advantage of spatial resolution of\10-20 lm.7,8 Because of its higher resolution compared to IVUS, OCT is able to more clearly differentiate the various layers of coronary arterial vessel wall and gives better characterization of intimal thickness.9,10 Non-invasive cardiac imaging surveillance is often used and may prove to be an effective alternative to ICA to reduce its associated complications.

ECHOCARDIOGRAPHY Transthoracic echocardiography (TTE) is routinely used for measuring cardiac function after heart transplant. Regional wall motion abnormalities (RWMA) found on cardiac echo have also been shown to have value for prognosis and RWMA are associated with major adverse cardiac event.17,21 However, RWMA found on echocardiography have low sensitivity (47%), but high specificity (84%) for the presence of coronary allograft vasculopathy (CAV).11 The addition of tissue Doppler imaging (TDI) may be useful as an adjunctive technique to detect CAV.12,13 TDI-derived peak systolic wall motion (Sm) velocity\10 cm/s was associated with a 97% likelihood for CAV whereas Sm values[11 cm/s excluded accelerated CAV with 90% probability.13 Serial pulse wave (PW)-TDI can potentially reduce unnecessary invasive measurements, especially in those patients with higher risk factors for catheterizations.12

STRESS ECHOCARDIOGRAPHY When stress echocardiography is employed for detection of CAV, dobutamine stress is often utilized

Journal of Nuclear CardiologyÒ

instead of exercise because of the blunted heart rate response to exercise common in post cardiac transplant patients. Dobutamine stress echocardiography (DSE) has varying sensitivity when compared to ICA/IVUS. DSE has an average sensitivity of about 72% and a specificity of approximately 88%.14 In addition to a certain ability to diagnose CAV, DSE also has prognostic value in patients post-transplant. Serial DSE findings were evaluated by Spes et al. who found that worsening of serial DSE indicated an increased risk of major adverse cardiovascular events (MACE) compared with no deterioration (relative risk 7.3, P = .0014).14 Serial normal DSE indicated a very low risk of events and a high predictive value for an uneventful clinical course.14 Novel methods have been proposed to improve the accuracy of DSE for detection of CAV and are currently being validated. For example, an initial study of adding end-systolic pressure-volume relationship to DSE has shown an improved sensitivity (from 67% to 100%) compared to DSE alone in a small group of patients.15 Also, global longitudinal strain (GLS) is a new echocardiographic measurement of systolic myocardial deformation which has been shown to correlate with the degree of CAV. GLS may develop to be a new method of monitoring graft function.16 CORONARY FLOW RESERVE CAV is often a diffuse process affecting vessels of all sizes and leading to microvasculopathy. This diffuse disease causes reduced coronary blood flow to the myocardium, often even without significant focal obstructive lesions in the major epicardial arteries. Coronary flow reserve (CFR) measurements obtained at the time of cardiac catheterization can potentially detect microvasculopathy early, even before any obvious epicardial coronary flow obstruction. CFR is expressed as a ratio of the maximal coronary flow velocity (cm/second) after pharmacologic stimulation relative to the basal flow velocity. An abnormal CFR is often defined as \2.0 or 2.5.17 In the non-transplant heart, an abnormal CFR predicts cardiac events on longterm follow up.18 Similarly, in heart transplant recipients, a change in coronary epicardial and microvascular endothelial function over time (as demonstrated by a fall in CFR) has been shown to be associated with the combined clinical endpoint of CAV development ([50% stenosis), ischemic events, and death.19 Assessment of coronary microvascular resistance and CFR measurement has required ICA in the past. Invasive assessment of coronary bed resistance has been performed by various methods, such as coronary pressure wire with modified software. Various vasodilators have been employed including acetylcholine, substance


P, nitroglycerine, adenosine, and papaverine.5,20 A detailed study of the invasive assessment of coronary microcirculation was carried out by Escande et al.21 These authors performed a comparison of four intracoronary physiological indices relative to actual microcirculatory histological changes by endomyocardial biopsy (EMB) in 17 transplanted patients. In their study, arteriolar obliteration and a reduction in the number of capillaries both contributed to deterioration of absolute microcirculatory indices, such as instantaneous hyperemic diastolic velocity pressure slope and coronary resistance index, and were associated with clinical events. However, relative flow indices such as CFR did not correlate with histologic changes or clinical events.34 These authors believe that epicardial endothelial dysfunction may precede any structural coronary changes such as intimal thickening, and they suggest that there are two distinct entities of CAV. To evaluate endothelial dysfunction after cardiac transplantation, Kubrich et al prospectively followed a large cohort of 185 patients for 5 years.22 In this study, epicardial endothelial dysfunction (relative risk [RR] 1.97; P = .03) independently predicted adverse outcomes.35 Despite the potential advantages of non-invasive coronary flow measurements for the early diagnosis of CAV, research to date has not demonstrated accuracy equivalent to coronary angiography with IVUS. Dobutamine contrast-enhanced transthoracic echocardiography (CE-TTE) is an emerging non-invasive method for measuring CFR and myocardial perfusion mismatch that aids the detection of significant CAD.23,24 Recent studies in cardiac transplant patients have shown that CE-TTE detects CAV with an accuracy of 85-89%.25,26 A low coronary flow velocity pattern has also been shown to be associated with CAV-related MACE.27 Although myocardial perfusion positron emission tomography (PET) has the ability to quantify absolute coronary flow in the general coronary disease populations and such measures contribute to the prognostic value of the examination, the role of PETderived coronary flow measurements has not been well studied in the cardiac transplant population.28 Cardiac magnetic resonance (CMR) imaging is a potentially attractive noninvasive modality for evaluation of the transplanted heart. Emerging evidence suggests that late gadolinium enhancement can detect CAVrelated myocardial infarction in early CAV in a significant proportion of cardiac transplant patients, many of whom who would be otherwise classified as low-risk based on ICA.29 Miller et al recently evaluated the role of CMR in forty-eight patients who had first undergone ICA with IVUS and fractional flow reserve (FFR).30 They employed multiparametric CMR, which evaluated regional and global ventricular function, absolute myocardial blood flow (MBF) quantification, and


myocardial tissue characterization. CMR-based myocardial perfusion reserve (MPR) was predictive of epicardial and microvascular components of CAV. The diagnostic performance of CMR MPR was significantly higher than ICA for detecting moderate and severe CAV.30 SPECT Myocardial perfusion imaging (MPI) with SPECT is frequently used clinically in surveillance for CAV (See Figures 1, 2). All series in the literature have been small in number and the sensitivity and specificity vary with the largest study observing a sensitivity of 84% and specificity of 70% with negative predictive value (NPV) at 12 months of 95% to 98%.31-34 Stress perfusion defect of[3 segments is the independent predictors of cardiac death (RR 5.6; P = .005) or re-transplantation and need for late coronary revascularization at more than two months (RR 6.1; P \ .002).34 The variability in the reported accuracy is in part due to the timing of the examination, the stressors utilized, the radiopharmaceutic employed, and the variable diagnostic criteria for CAV in the included studies.31,34-40 When CAV occurs, it frequently is diffuse in nature, involving the distal segments of numerous coronary vessels.41 Thus, the SPECT MPI display, which normalizes to the hottest pixel, may underestimate perfusion defects if multiple coronary territories are involved and there is no truly normal segment. The limits of spatial resolution of SPECT (approximately 1.6 m with collimation) are also relevant. The transplanted heart tends to be considerably smaller in size than the diseased one it replaced and left ventricular wall thickness is usually normal, at least initially. Thus, SPECT spatial resolution is more likely to be a relevant limitation in the diagnosis of CAV than for the routine CAD patient. In addition, certain imaging artifacts that can lower specificity for the diagnosis of CAV are more common in the transplant patient. For example, paradoxical septal motion can be exaggerated post heart transplant, especially in the setting of pericardial effusion. Studies comparing SPECT MPI using pharmacologic stress with dipyridamole to dobutamine stress echo in transplant patients have demonstrated comparable sensitivity (80% to 92%) and specificity (86% to 92%).38,40 The stress agents dipyridamole, adenosine, and dobutamine have been employed in numerous studies of cardiac transplant patients. Most pharmacologic stress for MPI in United States is currently being performed with the relatively recently developed selective A2A adenosine agonist regadenoson. The safety and tolerability of regadenoson were tested in OHT patients by Cavalcante et al.42 Compared to adenosine, regadenoson caused less conduction abnormalities in patients who were several years post-transplant. Regadenoson, therefore, is considered to be safer in these



Figure 1. SPECT Imaging and coronary angiography of cardiac allograft vasculopathy. (A) SPECT myocardial perfusion demonstrates a reversible left ventricular perfusion defect inferioriy and laterally (white arrows). (B) Coronary angiography revealed a severe diffuse stenosis in a large obtuse marginal vessel (white arrow) and collateral filling in a diffusely diseased right posterior descending artery (black arrows). The patient underwent percutaneous intervention to the obtuse marginal stenosis.

Figure 2. SPECT Imaging and coronary angiography of cardiac allograft vasculopathy. (A) SPECT myocardial perfusion demonstrates a reversible left ventricular perfusion defect inferiorly and anteriorly (arrows). (B) Coronary angiography revealed a severe diffuse stenosis in a large posterior descending artery (white arrows). (B) Diffuse stenosis in Distal LAD (B1); and OM1 (B2) (white arrows).

NPV (%)

98

98

99

94

98

98

96

65

53

18

42

53

41

25

37

78


PPV (%)


cardiac transplant patients compared to adenosine.42 There is inadequate evidence to say that regadenoson is safe early after transplant when the heart is denervated (Table 1).

98 13 Angiography± Adenosine 99m Tc tetrafosmin 99 2012 Thompson et al

35

70 84 Angiography± Exercise/ Dipyridamole Thallium-201/99mTc sestamibi 110 2010 Manrique et al34

71 89 Angiography± Dobutamine Thallium-201 47 2005 Wu et al36

87 82 Angiography± Dobutamine 99mTc sestamibi 63 2005 Hacker et al31

96 40 Angiography± Exercise Thallium-201 39 2004 Bacal et al37

86

55 90

92 Angiography± Dipyridamole 99 Tc sestamibi 78 2001

Angiography± Dobutamine 99m Tc tetrafosmin 50 2000

m

Cilberto et al38

Elhendy et al39

92 80 Angiography± Dipyridamole 99mTc sestamibi/ 99m Tc tetrafosmin 67 2000 Carlsen et al40

Tracer Patients Year Study

Table 1. Diagnostic accuracy of SPECT for the detection of CAV

Stress

Confirmatory Test

Sensitivity (%)

Specificity (%)

COMPUTED TOMOGRAPHY Coronary calcium scoring on gated, non-contrast CT scanning is often used to screen for coronary disease in asymptomatic patients at intermediate risk for CAD. The typical atherosclerotic process that causes CAD is quite different than the process of CAV, however, and coronary calcification seems to be an insensitive marker for transplant vasculopathy.43 Contrast-enhanced coronary CT angiography, on the other hand, despite limitations of temporal and spatial resolution, appears to be a promising modality for the early detection of CAV. The detection of obstructive CAV by coronary CT has been evaluated in multiple studies. Romeo et al initially reported a sensitivity of 83% and specificity of 95% with a 16-slice multidetector computed tomography (MDCT).44 Subsequent other studies have been carried out with 16-slice and 64-slice CT scanners with evaluation on per segment basis or patient basis (See Table 2).44-56 The overall sensitivity to detect obstructive CAV, as defined by [50% stenosis compared to ICA, is 99.2% on per-patient basis and 91.2% on a persegment basis. The specificity is 94.8% on a per segment basis and 89.6% on per patient basis with the NPV reaching 99.2% on per segment basis and 99.8% on perpatient basis (Table 2).40-52 With this high observed NPV, the investigators of these studies suggest that CT can be used as an alternative to coronary angiography and that ICA can be reserved for patient with indeterminate or positive findings on CT.57 Coronary angiography is known to underestimate CAV when compared to IVUS because of the often diffuse nature of the disease. CT has the theoretical potential to identify early CAV by demonstrating intimal thickening. In the recent Romeo et al, study, about 50% of coronary segments that were thickened on MDCT were considered to be normal by coronary angiography.44 Limits of spatial resolution are an issue for cardiac-computed tomography angiography (CTA) in this regard, however. The diagnostic ability of CT to identify obstructive CAV as defined by [0.5 mm of intimal thickening, compared to IVUS, has been evaluated in three studies (see Table 2).51,53,56 Only the proximal and mid-coronary segments were analyzed by IVUS scanning due to the small caliber of the distal vessels and the large diameter of IVUS probe. Overall MDCT had a sensitivity of 83% and specificity of 88% when compared to IVUS.51,53,56

2012

2012

2013

2009 2009

Kepka et al47

Von Ziegler et al46

Mittal et al45

Gregory et al56 Schepis et al51 19 30

130

46

20

19 13 30 26

64 64 (DSCT)

64

64 (DSCT)

64 (DSCT)

64 64 64 (DSCT) 64

CT slice

IVUS IVUS

ICA

ICA

ICA

ICA ICA ICA ICA

70 34

144

83

NR

NR NR 34 92

Time after Comparing transplant Modality (months) 5% (Per Patient) 6% (Per segment) 16% (Per segment) 19% (Per patient) 3% (Per segment) 10% (Per patient) 1% (Per segment) 6% (Per patient 1% (Per segment)

CAV prevalence 100 90 93 100 88 100 100 100 100 96 85 70 85

94 96.8 80 81 97 94 99 86 98.9 93 96.8 92 84

50 81.8 48 56 47 67 50 33 50 72 45.9 89 76

100 98.7 98 100 100 100 100 100 98.9 99 99.5 77 91

Sensitivity Specificity PPV NPV (%) (%) (%) (%)

CAV, Cardiac allograft vasculopathy; ICA, invasive coronary angiogram; CT, computed tomography; IVUS, intravascular ultrasound; PPV, positive predictive value; NPV, negative predictive value; DSCT, dual-source CT

2006 2010 2009 2009

Iyengar et al55 Nunoda et al48 Schepis et al51 Von Ziegler et al49

Study

No. Year patients

Table 2. Diagnostic accuracy of 64-slice Cardiac CT for the detection of CAV

Gupta et al Imaging in patients after cardiac transplantation Journal of Nuclear CardiologyÒ


There are very few studies that directly compare CT with other non-invasive imaging modalities in the evaluating CAV. In one study by Mastruoboni et al, dual-source CT coronary angiography was compared with dobutamine stress echo.58 Four patients were found to have significant coronary stenosis on CT, which was confirmed by coronary angiogram, while DSE detected only 2 of these patients. These limited data suggest a better sensitivity of evaluating CAV with CT than dobutamine stress echo.58 Temporal resolution remains a weakness of coronary CT angiography and motion artifacts account for the majority of non-analyzable coronary segments. Imaging laboratories normally try to achieve a resting heart rate of less than 60-70 beats per minute to optimize image quality and diagnostic accuracy. As a result of cardiac denervation, however, the resting heart rate in cardiac transplant recipients ranges from 80 to 110 beats/min and the response to beta blockade is inconsistent.44,49,59 Thus, CTA image quality can be a significant challenge in these patients. However, newer technologies such as faster gantry design, newer detector materials and designs, wider detector coverage, and iterative reconstruction algorithms hold real promise for solving these limitations. In a recent report, only 4% of coronary segments of cardiac transplant patients were non-analyzable on images obtained by dual-source CT, despite a heart rate of 80 bpm.51 Spatial resolution is also a significant limitation for the use of coronary CTA in the diagnosis of CAV. In the studies cited above, most excluded vessels \1 mm. Radiation is also a concern for coronary CTA.57 However, CT technology has advanced rapidly in recent years with development of newer techniques including acquisition protocols using high-pitch spiral scanning, prospective gating targeting the diastolic phase of the cardiac cycle, reduced-dose low-voltage CCT, and iterative reconstruction algorithms. Radiation dose was commonly 18-20 mSv a few years ago, while doses in the range of 1 mSv are reported with the newest technologies.60-62 As one can surmise from the discussion above, there are no generally accepted routine protocols for screening CAV in cardiac transplant patients. Many centers utilize annual ICA immediately after cardiac transplantation and less frequently afterwards. The 2010 International Society of Heart and Lung Transplant (ISHLT) Guidelines for the Care of Heart Transplant Recipients did not assign a non-invasive imaging technique as a first line screening technique.5 Echocardiography and SPECT have been the most extensively studied, although the results of various studies have sometimes been discordant, and therefore neither has found widespread acceptance as a routine surveillance tool.


ACUTE CARDIAC REJECTION Acute cardiac allograft rejection (ACR) is a cellmediated or antibody-mediated immunologic process. Using international standardized criteria, EMB is used to diagnose acute cellular rejection, which is predominantly a T-cell-mediated process.63,64 Antibody-mediated rejection (AMR) is the result of recipient pre-sensitization to donor antigens or of de novo donor-specific antibody production which eventually results in allograft dysfunction, acceleration of CAV and decreased survival.65 Histological grading schemes have been established by ISHLT for acute cellular rejection while a framework for grading AMR has been proposed.66 Advances in immunosuppression have resulted in a decrease in the incidence of acute cellular rejection and a shift toward AMR, otherwise known as acute humoral rejection.67-70 Despite advances in immunosuppressive therapy, ACR is still commonly present in the first year post cardiac transplantation and represents the leading cause of mortality during this period.71 Histological analysis of the right ventricular (RV) wall by EMB has been the gold standard technique for ACR surveillance. However, EMB is invasive and carries a reported complication rate of .5-1.5%, including myocardial perforation, cardiac tamponade, arrhythmia, access site complications, and significant tricuspid regurgitation.72 Non-invasive methods for screening for ACR are desirable and could conceivably be much cheaper and safer. Echocardiography and CMR have been the most studied imaging modality for ACR. Several echocardiographic parameters have been proposed as surveillance methods for ACR. However, markers such as left ventricular size, wall thickness, mass, and ejection fraction are insensitive ones.73-75 Pericardial effusion, seen in two-thirds of patients after cardiac transplantation at three months, is a poor marker as well. Doppler indices of the mitral inflow have been widely investigated, but have insufficient accuracy for detecting ACR.76 Various other well-established echo parameters and indices are proposed to evaluate for ACR but inconsistent results have limited their widespread use. The myocardial performance index, TDI, peak early diastolic wall motion velocity, and other parameters such as E/Ea ratio and late diastolic mitral annular velocity have shown inconsistent results.74,77-84 Emerging echocardiographic techniques, such as, myocardial deformation metrics, appear to be promising for detection of ACR, but further studies are needed. TDIderived peak systolic longitudinal strain was associated with ACR in one retrospective study.70 A threshold of 27.4% in peak systolic longitudinal strain was associated with a sensitivity and specificity of 82% for detecting


[grade 1B ACR.77 TDI-derived peak systolic radial strain was also found to be significantly reduced in ACR of grade [1B.77,78 However, Further prospective studies are warranted to determine the non-inferiority of this novel technique to detect ACR over EMB proven rejection. The major disadvantage of TDI-derived variables is that they are angle dependent and have frame rate limitations. Two-dimensional speckle tracing (2d-STE) is an angle-independent modality that can evaluate cardiac mechanical function.79,80 The subendocardial longitudinal-oriented fibers of the myocardium are very sensitive to ischemia and fibrosis and therefore can be affected in the early stages of rejection.79 2D-STE allows for the evaluation of longitudinal myocardial deformation. The role of GLS in 64 cardiac transplant recipients who had undergone 2D-STE and EMB was recently evaluated by Clemmensen et al.81 GLS was significantly (P \ .0001) reduced in grade 2R (-13.8%) ACR compared to grade 1R (-15.3%) and grade 0 (-16.2%).81 The traditional diastolic Doppler parameters E-wave deceleration time and isovolumetric relaxation time were unaffected by rejections whereas E/ A and E/e0 were significantly higher in the grade 2R group.81 Interestingly, the GLS improved in moderate ACR with therapy. Sera et al observed similar findings and found that a lower GLS was significantly associated with an increased risk of rejection.82 Left ventricular radial strain was shown to be significantly reduced in asymptomatic cardiac transplant recipients with increasing ACR in their study; however other studies have not observed the same results.82,83 These findings suggest that GLS could be useful in reducing the number of endomyocardial biopsies in asymptomatic cardiac transplant patients. CMR imaging has the potential to be a non-invasive modality of choice to detect ACR due to its ability to image at tissue and molecular level. The most widely investigated magnetic resonance imaging (MRI) approach for detecting ACR involves T2-weighted imaging. Animal models have shown a significantly positive correlation between T2-relaxation time and ACR histological severity. In humans, the largest study was conducted in 68 patients in which T2-relaxation time was significantly higher in grade 2 ACR (57 ? 5 ms) compared to grade 0 or 1 (50 ? 5 ms and 51 ? 8 ms).84 A high NPV of 97% is associated with a T2-relaxation time of[56 ms in detective grade 2 ACR.84 However, Wisenberg et al found T2-relaxation time to be elevated in all patients during the initial 25 days post-transplant, regardless of ACR status.85 Relative myocardial signal intensity in the early phase post-contrast has also been proposed as a marker for ACR in a small study by Taylor et al.86 These authors


found patients with grade 2 ACR who had a statistically significant increase in myocardial signal intensity compared to grade 1 and 0 ACR (4.1 vs 2.8; P = .001).76 While cardiac MR appears to show promise for the diagnosis of ACR, larger studies are needed to confirm these findings. IMAGING OF VENTRICULAR ASSIST DEVICES The landscape of the care of patients with heart failure has recently changed with the widespread application of mechanical circulatory support devices (MCSD). The different types of MCSD are listed in Table 3 and illustrated in Figure 3. With MCSD, multiple new disciplines now interface with the cardiac team, including those of engineering fluidics, electromagnetics, electronics, and software analysis. The cardio-mechanical and hemodynamic changes following ventricular assist device (VAD) implantation can be complex and range from unloading of the left ventricular, increasing the preload of RV, alterations in the valvular structure and functions, improvement in pulmonary hypertension and ultimately, sometimes, to myocardial recovery with LV remodeling. Several imaging tools have an obvious role in the management of VAD patients. In order to optimize the VAD functions to improve quality of life of recipients, imaging modalities are both complementary to clinical and laboratory assessment and also provide critical information regarding management decisions. Also, complications associated with MCSD are common and require monitoring, vigilance, and often-advanced imaging tools for proper diagnosis and prompt treatment. Multimodality imaging is used in the VAD patient, especially echocardiography, CT scanning and, to a lesser extent, nuclear cardiology techniques. No left ventricular assist devices (LVADs) are MRI compatible and CMR has virtually no role after LVAD. This section will review the established and emerging uses of cardiac imaging tools in LVAD patients: echocardiography, CT scanning, and nuclear scintigraphy. ECHOCARDIOGRAPHY Comprehensive echocardiographic evaluation, either as TTE or transesophageal echocardiogram (TEE), has gained high acceptance for the pre-implantation, peri-implantation, and post-implant follow-up of MCSD.87 In the pre-implantation phase of LVAD evaluation, TTE is the primary and most accepted modality due to its wide availability, ease of use, longer experience with the techniques, and non-invasive nature. TTE is able to provide comprehensive assessments of valvular structure and function, right and left ventricular



Table 3. Adult ventricular assist devices: types and function

Left ventricular assist devices types

Pump design

First-Generation LVADs HeartMate XVE Novacor LVAS Thoratec LVAD

Pulsatile flow pump

Second Generation HeartMate II MicroMed DeBakey pump§ Jarvik 2000 FlowMaker§

Continuous Flow Axial flow pump

Third Generation HeartWare HVAD Dura Heart LVAS§ Levacor VAD§

Centrifugal/intrapericardial

Device illustration

§ Investigational in US. Thoratec Vented Electric (VE) Heart Mate XVE (Thoratec Corp., Pleasanton, California); Novacor LVAS (World Heart Corp., Oakland, California); Thoratec LVAD (Thoratec Corp.); HeartMate II (Thoratec Corp.); MicroMed DeBakey pump (MicroMed Technologies, Houston, Texas); Jarvik FlowMaker (Jarvik Heart Inc., New York, New York); VentrAssist LVAS (Ventracor, Sydney, Australia); HeartWare (HeartWare Inc., Miami Lakes, Florida); DuraHeart (Terumo Heart Inc., Ann Arbor, Michigan); Levacor (World Heart) LV, left ventricular; LVAD, left ventricular assist device; LVAS, left ventricular assist system

functions, and serial measurements of cardiac hemodynamics. However, in the perioperative setting, TEE is most commonly used in order to assess RV function, intra-cardiac shunting, proper positioning of the inflow cannula in the LV cavity, proper LV decompression, and appropriate septal shift to adjust for the pump speed. Consequently, combined information from both TTE and TEE is often utilized in the post-operative settings.88,89 Prior to LVAD implantation, echocardiography is also useful for assessing valvular functions. The assessment of the aortic valve is very important. Aortic regurgitation (AR) in this setting in particular can cause wasteful recirculation and substantially reduce the pump

efficiency resulting in decreased systemic perfusion.90 Also, the risk of developing AR is increased during LVAD support because the aortic valve is exposed to a higher-pressure gradient.91,92 If clinically significant AR is detected during preoperative evaluation, aortic valve repair may be considered during the time of VAD implant to prevent loss of LVAD mechanical efficiency. The mitral valve is assessed for mitral annulus dimensions, for grading the degree of mitral regurgitation, and for identifying the etiology of mitral regurgitation.93-96 Mitral regurgitation is often significantly reduced after LVAD support; however, persistent severe MR after LVAD placement may indicate inadequate LV decompression.


Figure 3. HeartMate II battery operated pocket controller.

Right ventricle function assessment prior to ventricular assist support is very important to allow appropriate patient selection. It can also help predict the need for post-operative inotropic support and the requirement for RVAD implantation.97-99 Various RV echocardiographic parameters may be utilized to assess RV function. Among such echocardiographic parameters are global fractional area change (FAC), tricuspid annular plane systolic excursion, Doppler tissue derived lateral annular systolic velocity (S0 ), isovolumic acceleration, RV outflow tract fractional shortening, and longitudinal strain and strain rate.100,101


Low right ventricle stroke work index (RVSWI \ 600 mmHg 9 ml/m2 or less) was strongly correlated with prolonged inotropic use after LVAD implantation in a recent study by Frazier et al, supporting the role of RVSWI as an important pre-implantation risk factors for LVAD.102 Unlike some other parameters, measurements of RVSWI do require invasive assessment of mean pulmonary artery pressure (mPAP) or central venous pressure. Severe tricuspid regurgitation and severe elevated pulmonary artery pressure also have prognostic value in this setting and are associated with early postoperative RV failure. Serial Doppler assessment of pulmonary artery pressure is important as pulmonary artery pressure may normalize after LVAD support, permitting transplant candidacy at a later date.103 These echo parameters are integrated with clinical signs and symptoms to help decide the timing of initiation of circulatory support and to stratify the management protocol during intra- and post-operative settings. TTE being widely available and portable can provide cardiovascular hemodynamics in a rapid and reliable manner at the bedside. In addition, echocardiography provides rapid and immediate assessment of perioperative complications such as RV dysfunction, pericardial effusion and tamponade. Numerous validation studies have confirmed the applicability of echocardiographic hemodynamics for clinical decisionmaking in VAD patients.104-108 TEE is a readily available imaging tool in the various stages of LVAD evaluation, but is most often used in the perioperative settings. TEE may be utilized to assess direction of flow and severity of patent foramen ovales (PFO), usually with the help of agitated saline

Figure 4. Interventricular and interatrial septal motion with LVAD support. (A) Apical four chamber and (B) parasternal long axis views demonstrating slightly leftward interatrial and interventricular septal position respectively indicating adequate LV and LA decompression after left ventricular assist device activation causes (Green arrows).



Figure 5. Correction of aortic regurgitation with transcatheter aortic valve replacement (TAVR) in patient with LVAD. (A) Transesophageal echocardiography (TEE) demonstrates aortic regurgitation (green arrow) in a patient with HeartMate II LVAD. Red arrow highlights the flow in the inflow portion of the LVAD. (B) Transcatheter aortic valve replacement with Core Valve, Medtronic, Inc. (Red arrow). Yellow asterisks highlights the position of the inflow cannula.

and color flow Doppler. As the prevalence of PFO approaches about 27%,109 it is important to assess the severity of PFO before and after cardiopulmonary bypass. Biventricular failure may mask the flow and gradient across the interatrial septum as a result of increased right and left atrial pressures. After LVAD activation, there is an increase in right atrial pressure and flow due to increased venous return on the right side and then consequently a decrease in LA pressure due to LV unloading. These hemodynamic changes may result in paradoxical embolization or hypoxemia if a large PFO is present. Surgical closure of PFO is warranted if the PFO is the thought to be the cause of severe hypoxemia and hemodynamic compromise during LVAD implantation. Perioperative TEE is also helpful to detect air bubbles before the LVAD device is activated. Being lighter than the blood, air bubbles preferentially migrate to the anterior chest wall and along the anterior aortic root and may subsequently cause embolization of the right coronary artery.91 This embolization may result in severe RV dysfunction—a well-known LVAD complication in the early postimplantation setting. TEE is also routinely used in the perioperative setting for evaluation of LVAD function and adjustment of pump speed. Post LVAD implantation, a slightly leftward interventricular and interatrial septal position indicate adequate LV and LA decompression (Figure 4) and (Supplemental Movie 1). Alternatively, a rightward septal shift should arouse the suspicion of suboptimal

LVAD support, and an extreme leftward shift may provide a clue to excessive unloading, RV dysfunction, or significant tricuspid regurgitation. TEE can also help determine the position and alignment of the LV inflow cannula. The LVAD inflow cannula within the LV apex should be oriented aligned with the mitral valve opening and there should be laminar flow from the ventricle to the device. Normal filling velocities are between 1 and 2 m/s, and increased velocities should raise the suspicion of LVAD thrombosis or cannula obstruction (Figure 6).110,111 A small amount of pericardial effusion may result in early tamponade physiology and hemodynamic instability (Supplemental Movie 4). Standard echocardiographic approaches can estimate cannula velocity and, of course, detect pericardial effusions. There are also emerging echocardiographic imaging techniques, including Doppler tissue imaging, GLS, speckle-tracking echocardiography, which are being investigated to assess the performance to LVAD therapy.112,113 The use of echocardiogram to assess valvular function after LVAD implantation is also well established. The development of moderate to severe AR (Figure 5) is a well-known LVAD complication with a prevalence of up to 51% after long-term device implantation.114 The development of AR can result in ineffective device support and end organ malperfusion.115,116 Percutaneous transcatheter aortic valve replacement (TAVR) has been used to treat severe AR (Supplemental Movie 2, 3). In a small study of with five



Figure 6. Evidence of inflow cannula obstruction on transthoracic echocardiogram. 66 year old, asymptomatic male, who had 90 pounds weight loss after HeartMate II LVAD placement resulting in the abnormal angulation of the inflow portion of the LVAD. (A) Four chamber view showing the angle of the inflow cannula and flow (green arrow). (B) Markedly abnormal inflow cannula velocity (3.4 m/s peak systolic) and waveform (pulsatile). Abnormal angulation of the inflow portion of the LVAD was confirmed on the CT scan (Figure 7). Further work up did not show any evidence of pump thrombosis and patient continued to be asymptomatic.

Figure 7. CT images demonstrating the abnormal angulation of the Inflow Portion of the LVAD. 66 year old, asymptomatic male, who had 90 pounds weight loss after HeartMate II LVAD placement resulting in the abnormal angulation of the inflow portion of the LVAD. Transthoracic echocardiogram demonstrated markedly abnormal inflow (Figure 6). CT images (A) and (B) confirms the abnormal angulation of the inflow portion of the LVAD. Further work up did not show any evidence of pump thrombosis and patient continued to be asymptomatic.

patients, Parikh et al demonstrated the relative safety of TAVR to treat severe AR in patients with LVAD.123 However, TAVR in LVAD patients to treat AR is in the very early stage without any long-term, large-scale outcomes prospective studies. Moreover, migration of replaced valve into the ventricle has been seen. The safety and feasibility of TAVR in LAVD patients need further studies in a large cohort with long-term data.

CARDIAC-COMPUTED TOMOGRAPHY IMAGING OF VADS Cardiac-computed tomography (CCT) imaging of VADs, (Figures 8, 9) either with or without x-ray contrast enhancement, is used widely to confirm proper device positioning and to diagnose a long list of potential complications that occur with assist devices.



Figure 8. CT scan Images HeartMate II LVAD. (A) Multiplanar reformation (MPR) CT image showing appropriately placed inflow cannula (yellow arrow) in left ventricular (LV) cavity. (B) Volume rendered CT Image of HeartMate II left ventricular assist device showing the inflow cannula (yellow arrow) and outflow cannula (green arrow).

Figure 9. CT scan Images HeartWare LVAD. (A) Thick maximum intensity projection (MIP) CT image showing appropriately placed inflow cannula (yellow arrow) in left ventrtcular (LV) cavity. (B) Volume rendered CT Image of HeartWare left ventricular assist device showing the inflow cannula (yellow arrow) and pacemaker (green arrow).

CT provides complimentary information to echocardiography. For example, the proper orientation of the left ventricular apical cannula can easily be confirmed on non-contrast CT (Figure 7). Also, complications such as insertion site hematoma with fluid collection can be determined quickly (Figure 10). Body CT imaging is

also, of course, used routinely to diagnose other problems commonly encountered in critically ill patients such as pulmonary embolus, the locations of abscesses, and causes of acute abdomens. In the early post-operative period, image acquisition by TEE is often difficult due to mediastinal air, pleural



Figure 10. LVAD HeartMate II pocket hematoma. (A) Thick maximum intensity projection (MIP) CT IMAGE and (B) Volume rendering after LVAD insertion, CT scan demonstrates a large collection of LVAD pocket hematoma requiring surgical evacuation of the hematoma in the operation room.

effusion, drains, dressings, and limitation of patient positioning imposed by the mechanical ventilation and the ICU setting. Outflow cannulas are often not well visualized with echocardiography due to reverberation artifacts and post-operative changes. Difficulty in imaging the right ventricle by echocardiography is also a common problem in the immediate post-operative period, and accurate assessment of RV function is of great value in determining the need for continuation of inotropic support and RVAD support. Transesophageal echocardiography may address some of the challenges of peri and post-operative image acquisition, and may provide adequate assessment of left and RV function, valvular structure, hemodynamics, chamber thrombus, and ascending and descending aortic root.117 However, TEE is relatively invasive and can be limited by reverberation artifacts and operator variability of image acquisition. Also, the upper ascending aorta is often not clearly visualized on TEE because of a blind spot created by the right major bronchus. Contrast CT imaging overcomes these challenges by providing images free of significant reverberation artifacts. ECG gated CCT image acquisition can delineate the neutral interventricular septal position and a closed aortic valve in systole, indicators of a properly functioning LVAD with appropriate LV unloading. RV failure is a major contributor to morbidity and mortality after LVAD implantation. CCT can provide highly reproducible and accurate assessment of RV function in patients without LVAD.118 CT now appears

to have an emerging role in patients on assist devices. Garcia-Alvarez et al evaluated the feasibility and reproducibility of CCT as a primary imaging modality compared with echocardiography for the assessment of right ventricle (RV) function.119 In thirty-six patients with an implanted LVAD, CCT-quantified RV end-diastolic and end-systolic volumes and ejection fraction were compared with echo-calculated RV FAC, tricuspid annular plane systolic excursion, and RV end-diastolic short-to-long axis ratio. In this study, CCT proved to be highly effective and reproducible for the assessment of RV volumes and function in patients with LVAD support when compared with echocardiography and provided additional relevant post-operative findings such as cannula malposition, thrombus, pericardial effusion, hematoma, and lung infiltrate (Figure 11). Other studies also suggest a potential role of dynamic CT to measure the cardiac output in this patient group.120,121 There is also growing experience in the use of gated CTA in the diagnostic evaluation of patients with suspected LVAD dysfunction. In a small study by Acharya et al,14 patients with suspected LVADs dysfunction underwent CTA and six were found to have malpositioned LV cannula.122 In those patients with normal CTA findings post VAD implantation, the clinical course was stable, demonstrating an encouraging NPV for a normal CTA. However, the cohort was small and data were collected retrospectively. CTA also has limitations in patients with clinical instability and renal insufficiency and there are logistic issues of transporting critical ICU



Figure 11. Calculation of right ventricular volumes with ECG-gated cardiac CT. Examples of RV endocardial tracings (red) to calculate RV end-diastolic and end-systolic volumes in short-axis images by ECG-gated CCT (A), and RV endocardial tracing (green) to calculate RV end-diastolic and end-systolic areas using 2D echocardiography in an apical 4-chamber view (B). Asterisk indicates small pericardial effusion. RV, right ventricle; LV, left ventricle118.

patients to the imaging suite. The Acharya study provided evidence that CTA is safe, feasible, and a useful tool in the management of VAD-related issues, but the number of cases in this report is small. VAD thrombosis is an uncommon, but potentially catastrophic complication and is associated with increased mortality and morbidity.123 The actuarial freedom from device malfunction resulting in device replacement or death due to LVAD thrombosis is 93% at 1 year.124 Monitoring with lactate dehydrogenase (LDH) and plasma-free hemoglobin assessment should be periodically done throughout the duration of MCSD. Echocardiography is the primary modality for evaluation of LVAD thrombosis and increased velocity at the inflow cannula site may be suggestive of early LVAD narrowing from thrombus. Cardiac CT imaging can also be utilized to evaluate the position of the inflow cannula and of the anastomosis of the outflow cannula to the proximal part of ascending aorta.

However, the diagnosis of LVAD thrombosis often proves to be elusive and may require a combination of high clinical suspicion in the setting of elevated LDH [ 600 U/L, plus multimodality evaluation with serial echocardiography and CT images. The optimal treatment of LVAD thrombosis is yet not defined. However, intensification of anticoagulation with high target INR of 2.5-3.5 or adding either clopidogrel or dipyridamole (to routine aspirin) for dual antiplatelet therapy is the initial management strategy at our institution. A low threshold for surgical exchange of the device is considered to be the standard of care in patients who fail medical therapy.125 NUCLEAR CARDIOLOGY IMAGING OF LEFT VENTRICULAR ASSIST DEVICES LVADs were initially approved for use as a bridge to cardiac transplant therapy but are now increasingly being



Figure 12. Cardiac sympathetic imaging with mlBG in heart failure: heart/mediastinal ratio. quantification of cardiac 1123 mlBG heart to mediastinum (H/M) ratio on an anterior view of the thorax. Regions of interest (ROI) are drawn over the heart and medias. (A) Normal cardiac mlBG activity in a patient with HMR: 2.2. (B) Severely decreased cardiac mlBG activity in a patient with HMR:1.1.

utilized as destination therapy. Long-term LVAD support provides mechanical unloading of the myocardium resulting in reversal of the phenotypic changes of heart failure and may lead to reverse remodeling.126 This reverse remodeling varies considerably in individual patients and many unknown factors likely play a role.127 For example, alterations in myocyte geometry and size, up-regulation of cytokines, and changes in beta-receptor density and signaling pathway in the myocardium may contribute to the reverse remodeling.127 Nuclear imaging modality has the ability to capture these molecular changes at the subclinical level. Therefore, nuclear imaging may have a role in determining which patients will develop favorable myocardial remodeling and may have a role in the evaluation of novel therapies aimed at promoting myocardial recovery.128 In the following sections, we will discuss the role of 123I-mIBG and cardiac positron tomography (CT-PET) in the evaluation of patients on VADes. 123

I-MIBG SCINTIGRAPHY

The myocardium of patients with heart failure is characterized by a significant reduction in pre-synaptic norepinephrine (NE) uptake and post-synaptic beta-adrenoceptor density.129,130 This reduction may persist postmechanical circulatory support, and is associated with poor prognosis.131-134 There is some emerging evidence that

Figure 13. Myocardial blood flow of PET Images after complete and partial unloading of the LV during LVAD. PET scans of a healthy volunteer (top), a patient with an LVAD with a partially decompressed ventricle (middle) and a patient with an LVAD and a fully decompressed ventricle (bottom). Both patients had non-ischemic cardiomyopathies. Myocardial blood Flow (MBF) is demonstrated using N-13 ammonia. The scale at the bottom shows lowest flows to the left and highest flows to the right. The fully decompressed ventricle is shown to have significantly reduced MBF, whereas the partially decompressed ventricle has an MBF similar to the normal heart140.


cardiac sympathetic imaging with 123I-mIBG scintigraphy might help with the discrimination of which patients recover intrinsic myocardial function after LVAD support. Cardiac sympathetic activity, primarily expressed as the heart to mediastinal ratio (HM) ratio, reflects the degree of ‘‘denervation’’ of the myocardium (Figure 12), and is an independent prognostic marker in patients with heart failure. 123I-mIBG imaging studies have demonstrated that mechanical support to the failing human heart causes improvement in sympathetic innervation and also reverse the down-regulation of b-adrenergic receptors.135-137 Myocardial sympathetic innervation as assessed by 123I-mIBG scintigraphy is known to be dramatically altered in most LVAD patients (HMR late\1.6 and WR[30%) according to normal cardiac MIBG databases.138 At this time, the exact clinical role of cardiac mIBG is evolving but it may have a role in helping to predict the functional recovery after LVAD support, but much more work is needed. CARDIAC PET IMAGING For evaluation of cardiac ischemia in the patient of CAD, cardiac PET is a well-established, robust, and


reproducible technique. PET techniques can also be used to measure MBF and MPR utilizing one of several isotopes.139 Several interesting studies suggest that PET measures of myocardial flow might also have a role in optimizing VAD therapy. LVAD implantation immediately decreases left ventricular end-diastolic pressure with significant improvement in the mean arterial pressure and should plausibly result in improvement in MBF, reduction in myocardial consumption (MVO2), and subsequent improvement in endothelial function and myocardial remodeling. However, long-term benefits of complete unloading of the left ventricle remain to be seen. Maybaum et al, in a series of 20 patients, demonstrated that partial decompression of the left ventricle increases coronary blood flow more than fully decompressing the ventricle does (Figure 13).140 So far, the majority of the patients with MCSD are on full continuous support with the aim of myocardial reverse remodeling and recovery. An interesting consideration is whether PET measures of MBF might be used clinically to help optimize VAD therapy, including helping to maintain ideal coronary blood flow. PET has the potential to determine the loading condition after LVAD

Figure 14. Driveline Infection of LVAD. A 75 years old male status post HeartMate II implantation in April, 2011. AT 3.2 years, he was treated for drive line infection secondary with Serratia. Pantoea & Candida. However, due to persisted fatigue after treatment, he underwent FDGPET to help with infection localization. The driveline coursing through the skin and abdominal wall is seen on the CT scan MPR view (A) and the CT/PET emission overlay view (B). A fairly intense area of FDG uptake at the course of the driveline through the lower abdominal wall, consistent with infection, is seen on the non-attenuation corrected PET images (C, D). Suboptimal angulation of the cannula in the left ventricular apex is also appreciated on the modified coronal CT image (E). (F) is a volume rendered CT image of the chest showing orientation of the LVAD device.



to optimize the blood flow to myocardium that may, in turn, accelerate myocardial reverse remodeling.

improvements in treatment, survival, and better quality of life for these patients.

USE OF PET IMAGING WITH FDG TO DIAGNOSE VAD INFECTIONS

Disclosure

There is high incidence of sepsis related to the percutaneous drivelines among LVAD patients. In fact, the reported incidence of sepsis was 42% at one year in the REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure Trial).141 MCSD-related infections can be broadly categorized under driveline infections, pumppocket infections and LVAD-associated endocarditis. Ultrasound imaging is usually the first imaging modality applied in an attempt to diagnose for such infections.142 Limited data are available regarding use of Indium-111 WBC scintigraphy and radiolabeled-leukocyte SPECT/ CT to identify LVAD-related infection.143,144 There is emerging evidence that 18F fluorodeoxyglucose (FDG) PET/CT imaging of patients with LVADs may help make an early and accurate diagnosis of LVAD infections. In this setting, the CT images allow the precise localization/registration of the FDG activity. Recently, Kim et al evaluated the potential role of 18F FDG PET/ CT imaging in this patient group and the results appear promising.145 An example case of an LVAD-associated driveline infection diagnosed by FDG PET/CT from our institution is shown in Figure 14. FDG PET/CT imaging may also allow clinicians to monitor the response to therapy. The sensitivity and specificity of this approach for the diagnosis of infection are not known. CONCLUSION The growing population of patients post-cardiac transplantation needs careful follow-up and regular surveillance, especially to detect acute rejection and CAV. While none of the current imaging tools is ideal, several echocardiographic, nuclear, CT, and MR techniques have significant value and considerable progress has being made in recent years. Multimodality imaging techniques are frequently necessary in these patients. Like cardiac transplant patients, those who have undergone LVADs implantation are growing in number and tend to be among the very most complex. Echocardiography and CT imaging with and without contrast have established roles in the management of LVAD patients. CT may also have a limited role in the measurement of cardiac function. Nuclear techniques for coronary flow measurement and for localization of device infection may also prove to be useful in this group of patients. Considerably more developmental work is needed, however, to determine optimal imaging algorithms that lead to incremental

All authors affirm they have no conflicts of interest.

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Arrhythmias in Patients with Cardiac Implantable Electrical Devices after Implantation of a Left Ventricular Assist Device.

Heart transplantation after longest-term support with ventricular assist devices.

Left ventricular assist devices as a bridge to cardiac transplantation.

Stroke Risk and Mortality in Patients With Ventricular Assist Devices.

Improvement in blood glucose control in patients with diabetes after implantation of left ventricular assist devices.

Safety and efficacy of cardiac rehabilitation for patients with continuous flow left ventricular assist devices.

The Impact of Obesity on Patients Bridged to Transplantation With Continuous-Flow Left Ventricular Assist Devices.

Providing emergency care for patients with ventricular assist devices.

External cardiac compression during cardiopulmonary resuscitation of patients with left ventricular assist devices.

Detection of premature ventricular contractions on a ventricular electrocardiogram for patients with left ventricular assist devices.

Ventricular assist devices and increased blood product utilization for cardiac transplantation.

Outcome of cardiac transplantation in patients requiring prolonged continuous-flow left ventricular assist device support.

Ventricular reconditioning and pump explantation in patients supported by continuous-flow left ventricular assist devices.

Management of anticoagulation and antiplatelet therapy in patients with left ventricular assist devices.

Incidence and predictors of cognitive decline in patients with left ventricular assist devices.

Platelet dysfunction and acquired von Willebrand syndrome in patients with left ventricular assist devices.

Incidence, risk, and consequences of atrial arrhythmias in patients with continuous-flow left ventricular assist devices.

Atrial Arrhythmias and Electroanatomical Remodeling in Patients With Left Ventricular Assist Devices.

Hypertension and Stroke in Patients with Left Ventricular Assist Devices (LVADs).

A review of infections in patients with left ventricular assist devices: prevention, diagnosis and management.

Pediatric ventricular assist devices.

Ventricular assist devices.

In-hospital cardiopulmonary arrests in patients with left ventricular assist devices.

Capsule endoscopy in patients with cardiac pacemakers, implantable cardioverter defibrillators and left heart assist devices.