Hans B. Lehmkuhl

Noninvasive Diagnosis of Ischemia-Induced Wall Motion Abnormalities With the Use of High-Dose Dobutamine Stress MRI: Comparison With Dobutamine Stress Echocardiography

BACKGROUND The analysis of wall motion abnormalities with dobutamine stress echocardiography (DSE) is an established method for the detection of myocardial ischemia. With ultrafast magnetic resonance tomography, identical stress protocols as used for echocardiography can be applied. METHODS AND RESULTS In 208 consecutive patients (147 men, 61 women) with suspected coronary artery disease, DSE with harmonic imaging and dobutamine stress magnetic resonance (DSMR) (1.5 T) were performed before cardiac catheterization. DSMR images were acquired during short breath-holds in 3 short-axis views and a 4- and a 2-chamber view (gradient echo technique). Patients were examined at rest and during a standard dobutamine-atropine scheme until submaximal heart rate was reached. Regional wall motion was assessed in a 16-segment model. Significant coronary heart disease was defined as >/=50% diameter stenosis. Eighteen patients could not be examined by DSMR (claustrophobia 11 and adipositas 6) and 18 patients by DSE (poor image quality). Four patients did not reach target heart rate. In 107 patients, coronary artery disease was found. With DSMR, sensitivity was increased from 74.3% to 86.2% and specificity from 69.8% to 85.7% (both P<0.05) compared with DSE. Analysis for women yielded similar results. CONCLUSIONS High-dose dobutamine magnetic resonance tomography can be performed with a standard dobutamine/atropine stress protocol. Detection of wall motion abnormalities by DSMR yields a significantly higher diagnostic accuracy in comparison to DSE.

Protection from cytomegalovirus after transplantation is correlated with immediate early 1–specific CD8 T cells

T cells are crucial for the control of cytomegalovirus (CMV) in infected individuals. Although CMV-specific T cells can be quantified by various methods, clear correlates of protection from CMV disease have not been defined. However, responses to the pp65 protein are believed to play an important role. Here, the proportions of interferon γ–producing T cells following ex vivo activation with pools of overlapping peptides representing the pp65 and immediate early (IE)-1 proteins were determined at multiple time points and related to the development of CMV disease in 27 heart and lung transplant recipients. Frequencies of IE-1–specific CD8 T cells above 0.2 and 0.4% at day 0 and 2 wk, respectively, or 0.4% at any time during the first months discriminated patients who did not develop CMV disease from patients at risk, 50–60% of whom developed CMV disease. No similar distinction between risk groups was possible based on pp65-specific CD8 or CD4 T cell responses. Remarkably, CMV disease developed exclusively in patients with a dominant pp65-specific CD8 T cell response. In conclusion, high frequencies of IE-1 but not pp65-specific CD8 T cells correlate with protection from CMV disease. These results have important implications for monitoring T cell responses, adoptive cell therapy, and vaccine design.

Strain and Strain Rate Imaging by Echocardiography – Basic Concepts and Clinical Applicability

Echocardiographic strain and strain-rate imaging (deformation imaging) is a new non-invasive method for assessment of myocardial function. Due to its ability to differentiate between active and passive movement of myocardial segments, to quantify intraventricular dyssynchrony and to evaluate components of myocardial function, such as longitudinal myocardial shortening, that are not visually assessable, it allows comprehensive assessment of myocardial function and the spectrum of potential clinical applications is very wide. The high sensitivity of both tissue Doppler imaging (TDI) derived and two dimensional (2D) speckle tracking derived myocardial deformation (strain and strain rate) data for the early detection of myocardial dysfunction recommend these new non-invasive diagnostic methods for extensive clinical use. In addition to early detection and quantification of myocardial dysfunction of different etiologies, assessment of myocardial viability, detection of acute allograft rejection and early detection of allograft vasculopathy after heart transplantation, strain and strain rate data are helpful for therapeutic decisions and also useful for follow-up evaluations of therapeutic results in cardiology and cardiac surgery. Strain and strain rate data also provide valuable prognostic information, especially prediction of future reverse remodelling after left ventricular restoration surgery or after cardiac resynchronization therapy and prediction of short and median-term outcome without transplantation or ventricular assist device implantation of patients referred for heart transplantation. The Review explains the fundamental concepts of deformation imaging, describes in a comparative manner the two major deformation imaging methods (TDI-derived and speckle tracking 2D-strain derived) and discusses the clinical applicability of these new echocardiographic tools, which recently have become a subject of great interest for clinicians.

Long-Term Results in Patients With Idiopathic Dilated Cardiomyopathy After Weaning From Left Ventricular Assist Devices

Background—Since our first successful left ventricular assist device (LVAD) explantation in a patient with idiopathic dilated cardiomyopathy (IDCM) in 1995, an additional 31 IDCM patients have been weaned in our department. Echocardiographic evaluations during repeated “off-pump” trials were the cornerstone for weaning decisions. After 9 years of experience, we assessed the reliability of our weaning criteria in light of the long-term results. Methods and Results—We evaluated all of the IDCM patients who were weaned between March 1995 and March 2004 with regard to preservation of cardiac function without LVAD support and survival after weaning. Additionally, we reviewed our echocardiographic data to assess their predictive value for long-term stability of cardiac function after weaning. The 32 weaned IDCM patients showed a survival rate of 78.3%±8.1 at 5 years after LVAD explantation. Heart failure (HF) recurred during the first 3 years after weaning in 31.3%. Only 2 patients died because of HF after weaning; the other patients with HF recurrence were successfully transplanted. Off-pump LV end-diastolic diameter >55 mm and/or LVEF <45% before LVAD removal, as well as history of HF ≥5 years before LVAD implantation, appeared to be major risk factors for early recurrence of HF. Patients without any of these 3 risk factors showed no HF recurrence during the first 3 years after weaning, but at the same time, all of those with at least 2 of these 3 risk factors developed early recurrence of HF. In patients with HF recurrence during the first 3 postweaning years, a significant LVEF decrease already occurred during the first month after weaning, whereas in those with long-term stable cardiac function even at the end of the sixth postweaning month, the LVEF was not different from that before LVAD removal. Conclusions—For selected patients with IDCM, weaning from LVADs is a clinical option with good results over >9 years and should, therefore, be considered in those with cardiac recovery after LVAD implantation. Off-pump echocardiographic data are reliable for the detection of LV recovery and prediction of long-term cardiac stability after weaning.

Tricuspid Incompetence and Geometry of the Right Ventricle as Predictors of Right Ventricular Function After Implantation of a Left Ventricular Assist Device

BACKGROUND Implantation of a left ventricular assist device (LVAD) is an established treatment for end-stage heart failure. Right ventricular (RV) dysfunction develops in 20% to 50% of patients after LVAD implantation, leading to prolonged ICU stay and elevated mortality. However, the prediction of RV failure remains difficult. METHODS The pre-operative echocardiographic parameters, tricuspid incompetence (TI), RV end-diastolic diameter (cut-off >35 mm), RV ejection fraction (cut-off <30%), right atrial dimension (cut-off >50 mm) and short/long axis ratio (cut-off >0.6), were analyzed retrospectively in 54 patients. Patients were divided into two groups. One group consisted of patients with RV failure (n = 9), as defined by the presence of two of the following criteria in the first 48 hours after surgery: mean arterial pressure < or =55 mm Hg; central venous pressure > or =16 mm Hg; mixed venous saturation < or =55%; cardiac index 20 units; or need for an RVAD. The other patients comprised the non-RV-failure group (n = 45). RESULTS The RV failure group had a significantly higher short/long axis ratio of the RV (0.63 vs 0.52, p = 0.03; odds ratio 4.4, p = 0.011). For patients with a short/long axis ratio of the RV of <0.6, RV failure occurred in 7% of patients, as compared with 50% for patients with a ratio > or =0.6 (p = 0.013). Among patients with TI Grade III or IV, 75% developed RV failure as compared with 12% in patients with TI Grade I or II (p = 0.054). The odds ratio for RV failure after LVAD implantation for TI Grade III or IV was 4.7 (p = 0.012). CONCLUSIONS Pre-operative evaluation of tricuspid incompetence and RV geometry may help to select patients who would benefit from biventricular support.

Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial.

BACKGROUND Post-transplantation lymphoproliferative disorder (PTLD) develops in 1-10% of transplant recipients and can be Epstein-Barr virus (EBV) associated. To improve long-term efficacy after rituximab monotherapy and to avoid the toxic effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy seen in first-line treatment, we initiated a phase 2 trial to test whether the subsequent use of rituximab and CHOP would improve the outcome of patients with PTLD. METHODS In this international multicentre open-label phase 2 trial, treatment-naive adult solid-organ transplant recipients diagnosed with CD20-positive PTLD who had failed to respond to upfront immunosuppression reduction received four courses of rituximab (375 mg/m(2) intravenously) once a week followed by 4 weeks without treatment and four cycles of CHOP every 3 weeks. In case of disease progression during rituximab monotherapy, CHOP was started immediately. Supportive therapy with granulocyte-colony stimulating factor after chemotherapy was mandatory and antibiotic prophylaxis was recommended. The primary endpoint was treatment efficacy measured as response rates in all patients who completed treatment with rituximab and CHOP, per protocol, and response duration, in all patients who completed all planned therapy and responded. Secondary endpoints were frequency of infections, treatment-related mortality, and overall survival. This study is registered at ClinicalTrials.gov, number NCT01458548. FINDINGS 74 patients were enrolled between Dec 12, 2002 and May 5, 2008, of whom 70 patients were eligible to receive treatment. PTLD was of late type in 53 (76%) of 70 patients, monomorphic in 67 (96%) of 70, and histologically EBV associated in 29 (44%) of 66 cases. Four of 70 patients did not receive CHOP. 53 of 59 patients had a complete or partial response (90%, 95% CI 79-96), of which 40 (68%, 55-78) were complete responses. At data cutoff (June 1, 2011) median response duration in the 53 patients who had responded to treatment had not yet been reached (>79·1 months). The main adverse events were grade 3-4 leucopenia in 42 of 62 patients (68%, 55-78) and infections of grade 3-4 in 26 of 64 patients (41%, 29-53). Seven of 66 patients (11%, 5-21) had CHOP-associated treatment-related mortality. Median overall survival was 6·6 years (95% CI 2·8-10·4; n=70). INTERPRETATION Our results support the use of sequential immunochemotherapy with rituximab and CHOP in PTLD. FUNDING F Hoffmann-La Roche, Amgen Germany, Chugaï France.

Prediction of Cardiac Stability After Weaning From Left Ventricular Assist Devices in Patients With Idiopathic Dilated Cardiomyopathy

Background— During ventricular assist device (VAD) unloading, cardiac recovery is possible even in patients with chronic heart failure (HF). We sought parameters predictive of cardiac stability after VAD removal. Methods and Results— Among 81 patients weaned since March 1995, a homogenous group of 35 with idiopathic dilated cardiomyopathy weaned from left VADs was selected. We evaluated echo data obtained before left VAD implantation and during “off-pump” trials before explantation, histological changes, and serum anti-&bgr;1-adrenoceptor-autoantibody disappearance during unloading, duration of unloading, and HF duration. Postweaning 10-year survival with native hearts reached 70.7±9.2%. During the first 5 years, HF recurred in 13 patients (37.1%). Only 6 (17.1%) died after HF recurrence or noncardiac complications related to left VAD explantation. Comparison of patients with and without long-term cardiac stability showed that stable patients were younger, HF history and recovery time during unloading shorter, and preweaning left ventricular assessment revealed higher left ventricular ejection fraction, lower short/long axis ratios, and higher end diastolic relative wall thicknesses. For left ventricular ejection fraction ≥45% at end diastolic diameter of ≤55 mm, predictive value for ≥5-year cardiac stability was 87.5%. Left ventricular ejection fraction time course during the first 6 postweaning months appeared predictive for long-term stability. HF history >5 years and preweaning instability of cardiac improvement appeared predictive for HF recurrence. Conclusions— In idiopathic dilated cardiomyopathy, left VAD removal can be successful for >12 years even with incomplete cardiac recovery. Pre-explantation left ventricular ejection fraction, left ventricular end diastolic diameter and relative wall thicknesses, stability of unloading-induced cardiac recovery, duration of left VAD support, and HF duration before left VAD insertion allow identification of patients able to remain stable for >5 years. Time course of left ventricular ejection fraction during the first 6 postweaning months allows prognostic assessment.

Everolimus Versus Mycophenolate Mofetil in Heart Transplantation: A Randomized, Multicenter Trial

In an open‐label, 24‐month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced‐dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard‐dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12‐month composite incidence of biopsy‐proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow‐up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: –7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24‐month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12‐month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced‐dose cyclosporine offers similar efficacy to MMF with standard‐dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.

Prognostic Impact of Microvasculopathy on Survival After Heart Transplantation Evidence From 9713 Endomyocardial Biopsies

Background— Epicardial vasculopathy has been shown to be associated with poor outcome after heart transplantation. We demonstrate that histologically proven stenotic microvasculopathy is a novel prognostic factor for long-term survival. Methods and Results— In 9713 biopsies harvested within the first posttransplantation year from 873 patients (83% male; mean age, 49.1±0.6 years), light microscopic evaluations (×200) were performed for microvasculopathy, defined as stenotic endothelial and/or medial disease. Prevalence of severe epicardial vasculopathy was defined by presence of ≥75% luminal stenosis in coronary angiography (available in 611 of 873 patients), which was present in 118 of 611 patients (19%). For Kaplan-Meier analysis, we defined fatal cardiac events as lethal acute myocardial infarction, sudden cardiac death, and graft failure. Stenotic microvasculopathy was present in 379 of 873 patients (43%) and was due to medial (345/379; 91%) rather than endothelial disease (2/379; 1%) or a combination of both (31/379; 8%; P<0.001). Endothelial disease (median [95% CI], 12.07 [10.69 to 13.44] versus 12.73 years [10.16 to 15.30]; P=0.3329) and nonstenotic medial disease (12.44 [11.14 to 13.74] versus 12.43 years [10.51 to 14.35]; P=0.4047) did not decrease overall survival or time to fatal cardiac event. Stenotic microvasculopathy was associated with poor overall survival (10.90 [9.16 to 12.60] versus 13.40 years [11.79 to 15.07]; P=0.0374) and decreased freedom from fatal cardiac events (1, 5, 10 years, 95.6±1.4%, 86.9±2.3%, 75.5±3.1% versus 99.1±0.5%, 96.8±1.0%, 89.8±1.9%; P<0.0001). This finding was independent of epicardial transplant vasculopathy (P=0.0031). Conclusions— Stenotic microvasculopathy is frequent in routinely processed biopsies and a new prognostic factor for long-term survival after heart transplantation.

Heart failure reversal by ventricular unloading in patients with chronic cardiomyopathy: criteria for weaning from ventricular assist devices

Aims Unloading-promoted reversal of heart failure (HF) allows long-term transplant-free outcome after ventricular assist device (VAD) removal. However, because few patients with chronic cardiomyopathy (CCM) were weaned from VADs (the majority only recently), the reliability of criteria used for weaning decisions to predict long-term post-weaning success is barely known. After 15 years of weaning experience, we assessed this issue. Methods and results In 47 patients with CCM as the underlying cause for HF, who were part of a total of 90 patients weaned from bridge-to-transplant-designed VADs since 1995, we analysed data on cardiac morphology and function collected before VAD implantation, echocardiographic parameters recorded during ‘off-pump’ trials, duration of HF before implantation, and stability of recovery before and early after VAD removal. Post-weaning 5 year freedom from HF recurrence reached 66%. Only five patients (10.6%) died due to HF recurrence or weaning-related complications. Pre-explantation off-pump left ventricular ejection fraction (LVEF) of ≥50 and ≥45% revealed predictive values for cardiac stability lasting ≥5 years after VAD removal of 91.7 and 79.1%, respectively. With each unit of LVEF reduction, the risk of HF recurrence became 1.5 times higher. The predictive value of LVEF ≥45% also became >90% if additional parameters like pre-explantation LV size and geometry, stability of unloading-induced cardiac improvement before VAD removal, and HF duration before VAD implantation were also considered. Definite cut-off values for certain parameters (including tissue-Doppler-derived LV wall motion velocity) allowed formulation of weaning criteria with high predictability for post-weaning stability, also in patients with incomplete cardiac recovery. Conclusions Ventricular assist device removal in CCM patients is feasible and can be successful even after incomplete cardiac recovery. Parameters of pre-explantation cardiac function, LV size and geometry, their stability during final off-pump trials, and HF duration allow detection of patients with the potential to remain stable for >5 post-weaning years.