Stephan Schubert

Relationship of Immunosuppression to Epstein–Barr Viral Load and Lymphoproliferative Disease in Pediatric Heart Transplant Patients

BACKGROUND Post-transplant lymphoproliferative disease (PTLD) is a severe complication in transplant recipients. Detection of increased Epstein-Barr viral (EBV) load in the peripheral blood acts as a surrogate marker for increased risk of PTLD development. We prospectively monitored EBV load, immunosuppression and PTLD in pediatric heart transplant (HTx) patients to determine risk factors for an increased EBV load and risk of PTLD. METHODS Forty-one pediatric heart transplant recipients were included and underwent prospective monitoring of their immunosuppression and ethylene-diamine tetraacetic acid (EDTA) blood sampling for EBV load (copies/microg DNA) measurement using quantitative real-time polymerase chain reaction (PCR; TaqMan) during January 2001 to December 2006. RESULTS EBV load was measurable in 70% and was significantly increased (>2,000 copies/microg DNA) in 35% of the patients, with a median EBV load of 5,100 (range 0 to 50,665 copies/microg DNA). Increased EBV load was detected in patients receiving CsA-azathioprine or more than two doses of anti-thymocyte globulin (ATG) and in those <10 years of age, without any significant differences in CsA blood levels. Lowest or negative EBV load was measured in patients receiving CsA-mycophenolate mofetil (MMF) or CsA only. CsA blood levels were not predictable for increased EBV load or PTLD. Six patients developed a EBV-associated B-cell lymphoma (PTLD), among whom 4 (67%) were receiving CsA-azathioprine. CONCLUSIONS Frequent EBV load monitoring identifies patients at high risk for PTLD development. Azathioprine and ATG are major risk factors for increased EBV load and PTLD and patients may benefit from a change of immunosuppression in addition to pre-emptive anti-viral or anti-tumor strategies.

Left ventricular conditioning in the elderly patient to prevent congestive heart failure after transcatheter closure of atrial septal defect

Transcatheter closure of atrial septal defects (ASDs) is a safe and effective treatment. Over the past years, an increasing number of elderly patients (age > 60 years) have been admitted for transcatheter closure to prevent ongoing congestive heart failure from volume overload. However, recent data point to the risk of serious acute left ventricular dysfunction leading to pulmonary edema immediately after surgical or transcatheter ASD closure in some patients. In this study, we used a technique described before to recognize in advance patients at risk of left heart failure after ASD closure. Those patients at risk were then treated with preventive conditioning medication for 48–72 hr before definitive transcatheter ASD closure was performed. Fifty‐nine patients aged over 60 years (range, 60–81.8 years; median, 68 years) were admitted to our institution for transcatheter closure of an atrial septal defect. All patients received evaluation of atrial pressures before and during temporary balloon occlusion of the ASD. Patients with left ventricular restriction due to increased mean atrial pressures (> 10 mm Hg) during ASD occlusion received anticongestive conditioning medication with i.v. dopamine, milrinone, and furosemide for 48–72 hr before definitive ASD closure with an Amplatzer septal occluder was performed. In 44 patients without any signs of left ventricular restriction, ASD closure was performed within the first session. Fifteen (25%) out of 59 patients showed left ventricular restriction. In the majority of patients with LV restriction, the mean left atrial pressures with occluded ASD were significantly decreased after 48–72 hr of conditioning medication. Definitive ASD closure was then performed in a second session. Only two patients received a fenestrated 32 mm Amplatzer occluder due to persistent increased atrial pressures > 10 mm Hg even after conditioning medication. There were no significant differences in shunt, device size, or defect size between the two groups. Balloon occlusion of atrial septal defects identifies patients with left ventricular restrictive physiology before ASD closure. Intravenous anticongestive conditioning medication seems to be highly effective in preventing congestive heart failure after interventional closure of an ASD in the elderly patient with a restrictive left ventricle. Catheter Cardiovasc Interv 2005;64:333–337.

Transcatheter therapy of long extreme subatretic aortic coarctations with covered stents

We report our experience with the transcatheter treatment of long extreme subatretic coarctations in four adult patients by the implantation of covered stents. The minimal narrowing of the stenosis was 0.014″ to 2 mm; the hypoplastic distance measured between 21 and 42 mm. Polytetrafluoroethylene‐covered stents 39–50 mm long were implanted and 6 months later redilated. Residual pressure gradients ranged from 0 to 10 mm Hg. One stent fracture required the implantation of a second stent after 6 months. The follow‐up period ranges from 18 to 4 months and has been uneventful so far. Covered stents seem to have the potential to extend the limits of interventional therapy to extreme forms of aortic coarctations. Catheter Cardiovasc Interv 2004;63:236–239.

Transcatheter Tricuspid Valve-in-Valve Implantation for the Treatment of Dysfunctional Surgical Bioprosthetic Valves: An International, Multicenter Registry Study.

Background— Off-label use of transcatheter aortic and pulmonary valve prostheses for tricuspid valve-in-valve implantation (TVIV) within dysfunctional surgical tricuspid valve (TV) bioprostheses has been described in small reports. Methods and Results— An international, multicenter registry was developed to collect data on TVIV cases. Patient-related factors, procedural details and outcomes, and follow-up data were analyzed. Valve-in-ring or heterotopic TV implantation procedures were not included. Data were collected on 156 patients with bioprosthetic TV dysfunction who underwent catheterization with planned TVIV. The median age was 40 years, and 71% of patients were in New York Heart Association class III or IV. Among 152 patients in whom TVIV was attempted with a Melody (n=94) or Sapien (n=58) valve, implantation was successful in 150, with few serious complications. After TVIV, both the TV inflow gradient and tricuspid regurgitation grade improved significantly. During follow-up (median, 13.3 months), 22 patients died, 5 within 30 days; all 22 patients were in New York Heart Association class III or IV, and 9 were hospitalized before TVIV. There were 10 TV reinterventions, and 3 other patients had significant recurrent TV dysfunction. At follow-up, 77% of patients were in New York Heart Association class I or II (P<0.001 versus before TVIV). Outcomes did not differ according to surgical valve size or TVIV valve type. Conclusions— TVIV with commercially available transcatheter prostheses is technically and clinically successful in patients of various ages across a wide range of valve size. Although preimplantation clinical status was associated with outcome, many patients in New York Heart Association class III or IV at baseline improved. TVIV should be considered a viable option for treatment of failing TV bioprostheses.

MRI-based computational fluid dynamics for diagnosis and treatment prediction: clinical validation study in patients with coarctation of aorta.

To reduce the need for diagnostic catheterization and optimize treatment in a variety of congenital heart diseases, magnetic resonance imaging (MRI)‐based computational fluid dynamics (CFD) is proposed. However, data about the accuracy of CFD in a clinical context are still sparse. To fill this gap, this study compares MRI‐based CFD to catheterization in the coarctation of aorta (CoA) setting.

Self–fabricated fenestrated Amplatzer occluders for transcatheter closure of atrial septal defect in patients with left ventricular restriction: midterm results

SummaryTo avoid left ventricular failure after transcatheter closure of atrial septal defects in elderly patients with restrictive left ventricular physiology, partial occlusion by fenestrated devices may be an option. If complete defect closure is not possible in these patients, significant reduction of left to right shunting usually results in clinical benefit. We report two patients in whom deterioration of left ventricular function could be avoided by implantation of self–fabricated fenestrated Amplatzer Septal Occluders (ASO) in patients with ongoing restrictive left ventricular physiology. We describe technical preparation of the standard occluder, the specific implantation technique, and the initial and the intermediate term results up to 24 months.

Percutaneous Tricuspid Valve Implantation: Two-Center Experience With Midterm Results

Background—Severe tricuspid valve (TV) dysfunction may lead to surgical TV replacement with a biological valve prosthesis in patients with congenital heart disease. To expand the lifetime of this valve and reduce the number of surgeries, percutaneous TV implantation (PTVI) may be an effective alternative to repeated surgery. We report on our 2-center experience with PTVI. Methods and Results—Between 2008 and 2014, 17 percutaneous valves were implanted in 16 patients with TV bioprosthesis dysfunction (9 females) from 2 centers. Median age and weight were 31.3 years (5–77.2) and 65.2 kg (17.7–107); 14 patients had congenital heart disease (univentricular heart with a right atrial to right ventricle bioprosthesis in 3, Ebstein’s anomaly of the TV in 5, and other in 6), and 2 had acquired TV dysfunction. All procedures were successful (Melody n=7, Sapien 26 mm valve n=4, Sapien XT 29 mm valve n=6). One valve showed early dysfunction. It was replaced surgically and shortly after that a repeated PTVI was performed. The median duration of follow-up was 2.1 years (3 days to 6.3 years). The percutaneous valve was performing well in 15 of 16 patients. Conclusions—PTVI was safe and effectively improved TV function in all but 1 patient at midterm follow-up. We think that PTVI is a good alternative to repeated surgical TV replacements and that it may reduce the total number of open heart surgeries in these patients.

Pressure Fields by Flow-Sensitive, 4D, Velocity-Encoded CMR in Patients With Aortic Coarctation

This study compared pressure fields by 4-dimensional (4D), velocity-encoded cine (VEC) cardiac magnetic resonance imaging (CMR) with pressures measured by the clinical gold standard catheterization. Thirteen patients (n = 7 male, n = 6 female) with coarctation were studied. The 4D-VEC-CMR pressure fields were computed by solving the Pressure-Poisson equation. The agreement between catheterization and CMR-based methods was determined at 5 different measurement sites along the aorta. For all sites, the correlation coefficients between measures varied between 0.86 and 0.97 (p < 0.001). The Bland-Altman test showed good agreement between peak systolic pressure gradients across the coarctation. The nonsignificant (p > 0.2) bias was +2.3 mm Hg (± 6.4 mm Hg, 2 SDs) for calibration with dynamic pressures and +1.5 mm Hg (± 4.6 mm Hg, 2 SDs) for calibration with static pressure. In a clinical setting of coarctation, pressure fields can be accurately computed from 4D-VEC-CMR-derived flows. In patients with coarctation, this noninvasive technique might evolve to an alternative to invasive catheterization.

Pediatric heart transplantation: 23-year single-center experience.

OBJECTIVE Early and late mortality have significantly improved during recent decades in pediatric patients after heart transplantation (HTx). Nevertheless early and late morbidity and mortality are influenced by acute rejection, cardiac allograft vasculopathy (CAV), malignancy, renal failure, and graft failure. METHODS We evaluated our results after HTx in children under the age of 18 years with 23 years of follow-up. Perioperative characteristics, probability of survival, and time-related morbidity were retrospectively analyzed. RESULTS We included 169 pediatric HTx recipients, transplanted between 05/1986 and 05/2010. One hundred and one were males with a median age of 8.7 (0.02-23.2) years at the time of HTx. Main preoperative diagnoses were cardiomyopathy (CMP) (n = 139) with a median survival of 7.0 (0-23.2) years and congenital heart disease (CHD) (n = 30), median survival 11.3 (0-19.9) years. Overall survival at 1, 5, 10, and 15 years was 87%, 76%, 68%, and 50%, respectively. Patient survival was significantly reduced in patients with 0-1 year at the time of HTx versus 1-10 and 11-18 years: 2.3 (0-13.2) years versus 1-10 years = 8.6 (0-23.2) years; 11-18 years = 5.9 (0.003-18.5) years. Fifty-one patients were on mechanical circulatory support as a bridge-to-HTx with increased early but not late mortality. Ten patients underwent retransplant due to acute or chronic graft failure after a median posttransplant time of 12.25 (0.3-17.45) years. Late mortality was influenced by rejection, infection, posttransplant lymphoproliferative disease (PTLD) (11.8%), or CAV with an incidence of 25% at 5 years, 50% at 10 years, and approximately 75% at 15 years. CONCLUSIONS Pediatric HTx is a safe and effective treatment for terminal heart failure. In our experience, there is no adverse effect of previous cardiac assist device implantation in long-term follow-up. Virtually all anatomic malformations are amenable to orthotopic HTx. Significant progress has been achieved in controlling rejection through improved immunosuppression and noninvasive rejection monitoring.

Comparison of the Tissue Doppler-Derived Left Ventricular Tei Index to that Obtained by Pulse Doppler in Patients with Congenital and Acquired Heart Disease

We compared the left ventricular Tei index measured by tissue Doppler imaging (TDI) to that obtained by pulsed Doppler (PW) in patients with congenital heart disease. In 40 consecutive patients with a variety of congenital and acquired heart diseases, the left ventricular (LV) PW Doppler-derived Tei index was assessed on-line as previously described. TDI-derived anatomic curved M-mode and the unprocessed velocity trace from the basal septum were used to time the opening and closure of the mitral and aortic valves in one cardiac cycle, respectively. The TDI Tei index was calculated off-line according to the equation (isovolumetric relaxation time + isovolumetric contraction time)/ ejection time. The Tei index calculated from TDI correlated significantly with that measured by pulsed Doppler (r = 0.92, p = 0.001). The mean difference (range) between pulsed Doppler-derived Tei index and TDI-derived Tei index was 0.005 (−0.07–0.06), which was within the limits of agreements. Interobserver variability for the TDI-derived Tei index was 5 ± 3%. The TDI Tei index can be used to assess the global LV function in patients with congenital heart disease. In contrast to the PW Doppler-derived Tei index, the TDI-derived Tei index obtained from the same cardiac cycle may help to differentiate systolic from diastolic dysfunction by providing specific information on the isovolumetric intervals.