Christoph Knosalla

Uric Acid and Survival in Chronic Heart Failure Validation and Application in Metabolic, Functional, and Hemodynamic Staging

Background—Serum uric acid (UA) could be a valid prognostic marker and useful for metabolic, hemodynamic, and functional (MFH) staging in chronic heart failure (CHF). Methods and Results—For the derivation study, 112 patients with CHF (age 59±12 years, peak oxygen consumption [&OV0312;o2] 17±7 mL/kg per minute) were recruited. In separate studies, we validated the prognostic value of UA (n=182) and investigated the relationship between MFH score and the decision to list patients for heart transplantation (n=120). In the derivation study, the best mortality predicting UA cutoff (at 12 months) was 565 &mgr;mol/L (9.50 mg/dL) (independently of age, peak &OV0312;o2, left ventricular ejection fraction, diuretic dose, sodium, creatinine, and urea;P <0.0001). In the validation study, UA ≥565 &mgr;mol/L predicted mortality (hazard ratio, 7.14;P <0.0001). In 16 patients (from both studies) with UA ≥565 &mgr;mol/L, left ventricular ejection fraction ≤25% and peak &OV0312;o2 ≤14 mL/kg per min (MFH score 3), 12-month survival was lowest (31%) compared with patients with 2 (64%), 1 (77%), or no (98%, P <0.0001) risk factor. In an independent study, 51% of patients with MFH score 2 and 81% of patients with MFH score 3 were listed for transplantation. The positive predictive value of not being listed for heart transplantation with an MFH score of 0 or 1 was 100%. Conclusions—High serum UA levels are a strong, independent marker of impaired prognosis in patients with moderate to severe CHF. The relationship between serum UA and survival in CHF is graded. MFH staging of patients with CHF is feasible.

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.

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.

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.

Suppression of Natural and Elicited Antibodies in Pig-to-Baboon Heart Transplantation Using a Human Anti-Human CD154 mAb-Based Regimen

Natural and elicited antipig antibodies (Abs) lead to acute humoral xenograft rejection (AHXR). Ten baboons underwent heterotopic heart transplantation (Tx) from human decay‐accelerating factor (hDAF) pigs. Depletion of anti‐Galα1, 3Gal (Gal) Abs was achieved by the infusion of a Gal glycoconjugate from day – 1. Immunosuppression included induction of antithymocyte globulin, thymic irradiation, and cobra venom factor, and maintenance with a human antihuman CD154 mAb, mycophenolate mofetil, and methylprednisolone; heparin and prophylactic ganciclovir were also administered. Pig heart survival ranged from 4 to 139 (mean 37, median 27) days, with three functioning for >50 days. Graft failure (n = 8) was from classical AHXR [ 4], thrombotic microangiopathy [ 3], or intragraft thrombosis [ 1], with death (n = 2) from pneumonia [ 1], or possible drug toxicity (with features of thrombotic microangiopathy) [ 1]. Anti‐Gal Abs (in μg/mL) were depleted by Gal glycoconjugate before graft implantation from means of 41.3 to 6.3 (IgM) and 12.4–4.6 (IgG), respectively, and at graft excision were 6.3 and 1.7 μg/mL, respectively. No elicited Abs developed, and no cellular infiltration was seen. The treatment regimen was effective in maintaining low anti‐Gal Ab levels and in delaying or preventing AHXR. The combination of costimulatory blockade and heparin with Tx of a Gal‐negative pig organ may prolong graft survival further.

Thrombotic microangiopathy and graft arteriopathy in pig hearts following transplantation into baboons

Abstract:  Background:  Acute humoral xenograft rejection (AHXR) is an immunologic barrier in pig‐to‐baboon organ transplantation (Tx). We report microvascular thrombosis and myocardial necrosis in a series of cardiac xenografts.

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.

Using aortic allograft material to treat mycotic aneurysms of the thoracic aorta

BACKGROUND Although mycotic aneurysms are rare in this age of antibiotics, they nevertheless represent life-threatening lesions of the aortic wall because of their high incidence of rupture and significantly high rate of recurrence. METHODS Between March 1988 and August 1994, cryopreserved allograft material was used to treat 8 patients (mean age, 62.5 years; range, 47 to 80 years) with mycotic aneurysms of the thoracic aorta at our institution. Two patients had emergency operations; the other operations in 6 patients were elective. The aneurysms were located at the previous cannulation site of the aorta (n = 1) or at the donor/recipient aortic anastomosis (n = 1) in the patients who had heart transplantation, in the ascending aorta in 3 patients with aortic valve endocarditis, in the aortic arch in 2, and in the descending aorta in 1. The operative technique consisted of excision of the mycotic aneurysm followed by allograft patch reconstruction in 5 patients, an allograft composite graft replacement of the ascending aorta in 2 patients with endocarditis, and combined aortic allograft root replacement and allograft patch reconstruction of the ascending aorta in 1 patient. RESULTS The underlying infections of the aorta were treated successfully in 6 patients. One heart transplant recipient had reoperation because of recurrent mycotic aneurysm after allograft patch reconstruction at the donor/recipient anastomosis. There was one early death involving a patient with Salmonella sp sepsis. CONCLUSIONS The use of aortic allograft material for repairing mycotic aortic aneurysms is a promising and effective operative concept for managing thoracic aortic infections.

A Randomized Multicenter Trial of Minimally Invasive Rapid Deployment Versus Conventional Full Sternotomy Aortic Valve Replacement

BACKGROUND Minimally invasive surgical procedures (MIS) may offer several advantages over conventional full sternotomy (FS) aortic valve replacement (AVR). A novel class of aortic valve prostheses has been developed for rapid-deployment AVR (RDAVR). We report a randomized, multicenter trial comparing the outcomes for MIS-RDAVR with those of conventional FS-AVR. METHODS A total of 100 patients with aortic stenosis were enrolled in a prospective, multicenter, randomized comparison trial (CADENCE-MIS). Exclusion criteria included ejection fraction below 25%, AVR requiring concomitant procedures, and recent myocardial infarction or stroke. Patients were randomized to undergo MIS-RDAVR through an upper hemisternotomy (n = 51) or AVR by FS with a conventional stented bioprosthesis (n = 49). Three patients were excluded before the procedure, and 3 more patients who were randomized to undergo RDAVR were excluded because of their anatomy. Procedural, early clinical outcomes, and functional outcomes were assessed for the remaining 94 patients. Hemodynamic performance was assessed by an echocardiography core laboratory. RESULTS Implanted valve sizes were similar between groups (22.9 ± 2.1 vs 23.0 ± 2.1 mm, p = 0.9). MIS-RDAVR was associated with significantly reduced aortic cross-clamp times compared with FS-AVR (41.3 ± 20.3 vs 54.0 ± 20.3 minutes, p < 0.001), although cardiopulmonary bypass times were similar (68.8 ± 29.0 vs 74.4 ± 28.4 minutes, p = 0.21). Early clinical outcomes were similar between the two groups, including quality of life measures. The RDAVR patients had a significantly lower mean transvalvular gradient (8.5 vs 10.3 mm Hg, p = 0.044) and a lower prevalence of patient-prosthesis mismatch (0% vs 15.0%, p = 0.013) 3 months postoperatively compared with the FS-AVR patients. CONCLUSIONS RDAVR by the MIS approach is associated with significantly reduced myocardial ischemic time and better valvular hemodynamic function than FS-AVR with a conventional stented bioprosthesis. Rapid deployment valves may facilitate the performance of MIS-AVR.

Plasmapheresis and cyclophosphamide in the treatment of humoral rejection after heart transplantation.

BACKGROUND Clinical reports on humoral rejection after heart transplantation showed that these episodes were often more severe than those mediated through T lymphocytes and that the patients prognosis was significantly worsened. METHODS To evaluate the impact of plasmapheresis on the course of humoral rejection with hemodynamic compromise (HRHC) episodes, we retrospectively investigated the records of 1,108 heart transplant patients. All patients received triple-drug immunosuppression (cyclosporine a, azathioprine, prednisone) and cytolytic antibodies for induction. Between April 1986 and December 1990, HRHC episodes were treated with cortisone boli and cytolytic antibodies for at least 3 days (Group A). Between January 1991 and April 1999, HRHC episodes were treated with cortisone boli, cytolytic antibodies, and plasmapheresis for at least 3 days (Group B). All patients who survived their first HRHC episode received cyclophosphamide instead of azathioprine as maintenance immunosuppression. RESULTS Altogether we observed 29 HRHC episodes. In 11 cases, no therapy could be administered or the therapy regimen did not correspond to either Protocol A or B. In the remaining 18 HRHC episodes, 7 episodes in 7 patients were treated without plasmapheresis (Group A), but only 2 patients survived, whereas in 11 HRHC episodes in 6 patients, therapy included plasmapheresis (Group B) and all patients survived (p = 0.002). Four of 6 patients who received cyclophosphamide after their first HRHC episode experienced at least 1 further HRHC episode. CONCLUSIONS Plasmapheresis seems to improve outcomes in HRHC. However, cyclophosphamide as a maintenance immunosuppressive drug failed to prevent further humoral rejection episodes.