Falk-Udo Sack

Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death

BACKGROUND Cardiac light-chain amyloidosis carries a high risk for death predominantly from progressive cardiomyopathy or sudden death (SCD). Independent risk factors for SCD are syncope and complex nonsustained ventricular arrhythmias. OBJECTIVE The purpose of this study was to test whether prophylactic placement of an implantable cardioverter-defibrillator (ICD) reduces SCD in patients with cardiac amyloidosis. METHODS Nineteen patients with histologically proven cardiac amyloidosis and a history of syncope and/or ventricular extra beats (Lown grade IVa or higher) received an ICD. RESULTS During a mean follow-up of 811 +/- 151 days, two patients with sustained ventricular tachyarrhythmias were successfully treated by the ICD. Two patients underwent heart transplantation, and seven patients died due to electromechanical dissociation (n = 6) or glioblastoma (n = 1). Nonsurvivors more often showed progression of left ventricular wall thickness, low-voltage pattern, ventricular arrhythmias (Lown grade IVa or higher), and higher N-terminal pro-brain natriuretic peptide levels than did survivors. Bradycardias requiring ventricular pacing (VVI 40/min <1%, DDD 60/min 6% +/- 1%) occurred only rarely. CONCLUSION Patients with cardiac amyloidosis predominantly die as a result of electromechanical dissociation and other diagnoses not amenable to ICD therapy. Selected patients with cardiac amyloidosis may benefit from ICD placement. Better predictors of arrhythmia-associated SCD and randomized trials are required to elucidate the impact of ICD placement in high-risk patients with cardiac amyloidosis.

Elevated serum concentrations of cardiac troponin T in acute allograft rejection after human heart transplantation

OBJECTIVES This study evaluates the concept and diagnostic efficacy of using serum troponin T for the detection of cardiac graft rejection. BACKGROUND Cardiac troponin T is a cardiospecific myofibrillar protein, which is only detectable in the circulation after cardiac myocyte damage. It might be expected to be released during acute heart allograft rejection, allowing noninvasive rejection diagnosis. METHODS In 35 control subjects and in 422 samples from 95 clinically unremarkable heart allograft recipients more than 3 months postoperatively, troponin T serum concentrations were compared to the histological grade of acute graft rejection in concurrent endomyocardial biopsies. RESULTS Mean troponin T serum concentrations were identical in control subjects (23.2 +/- 1.4 ng/liter) and in heart transplant recipients without graft rejection (International Society for Heart and Lung Transplantation [ISHLT] grade 0; 22.4 +/- 1.7 ng/liter). Mean troponin T concentrations increased in parallel with the severity of graft rejection (ISHLT grade 1: 27.8 +/- 1.8 ng/liter; grade 2: 33.2 +/- 2.7 ng/liter; grade 3A: 54.6 +/- 6.5 ng/liter; grade 3B and 4: 105.4 +/- 53.7 ng/liter; p < 0.001 for grades 3 and 4 vs. grades 0 and 1). The proportion of positive samples also increased in parallel with rejection severity, reaching 100% in rejections of grade 3B and 4. Sensitivity and specificity for the detection of significant graft rejection (ISHLT grade 3/4) were 80.4% and 61.8%, respectively. The negative predictive value was most remarkable with 96.2%. Intraindividual longitudinal analysis of troponin T levels and biopsy results in 15 patients during long-term follow-up confirmed these findings. CONCLUSIONS The present data demonstrate that acute allograft rejection after human heart transplantation is often associated with increased serum concentrations of troponin T. All cases of serious forms of graft rejection would have been detected before the development of clinical symptoms. Measurement of troponin T levels may become a useful ancillary parameter for noninvasive rejection diagnosis, being most valuable in the exclusion of severe cardiac graft rejection.

Cyclosporine withdrawal improves renal function in heart transplant patients on reduced-dose cyclosporine therapy.

Renal failure is a major cause of morbidity after heart transplantation. It is unclear whether calcineurin inhibitor (CNI) free immunosuppression provides more nephroprotection than low‐dose CNI therapy. Thirty‐nine patients with renal failure on low‐dose cyclosporine A (CsA) were studied (62.9 ± 8.7 years, five female, 8.2 ± 4.3 years posttransplant, serum creatinine: 1.9 ± 0.3 mg/dL, calculated GFR (cGFR): 48.2 ± 18.3 mL/min, CsA C0 level: 64.0 ± 19.9 ng/mL). All patients had been treated with low‐dose CsA >6 months, renal function was stable or slowly decreasing (creatinine 1.7–3.5 mg/dL). Nineteen patients were randomized to discontinuation of CsA and overlapping rapamycin therapy initiation (RAPA), 20 patients continued low‐dose CsA (control). Three patients (16%) discontinued rapamycin medication for side effects (diarrhea, skin rash), two patients developed pneumonia and pulmonary embolism, respectively, no rejection or other infectious complications were seen. After 6 months, renal function in the control group was unchanged. In the RAPA group, renal function markedly improved (creatinine: 2.08 ± 0.15 to 1.67 ± 0.13 mg/dL, cGFR: 48.5 ± 21.4 to 61.7 ± 21.4 mL/min (p < 0.001 within and between groups)). In carefully selected late survivors following heart transplantion who are at low risk of rejection, CNI‐free rapamycin‐based immunosuppression improves cGFR even in those already receiving low‐dose CsA therapy. The results of this study warrant further confirmation in larger clinical trials that are powered to assess clinical outcomes.

Staged heart transplantation and chemotherapy as a treatment option in patients with severe cardiac light-chain amyloidosis

The prognosis of advanced cardiac light‐chain amyloidosis is poor. Heart transplantation might enable causative therapy and ultimately improve prognosis.

Extracellular matrix proteins and matrix metalloproteinases differ between various right and left ventricular sites in end-stage cardiomyopathies

This study was undertaken to investigate whether there might be differences in the distribution of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), depending on their specific sites within the heart. We investigated 33 explanted human hearts, 15 with dilated cardiomyopathy (DCM) and 18 with ischemic cardiomyopathy (ICM). Transmural samples from the right ventricle, the interventricular septum and the left ventricle, either from near the apex or from near the base were taken from every heart. Frozen sections were processed for connective tissue staining and immunohistochemistry for collagens type I, III, IV, laminin and fibronectin, as well as MMP-1, -2 and -9. Volume densities of laminin in ICM as well as of fibronectin and collagen types I and IV in DCM showed significant differences between right and left ventricular sites. The volume densities of matrix proteins usually did not reveal significant differences among the three left ventricular sites tested in both DCM and ICM. MMPs partly showed differences between the right and the left ventricular myocardium. These results suggest that the distributions of ECM proteins and MMPs differ between the two ventricles in both end-stage DCM and ICM. This gives rise to the hypothesis that a specific pattern of ECM degradation exists in the right and left ventricular myocardium.

Risk stratification in cardiac amyloidosis: novel approaches.

Amyloidosis is a term for diseases with extracellular deposition of insoluble beta-fibrillar proteins in different organs. The heart is primarily involved in more than half of patients with immunoglobulin light-chain amyloidosis or hereditary amyloidosis and associated with poor prognosis. Different traditional diagnostic tools that have been described for risk stratification lack of sufficient sensitivity and specificity for patient survival. Until November 2004 in 50 consecutive patients with light chain amyloidosis and 15 patients with hereditary amyloidosis electrocardiography, echocardiography, Holter monitoring, cardiopulmonary exercise test, lung function testing, tilt-test, and laboratory investigations have been performed at our department. Cardiac amyloidosis was found in 32 patients. Interventricular septum (14.3±0.5 mm vs. 12.3±0.7 mm, P<0.05), plasma NT-proBNP (7154±2122 ng/l vs. 380±113 ng/l; P<0.01), cardiac Troponin T (0.105±0.030 vs. 0.019±0.010 &mgr;g/l; P<0.05) were increased in patients with cardiac amyloidosis as compared to patients light chain amyloidosis but no cardiac involvement. Maximal inspiratory (Pimax) and expiratory (Pemax) mouth pressure were decreased with CA compared to controls. Correlation of NT-proBNP and interventricular septum thickness (r=0.53, P=0.029) as well as and Pimax (r=0.72, P<0.01) or Pemax (r=0.69; P<0.01) was noticed. A correlation of grade of arrhythmias in Holter monitoring and syncopes was not observed.Cardiac involvement of amyloid disease carries a poor prognosis and is not well characterized by classic heart failure determinants. Heart transplantation based on novel risk markers including NT-proBNP might be a suitable therapeutic approach for patients with manifest cardiac amyloidosis, but will require alternative patient selection and listing criteria.

Efficacy and Safety of Very Low-Dose Self-Management of Oral Anticoagulation in Patients With Mechanical Heart Valve Replacement

BACKGROUND Self-management improves oral anticoagulation control. Here we provide data of a preplanned interim analysis of very low-dose early self-controlled anticoagulation. METHODS In a prospective, randomized, multicenter trial, 1,137 patients performed low-dose international normalized ratio (INR) self-management with a target INR range of 1.8. to 2.8 for aortic valve replacement recipients and 2.5 to 3.5 for mitral or double valve replacement recipients for the first six postoperative months. Thereafter, 379 patients continued to achieve the aforementioned INR target range (LOW group), whereas the INR target value was set at 2.0 (range, 1.6 to 2.1) for the remaining patients with aortic valve replacement and 2.3 (range, 2.0 to 2.5) for the remaining patients with mitral valve or double valve replacement. One half of this latter group had to check their INR values once a week (VL1 group) the other half twice a week (VL2 group). Patients were followed up for 24 months. RESULTS Beyond study month six, the incidence of thromboembolic events that required hospital admission was 0.58%, 0.0%, and 0.58% in the LOW, VL1, and VL2 groups, respectively (p = 0.368). The incidence of bleeding events per patient-year was 1.16%, 1.07%, and 0.58% in the LOW, VL1, and VL2 groups, respectively (p = 0.665). Mortality rate did not differ among study groups. CONCLUSIONS Data demonstrate the efficacy and safety of very low-dose INR self-management.

Heart rate reduction for 12 months with ivabradine reduces left ventricular mass in cardiac allograft recipients.

Background. Graft denervation in heart transplant recipients causes sinus tachycardia, occasionally requiring pharmacologic heart rate reduction. Currently, no 12-month data regarding effects of the novel If channel antagonist ivabradine on heart rate control, effects on left ventricular mass, tolerability, and safety are available in patients after heart transplantation (HTX). Methods. Mean heart rate, left ventricular mass indexed (LVMI) to body surface area, tolerability, and safety of ivabradine therapy were evaluated at baseline and after 12 months in 30 HTX recipients with marked sinus tachycardia. Results. In three patients (10.0% of total), ivabradine medication was discontinued. Further analysis was based on 27 patients with 12-month drug exposure. Mean patient age was 53.3±11.3 years, and mean time after HTX was 5.0±4.8 years. Mean ivabradine dose was 12.5 mg/day (±3.3 mg). Mean heart rate was reduced from 96.2±8.6 beats per minute (bpm) at baseline to 80.9±8.1 bpm at follow-up (P<0.0001). A statistically significant effect of heart rate reduction on LVMI was observed (104.3±22.7 g at baseline vs. 95.9±18.5 g at follow-up, P=0.04). No statistically significant changes in immunosuppressive drug dosage or blood levels were observed, except from a lower mycophenolate mofetil dose at follow-up (P=0.01). Safety laboratory values were unchanged. No phosphenes were observed. Conclusions. Heart rate reduction with ivabradine is effective and safe in heart transplant recipients. After 12 months, significant effects on LVMI were observed. Therefore, ivabradine may offer a beneficial effect on left ventricular remodelling in HTX patients.

Malignancies After Heart Transplantation: Incidence, Risk Factors, and Effects of Calcineurin Inhibitor Withdrawal

The objectives of the present study were to evaluate the incidence of malignancies and to describe the effects of immunosuppression on survival and recurrence of malignancies after heart transplantation (HTX). Data were analyzed in 211 cardiac allograft recipients, in whom HTX was performed between 1989 and 2005. All of these patients survived for more than 2 years after HTX and received induction therapy with antithymocyte globulin (RATG) guided by T-cell monitoring since 1994. An immunosuppressive regimen consisting of cyclosporine A (CsA) combined with azathioprine was followed by CsA and mycophenolate mofetil (MMF) in 2001; mammalian target of rapamycin (mTOR) inhibitors (everolimus/sirolimus) were used since 2003. Mean patient age at HTX was 51.4 ± 10.5 years; mean follow-up time after HTX 9.2 ± 4.7 years. Overall incidence of neoplasias was 30.8%. Individual risk factors associated with a higher risk of malignancy after HTX were higher age at transplantation (P = .003), male gender (P = .005) and ischemic cardiomyopathy before HTX (P = .04). Administration of azathioprine (P < .0001) or a calcineurin inhibitor (CNI) (P = .02) for more than 1 year was associated with development of malignancy, whereas significantly fewer malignancies were noticed in patients receiving an mTOR-inhibitor (P < .0001). Kaplan-Meier analysis demonstrated a strong statistical trend toward an improved survival in patients with a noncutaneous neoplasia switched to a CNI-free protocol (P = .05). This study demonstrated the impact of a variety of individual risk factors and immunosuppressive drugs on development of malignancy after HTX. Markedly fewer patients with noncutaneous malignancies died after switch to a CNI-free regimen, not quite reaching statistical significance by Kaplan-Meier analysis, however.

White cell-endothelium interaction during postischemic reperfusion of skin and skeletal muscle.

Reperfusion failure after prolonged ischemia is characterized by sequestration of granulocytes within the microvasculature of the ischemic organs and tissues. Leukocytes, activated by tissue trauma, complement factor C5 and/or endotoxin interact with the endothelium surface and eventually emigrate through the vessel wall into the perivascular tissue. Sticking and emigration of polymorphonuclear granulocytes (PMN) is associated with formation of oxygen derived radicals and leakage of plasma through the microvascular walls indicating disturbance of the endothelial barrier function.1,2