Joerg Stypmann

Left ventricular pressure and volume unloading during pulsatile versus nonpulsatile left ventricular assist device support

BACKGROUND Nonpulsatile axial or centrifugal pumps are the latest generation of left ventricular assist devices (LVAD). Whether left ventricular (LV) unloading and outcome in these devices is similar to pulsatile LVADs during long-term support has not been investigated. We compared LV unloading and mortality between different types of LVAD support (pulsatile versus nonpulsatile). METHODS In 31 patients undergoing long-term LVAD implantation (nonpulsatile = 10, pulsatile = 21) preoperative and postoperative echocardiographic and hemodynamic assessment with right heart catheterization had been obtained. RESULTS All patients had similar echocardiographic, hemodynamic, and clinical heart failure characteristics at baseline. The degree of LV pressure unloading was the same in both device types, caused by similar reduction of mean pulmonary pressure (18.6 +/- 5.1 versus 18.3 +/- 7.5 mm Hg) and pulmonary capillary wedge pressure (8.9 +/- 4.4 versus 8.0 +/- 7.0 mm Hg). Left ventricular volume unloading was pronounced with a pulsatile device owing to a statistically significant higher pump output (5.1 +/- 1.0 L/min) in comparison with nonpulsatile LVADs (3.6 +/- 0.9 L/min, p < 0.001). Echocardiographic-determined end-systolic indicators confirm this augmentation in pulsatile LVADs. Etiology or the time interval of hemodynamic reassessment had no impact in left ventricular pressure unloading, but LV volume unloading decreased between day 60 and 120 in patients with nonpulsatile LVADs. The preoperative and postoperative transplant mortality was comparable in both groups. CONCLUSIONS Left ventricular pressure unloading is similar in patients with nonpulsatile as compared with pulsatile implantable long-term assist devices. Left ventricular volume unloading is pronounced in pulsatile LVADs.

Concordance Among Pathologists in the Second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II)

Background There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs). Methods We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades ≥2R merged because of small numbers). Results Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade ≥2R by at least one were assigned this grade by both. Conclusion The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade ≥2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteria—EMB based or otherwise—that correspond better with the pathophysiology of the transplanted heart.

Adriamycin-induced cardiomyopathy in the dog--an appropriate model for research on partial left ventriculectomy?

OBJECTIVE To evaluate the adriamycin-induced cardiomyopathy in the dog for research on partial left ventriculectomy (PLV). METHODS An intracoronary catheter was introduced into the left main stem via the first diagonal branch in a retrograde fashion in 6 adult FBI (Foxhound Boehringer Ingelheim) dogs weighing 30 to 35 kg. The catheter was connected to a percutaneous access port that was used for weekly adriamycin administration (10 mg over a 1-hour period for 5 times). Follow-up examinations (transthoracic echocardiography, hemodynamic parameters, cardiopulmonary status, and neurohormones) were done before, 1 week after the last adriamycin administration, and 6 weeks later. After the last measurements, all dogs were euthanized with saturated potassium chloride under general anesthesia and the hearts were excised for histologic examinations. All data were calculated as mean values and standard error of the mean. Differences were calculated by the Wilcoxon signed rank test for paired and unpaired data. p values less than 0.05 were considered significant. RESULTS Central venous pressure (2.2 +/- 0.8 vs 5.2 +/- 0.4 mm Hg, p = 0.03), mean pulmonary artery pressure (8.6 +/- 1.1 vs 12.4 +/- 0.5 mm Hg, p = 0.03), pulmonary wedge pressure (2.6 +/- 0.9 vs 7.0 +/- 0 mm Hg, p = 0.03), left ventricular endsystolic diameter (2.5 +/- 0.2 vs 3.1 +/- 0.4 cm, p = 0.03), and enddiastolic (4.5 +/- 0.2 vs 4.9 +/- 0.2 cm, p = 0.03) diameter increased significantly after adriamycin administration, whereas cardiac output (4.0 +/- 0.3 vs 3.3 +/- 0.1 liter/min, p = 0.03), stroke volume index (66.0 +/- 7.4 vs 54.0 +/- 3.9 ml/beat/m(2), p = 0.03), and ejection fraction (61.1 +/- 5.1 vs 37.7 +/- 5.7%, p = 0.03) decreased markedly. These changes were accompanied by a significant decline of oxygen delivery (1130 +/- 170 vs 790 +/- 65 ml/min, p = 0.03), which led to an enhanced oxygen extraction (0.12 +/- 0.01 vs 0.24 +/- 0.01, p = 0.03). Consequently, venous oxygen saturation (82.7 +/- 4.1 vs 71.3 +/- 2.5%, p = 0.03) decreased. Troponin I (0.02 +/- 0.025 vs 1.7 +/- 0.6 ng/ml, p = 0.03) and the anti-diuretic hormone (1.9 +/- 0.9 vs 20.0 +/- 1.9 pg/ml, p = 0.03) increased significantly after adriamycin administration. Deterioration of cardiac function continued after termination of adriamycin administration, albeit slower than during adriamycin administration. All hearts had severe histologic alterations, which were characteristic of adriamycin-induced toxicity: cytoplasmic vacuolation, myocyte degeneration, and increased fibrosis. CONCLUSIONS The adriamycin-induced cardiomyopathy in the dog is similar to the dilated cardiomyopathy in humans and may be an appropriate model for PLV.

Surgical Management of Extensive Lipomatous Hypertrophy of the Right Atrium

Lipomatous hypertrophy of the right atrium is a rare lesion that is usually limited to the interatrial septum. The authors report on a patient that suffered from an extensive lipomatous hypertrophy, which protruded into the right and left atrium as well as the superior vena cava and caused inflow obstruction. Therapeutic management is discussed.

Sex Mismatch in Heart Transplantation Is Associated With Increased Number of Severe Rejection Episodes and Shorter Long-Term Survival

BACKGROUND Heart transplantation is the criterion standard for treating end-stage heart failure. Male sex of both the donor organ and the recipient is advantageous for survival, possibly owing to hemodynamic or immunologic reasons. The effect of sex mismatch on long-term survival in male heart transplant recipients is less known. PATIENTS AND METHODS In this prospective single-center study, we reviewed follow-up data for 57 sex-mismatched and 179 sex-matched men who underwent orthotopic heart transplantation between 1990 and 2002. RESULTS Median survival was significantly shorter in the sex-mismatched group (8.1 vs 12.9 years; P < .04). Subgroup analysis revealed that this was even more pronounced in male heart recipients with coronary artery disease (2.4 vs 12.9 years; P < .001). Female donor organs were significantly smaller (left ventricular end-diastolic diameter 49 vs 51 mm; P < .05), and recipients more often experienced clinically relevant episodes of cellular rejection during the first 3 months posttransplantation (International Society for Heart and Lung Transplantation grade 3, 5.6% vs 3.1%; P < .001). Global left ventricular function, and immunosuppressive and inflammatory parameters did not differ. CONCLUSION In male orthotopic heart transplant recipients, sex mismatch is associated with adverse outcome owing to increased number and severity of episodes of graft rejection.

Vasoactive peptides during long-term follow-up of patients after cardiac transplantation

BACKGROUND Vasoactive peptides are accepted indicators of the degree of heart failure and its progression or improvement following medical therapy. Normalization of cardiac hemodynamics by cardiac transplantation (HTx) may lead to normalization of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) plasma levels shortly after the procedure. METHODS Long-term follow-up was done for 14 consecutive patients, 12 men and 2 women, 49 years of age (range 24 to 64 years). ANP and BNP were measured by radioimmunoassay (RIA) in central venous plasma samples (before breakfast, at steady state) at the following intervals after HTx: 7 to 30 (1), 31 to 60 (2), 61 to 90 (3), 120 to 180 (4) and 210 to 365 (5) days. RESULTS During follow-up, ANP decreased significantly within 2 months after HTx and continued of this level, whereas BNP decreased continuously without reaching normal values. The mean ratio of ANP:BNP increased from 3.23 to 8.01 during follow-up. Whereas right atrial pressure (RAP), right ventricular pressure (RVP), right ventricular end-diastolic pressure (RVEDP) and pulmonary capillary wedge pressure (PCWP) did not change during follow-up, cardiac output (CO) improved slightly, but significantly from 5.21 liters/min to 5.9 liters/min (p = 0.035). CONCLUSIONS Normalization of left ventricular function after orthotopic HTx does not induce an early diminution of ANP and BNP plasma levels to normal concentrations. Although elevated ANP concentrations showed only minimal changes within 1 year, BNP decreased significantly as early as 2 months after HTx, without reaching normal values during the year of follow-up. Also, the ratio of ANP and BNP increased significantly from 3.23 to 8.01. These results demonstrate the contribution of other factors beyond cardiac function that determine the levels of these peptides.

Elimination of norovirus in a chronic carrier under immunosuppression after heart transplantation – effect of everolimus

Dear Sirs, Immunosuppression is a valuable tool to enable transplantation of solid organs, but it is also strongly connected to infectious problems. Susceptibility to bacterial and viral infections, amongst others norovirus, is significantly higher under immunosuppression. Norovirus can be life-threatening in patients after heart-transplantation and is difficult to treat, particularly in chronic carriers. We would like to present the case of a 24-year-old woman who was first admitted to our department in December 2008, when severe postpartal cardiomyopathy was diagnosed. EF was 19% with dyspnoea at rest post partum of her first child, before pregnancy capacity was not restricted at all. Apart from a heparin-induced thrombocytopenia type II, there were no relevant preexisting diseases. At the end of January 2009, an LVAD had to be implanted as bridging to transplant, and there were no signs of recovery of LV-function under full CHF-medication. The patient was discharged during mid of April 2009 and lived at home until she underwent heterotopic heart-transplantation in April 2010. FK506, mycophenolic acid and prednisolone was used as immunosuppression. At the end of December 2010, the patient suffered from an acute norovirus infection with diarrhoea, vomiting and severe weight loss (from 64 to 54 kg). Norovirus was confirmed using qualitative PCR. During the following weeks, the patient continuously suffered from recurrent diarrhoea, and PCR for norovirus was continuously positive, and thus she was chronic carrier for norovirus. At the end of February 2011, immunosuppression was switched to Everolimus + mycophenolic acid + prednisolone because of significant decrease of renal function (reduction of glomerular filtration rate from >60 to minimal 20 ml/min/1.73 m). Under this immunosuppressant regime, diarrhoea stopped. Eight weeks after switching of to Everolimus, PCR for norovirus became negative in several consecutive measurements. Renal function significantly improved within few weeks. Everolimus was well tolerated by the patient. Finally, the mechanism of this action remains unclear and we can only speculate. It is well documented that there is a significant lower rate of cytomegalovirus-infections under everolimus and other proliferation signal inhibitors [1–3]. It has also been shown that this is not because of a direct effect of PSI on viral replication pathways, as there is no relevant effect of PSI in isolated cell-cultures infected with cytomegalovirus [4]. It is generally accepted that the cytomegalovirusreducing effect is because of indirect affection of viral amplification by blocking cellular proliferation and impairing the phosphatidylinositol 3-kinase pathway. In our opinion, this is probably also the mechanism leading to elimination of Norovirus in our patient. In addition, attenuation of immunosuppression might have played a role in viral eradiation. In conclusion, everolimus could – because of this ‘pleiotrophic side effect’ – be a valuable alternative to ‘classical’ immunosuppressive drugs in selected patients early after heart-transplantation with chronic viral infectious problems.

Calcineurin Inhibitor-free Immunosuppression Using Everolimus (Certican) after Heart Transplantation: 2 years' Follow-up from the University Hospital Münster

BACKGROUND Everolimus is a proliferation-signal inhibitor which was introduced for heart transplant recipients in 2004. To date, there are only sparse data about long-term calcineurin inhibitor (CNI)-free immunosuppression using everolimus. METHODS After heart transplantation, patients receiving everolimus were consecutively enrolled. Reasons for switching to everolimus were side effects of CNI immunosuppression, such as deterioration of kidney function and recurrent rejection episodes. All 60 patients underwent standardized switching protocols, 42 patients completed 24-month follow-up. Blood was sampled for lipid status, renal function, routine controls, and levels of immunosuppressive agents. On days 0, 14, and 28, and then every 3 months, echocardiography and physical examination were performed. RESULTS After switching to everolimus, most patients recovered from the side effects. Renal function improved significantly after 24 months (creatinine, 2.1 ± 0.6 vs 1.8 ± 1 mg/dL; P < .001; creatinine clearance, 41.8 ± 22 vs 48.6 ± 21.8 mL/min; P < .001). Median blood pressure increased from 120.0/75.0 mm Hg at baseline to 123.8/80.0 mm Hg at month 24 (P values .008 and .003 for systolic and diastolic pressures, respectively). Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Levels of interleukin-6 were stable between baseline and 24-month levels. Temporary adverse events occurred in 8 patients [13.3%: interstitial pneumonia (n = 2), skin disorders (n = 2); reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3)]. CONCLUSION CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance of heart transplant recipients. Arterial hypertension and renal function significantly improved. CNI-induced side effects, such as tremor, peripheral edema, hirsutism, and gingival hyperplasia, markedly improved in most patients.

Prospective study of everolimus with calcineurin inhibitor-free immunosuppression in maintenance heart transplant patients: results at 2 years.

Background. Few studies have examined everolimus therapy with calcineurin inhibitor (CNI) withdrawal in maintenance heart transplant patients. Methods. In a prospective, single-arm, single-center study, CNI-treated heart transplant patients were converted to everolimus and were followed up for 24 months. The primary endpoints were kidney function and arterial hypertension at 12 and 24 months after conversion. Results. Fifty-eight patients were recruited (mean time posttransplant 5.6±3.7 years), 55 of whom (91.7%) had renal impairment. Mean creatinine clearance increased from 43.6±21.1 mL/min to 49.5±21.2 mL/min at month 24 (P=0.02). Median blood pressure increased from 120/80 mm Hg at baseline to 122.5/80 mm Hg (P=0.008 and 0.006 for systolic and diastolic pressure, respectively). Lipid parameters did not change significantly over the 24-month follow-up. Early resolution of most non-renal CNI-related adverse events was sustained. CNI therapy was re-introduced at a mean of 309 days (range, 31–684 days) in eight patients after month 6 due to adverse events (n=13) or withdrawal of consent (n=2). No significant changes in cardiac function parameters were observed. Conclusions. CNI-free immunosuppression with everolimus is an effective and safe option in selected heart transplant maintenance patients. Most adverse effects under everolimus occurred early after conversion and generally resolved without intervention within a few weeks. Refining selection criteria may reduce the need to re-introduce CNI therapy.

Clinical experience with nine patients supported by the continuous flow Debakey VAD.

Introduction: Pulsatile left ventricular assist devices (LVADs) have been established for bridging of selected patients with advanced congestive heart failure to transplantation. Their clinical application, however, has been complicated by bleeding, thromboembolic and infectious adverse events. Recently, continuous flow LVADs have been introduced. They are expected to be associated with a reduced risk for such complications. Here we report our experience with 9 patients on the continuous flow DeBakey VADTM. Patients and Methods: Since February 2000, 9 patients have been supported by the continuous flow DeBakey VADTM at our institution (all male, 38.6613.1 years, 3 DCM, 3 ICM, 1 congenital, 1 postcardiotomy, 1 myocardial infarction). Before implantation, patients were in severe heart failure (NYHA IV) requiring inotropic support. Cardiac index was 1.6460.49 l/min/m2. All patients fulfilled the requirements for listing to heart transplantation and were put on the waiting list at the time of LVAD implantation. Results: Current total support time (as of October 17, 2000) amounts to 900 patient days (14 2 232 days). One patient was transplanted 226 days following LVAD implantation, six patients are currently still on LVAD support. One patient died on postoperative day (POD) 14 due to multiorgan failure developing following preoperative cardiogenic shock due to myocardial infarction, one patient died on POD 15 after a thrombus generated from the left ventricle had caused the pump to stop. Bleeding complications requiring rethoracotomy occurred in 3 patients. There was no thromboembolic event. No driveline or device infection was observed. Moderate hemolysis was seen in 3 patients. In 4 patients, the LVAD was replaced (POD 76, 76, 137, 170) for another DeBakey VADTM. Device exchanges were associated with thrombus; however, its origin could not be determined. Conclusion: Our experience with the DeBakey VADTM indicates that it is associated with a low risk for bleeding, hemolysis, thromboembolic and infectious complications which makes it a valuable alternative to pulsatile LVADs. Thrombus in the pump may be addressed with improved anticoagulation and platelet inhibition.