Clinical, haemodynamic and echocardiographic features of early cardiac graft dysfunction.

BACKGROUND: The main cause of early death after heart transplantation (HTx) is so-called early primary or secondary graft failure (GF). The risk of profound GF has not declined in the past decade, as the consequence of the liberalisation of donor acceptance criteria because of the scarcity of donors. It is therefore important to try to diagnose graft failure and recognise the mechanisms of early graft dysfunction. AIM: To establish haemodynamic and echocardiographic criteria of early GF to define patients who should be considered for assist device support or re-transplantation. METHODS: Between January 2000 and March 2009, 116 HTx patients were studied. On the basis of echocardiography and continuous invasive monitoring, three groups were identified: (1) The true graft failure group (GF) consisted of 46 patients; (2) The latent right ventricular (RV) dysfunction group (RV-D) consisted of 25 patients with small left ventricular (LV) chamber (〈 39 mm) and RV ejection fraction (RVEF) 〈 50%; (3) The control group consisted of 45 consecutive HTx patients without any haemodynamic complications. RESULTS: Postoperatively, only the GF group required large doses of norepinephrine (〉 0.3 µmg/kg/min) and inhalative NO (40 ppm). Nevertheless, right and left filling pressures were significantly higher than in the controls (right 12 ± 3.6 vs. 9.0 ± 2 and left atrial pressure 13.0 ± 3.2 vs. 9.6 ± 2 mm Hg, both p 〈 0.001). Cardiac index was significantly smaller (2.9 ± 0.7 vs. 3.7 ± 0.9, p 〈 0.001) but neither pulmonary artery pressure (29.5 ± 6 vs. 29.7 ± 7 mm Hg) nor transpulmonary gradient (6 ± 5 vs. 5.1 ± 5 mm Hg) nor pulmonary vascular resistance (273 ± 97 vs. 287 ± 144 dyn × s × cm-5) differed significantly from those of the control group. In the GF group, LV end diastolic dimension (LVEDD) was significantly smaller and function poorer than in controls (39.8 ± 5 vs. 44.4 ± 5 mm, respectively, p = 0.001). RV function was also significantly worse (RVEF 42.2 ± 14% vs. 56.0 ± 9%), respectively, p = 0.001), whereas RV dimension did not differ significantly. Mechanical support after failure of the initial medical treatment was necessary in 37% of patients; 29 (63.0%) patients from the GF group died, the cause of death being sepsis with multi-organ failure. In the RV-D group, remodelling was quite similar but LVEF was excellent and maximal systolic velocity from the posterior wall was significantly higher than in GF. No death occurred. CONCLUSIONS: True early GF represents a grave haemodynamic situation with high mortality. Bedside echocardiography helps to distinguish between latent RV dysfunction and true GF.

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.

Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients.

OBJECTIVE: Conflicting data still exist concerning the reversibility of secondary severe 'fixed' pulmonary hypertension (PH) by the use of left ventricular assist device (LVAD) support in terms of time necessary to provide a bridge to 'transplantability'. METHODS: We retrospectively reviewed 145 patients with heart failure and severe PH treated by LVAD support between 2000 and 2009. There were 133 men (91.7%) and 12 women (8.3%) with a mean age of 52.95±12.01 years. Patients were divided into two groups depending on preoperative PH reversibility. Fixed PH was defined by a mean pulmonary arterial pressure (mPAP) >25 mmHg, a pulmonary vascular resistance (PVR) >2.5 Wood Unit (WU) and a transpulmonary gradient (TPG) >12 mmHg, despite pharmacological treatment. RESULTS: Fifty-six patients had fixed PH (group A) and 89 reversible PH (group B). Only 27 patients of group A underwent right heart catheterization evaluation during LVAD support; the remaining 29 patients had other contraindications to heart transplantation (HTx). The 27 patients were divided into three subgroups on the basis of examination time during LVAD support: <6 months (11 patients), between 6 and 12 months (six patients) and >12 months (10 patients). The mPAP, PVR, and TPG decreased significantly during LVAD support (mPAP, 37.26±6.35 mmHg vs 21.00±7.51 mmHg, p=0.007; PVR, 3.49±1.47 WU vs 1.53±0.66 WU, p=0.000; and TPG, 15.04±5.22 mmHg vs 7.78±3.21 mmHg, p=0.019). A significant reduction of all parameters was observed during the first 6 months and later on there was no further decrease. There were no significant differences between the three subgroups (mPAP, p=0.680; PVR, p=0.723; and TPG, p=0.679) in terms of time of reversibility. LVAD support allowed 19 patients to be transplanted. CONCLUSIONS: Patients with fixed PH can be treated with LVAD support. Our data suggest that 6 months after LVAD implantation it is possible to observe an important reduction of PH and evaluate the potential transplantability of patients. Longer support does not add any effect of LVAD on PH.

Long-term mechanical circulatory support in 198 patients: largest single-center experience worldwide.

During recent years, mechanical circulatory support (MCS) devices have been increasingly used for long-term support. Nevertheless, problems of embolic and bleeding complication, infections, and technical failure still inhibit successful permanent support. We analyzed the courses of 198 patients who were supported for >1 year by 12 different MCS devices. Of the 198 patients, 87 had first-generation MCS devices (pulsatile), 43 second-generation devices (nonpulsatile with standard bearings), and 68 third-generation devices (nonpulsatile with magnetic bearings), implanted between July 1994 and March 2009. The mean time on support of the total group was ∼ 2 years (690 ± 321 [366-1,875] days). Of the first generation, 83 patients (95%) could be discharged; in the second and third group, all patients could be discharged. Rehospitalizations were observed in all patients. Reasons for readmission were coagulation disorders, wound infections, stroke, and technical failure. Seventy-seven patients received heart transplantation, 66 are still receiving support, 53 died, and two patients have been weaned from the device. All types of devices can be used for extended periods of time. Device- and nondevice-related rehospitalizations were observed in all three groups of patients. Close outpatient monitoring and support are crucial to ensure good long-term results.

Left ventricular assist device or heart transplantation: impact of transpulmonary gradient and pulmonary vascular resistance on decision making.

OBJECTIVES: Fixed pulmonary hypertension is a contraindication for heart transplantation. Left ventricular assist device support may lower it and bridge patients to heart transplantation. The aim of the study was to investigate the optimal parameters for treatment decisions and the time course of their potential reversal to normal values during preoperative inotropic support. METHODS: Mean pulmonary arterial pressure, pulmonary vascular resistance and transpulmonary gradient were retrospectively analysed in 120 heart failure patients with severe pulmonary hypertension (mean age 51.7 ± 1.1 years, 93.3% males) treated between 2000 and 2009 with inotropes before left ventricular assist device implantation. The population was divided into three groups: patients with mean pulmonary arterial pressure > 25 mm Hg (group A, n = 113), patients with pulmonary vascular resistance > 2.5 Wood units (WU) (group B, n = 75) and patients with transpulmonary gradient > 12 mm Hg (group C, n = 55). Patients could be assigned to more than one group. RESULTS: After 24h of inotropic support, pulmonary vascular resistance decreased (4.1 ± 0.2 to 3 ± 0.1, -25%, p<0.001), as did the transpulmonary gradient (17 ± 0.5 to 14 ± 0.7, -18%, p < 0.001). There was no significant decrease of mean pulmonary arterial pressure. Fifty percent of patients presented transpulmonary gradient < 12 mmHg on the 3rd day and pulmonary vascular resistance < 2.5 WU on the 4th day. No further changes were observed in the following days. Left ventricular assist device support allowed 63 patients to be listed for heart transplantation and 40 received transplantation. A 30-day mortality after heart transplantation was higher in patients with fixed pulmonary hypertension, despite inotropes, than in those with reversible hypertension in groups B and C (12.5% and 11.1% vs 0%, respectively). CONCLUSIONS: Transpulmonary gradient and pulmonary vascular resistance, but not mean pulmonary arterial pressure, are predictive parameters for successful heart transplantation in cases of severe postcapillary pulmonary hypertension. When no significant decrease in pulmonary vascular resistance and transpulmonary gradient after 3-4 days of pharmacological therapy is observed, mechanical circulatory support is the only option to bridge end-stage heart failure patients to heart transplantation. Survival after heart transplantation is strictly related to the reversibility of pulmonary vascular resistance and transpulmonary gradient before assist implantation, but not related to mean pulmonary artery pressure.

Impact of different long-term maintenance immunosuppressive therapy strategies on patients' outcome after heart transplantation.

The introduction of cyclosporine in the early 1980s meant a decisive improvement in post-transplant outcomes for all solid-organ transplants and, in particular, it allowed heart transplantation to emerge as a viable therapeutic option for patients with end-stage cardiac failure. Many factors, including recipient and donor selection, organ preservation and the technical aspects of the transplant itself, influence post-operative outcomes following heart transplantation but the continued need to treat the recipient's immune response plays a key role in determining long-term outcomes. Thereby interactions between immunosuppressive drugs used in different combinations play an important role in patients' outcome. After more than two decades, significant controversy still exists as to the best immunosuppressive regimen for long-term maintenance. During the 1990s and 2000s, newer immunosuppressive medications, specifically, tacrolimus, mycophenolate mofetil, sirolimus, everolimus and the IL-2 receptor blockers (daclizumab and basiliximab), were introduced that allow the clinician several options to try to minimize side effects and maximize the desired therapeutic effects. The side effects involve direct organ toxicity (e.g. renal and hepatic dysfunction), metabolic disturbances, (e.g. diabetes, hyperlipidemia and hypertension), neurotoxicity, and several other significant adverse events, such as cholestasis and myelosuppression. Newer immunosuppressive drugs can impair wound healing, induce lung toxicity and produce various cytopenic states. Steroids continue to plague patients with their well-known side effects. This article reviews the current data on the benefits and risks of the various therapeutic regimens available, which are analyzed under three main themes: calcineurin inhibitor based therapies, calcineurin minimization protocols and calcineurin free regimens.

Mechanical circulatory support in patients of advanced age.

AIMS: In recent years, non-pulsatile assist devices have been increasingly used for long-term circulatory support. However, it remains to be established whether pulsatile and non-pulsatile systems can ensure a similarly low rate of complications for extended periods of time in elderly patients. METHODS AND RESULTS: Of 174 patients implanted between June 1991 and January 2009 [mean age: 65 +/- 3.7 (60-80) years], 64 were on pulsatile (39 Berlin Heart EXCOR, 18 Novacor, 4 LionHeart, and 3 HeartMate I) and 110 on non-pulsatile assist devices (65 Berlin Heart INCOR, 18 DeBakey, 14 HeartMate II, 7 DuraHeart, and 6 Jarvik2000). In the pulsatile group, the mean support time was 157 +/- 343 (1-1836) days, and in the non-pulsatile group 281 +/- 336 (1-1619) days (P < 0.05). The 1-year survival was 15% in the pulsatile group and 36% in the non-pulsatile group, and 2-year survival was 12 and 26%, respectively (P < 0.05). In the pulsatile group, 11 patients (17%) were supported for >6 months, 7 patients (11%) for >1 year, and 3 patients (5%) for >2 years, and 3 patients underwent heart transplantation, 3 were weaned, and 3 still have a device. In the non-pulsatile group, 46 patients (42%) were supported for >6 months, 34 (28%) for >1 year, and 14 (13%) for >2 years, and 17 patients are still on support, 9 underwent transplantation, and 3 were weaned. CONCLUSION: Although both types of device can be used for extended periods of time, non-pulsatile systems have a significantly higher survival rate in elderly patients. They allow elderly patients additional years of life in their familiar environment.

Heart transplantation in women with dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is responsible for over half of all heart transplants. Fewer women with DCM undergo heart transplants than men with DCM; the reasons for this state of affairs are unclear. METHODS AND RESULTS: We analyzed prospectively a cohort of 698 DCM patients who were referred to our heart transplant center. Only 15.5% of them were women. Women and men did not differ in age or ejection fraction (24%). Women were more frequently in New York Heart Association class III-IV, had lower exercise tolerance, worse pulmonary function, and poorer kidney function (all P<0.05) than men. Women were less commonly diabetic (14% vs. 23%; P<0.05). Similar percentages of women and men who were referred were transplanted; the women spent less time on the waiting list (153+/-37 days for women and 314+/-29 days for men; P<0.05). The 10-year survival rate of women and men after transplantation was similar (57% and 45%, respectively; P<0.203). We compared our current data to our overall experience from 1985 till date (n=972), and also with the Eurotransplant heart dataset. Similar to our current findings, far lower percentages of DCM patients in both cohorts were women, although the 10-year survival of female and male DCM patients after transplantation was not different. CONCLUSIONS: Because women were referred with more severe heart failure but fewer relative contraindications, it seems that the option of transplantation is less intensely considered for women, particularly for those with comorbidities, by the referring physicians. Because women with DCM do as well as men after transplantation, efforts should be undertaken to improve referral of women.

Quilty in biopsy is associated with poor prognosis after heart transplantation.

We tested if Quilty (endocardial infiltration of lymphocytes) in routinely processed endomyocardial biopsy is associated with poor outcome after heart transplantation (HTx). Biopsies (n=9829) harvested within the first post-transplant year from 938 patients (778 men, mean age 49 years) were evaluated for Quilty and acute cellular rejection (according to the International Society for Heart and Lung Transplantation, ISHLT, classification). Transplant vasculopathy was evaluated by coronary angiography, and severe stenosis was found in 19% of patients. Survival was tested by Kaplan-Meier and Cox regression analyses for all-cause mortality and major cardiac events (lethal acute cellular rejection, graft loss or myocardial infarction). We found 1840 (19%) Quilty-positive biopsies in 487 Quilty-positive patients (52%). Quilty was more prevalent in women (p=0.038) and younger men (p=0.001), and was correlated with ISHLT grade 1R (OR 1.45, 95% CI 1.36-1.55; p<0.001) and ISHLT grade 2R (OR 2.48, 95% CI 2.21-3.41; p<0.001). Quilty in any biopsy was associated with a higher all-cause mortality (log rank p=0.045) due to a higher risk for major cardiac event (p=0.0001). Multivariate regression analysis showed Quilty (RR 1.69, 95%CI 1.05-2.73) and transplant vasculopathy (RR 2.78, 95%CI 1.68-4.61) as risk factors for major cardiac events and treated hyperlipidemia as lowering the risk for major cardiac events (RR 0.47, 95%CI 0.28-0.77). Quilty is associated with graft loss and poor outcome post HTx. Index biopsy during the first post-transplant year is a useful tool to identify patients at risk and is recommended during routine post-transplant management.

Coronary flow reserve measurement detects transplant coronary artery disease in pediatric heart transplant patients.

BACKGROUND: Cardiac allograft vasculopathy (CAV) in patients who have undergone heart transplantation leads to graft dysfunction and is still the major concern for long-term survival. Evaluation of coronary flow velocity reserve (CFR) has been established for diagnosis of CAV. Systemic application of adenosine vs intracoronary testing for CFR has been validated in adults; however, its accuracy in pediatric patients has not yet been proven. METHODS: CFR was prospectively measured in 33 clinically asymptomatic pediatric heart transplant recipients. CFR measurements were made in the left anterior descending (LAD) artery using a 0.014-inch Doppler FloWire (Cardiometrics). CFR was defined as the ratio of hyperemic (after adenosine injection) to basal (before adenosine) average peak velocity (APV). Adenosine (Adrekar) was administered by intracoronary (15 or 30 mug bolus) and systemic (0.1 mg/kg) injection in each patient. Epicardial CAV was evaluated in coronary angiograms (Stanford criteria) and microvasculopathy was diagnosed in endomyocardial biopsies (evidence of luminal stenosis) blinded to clinical data. RESULTS: Thirty-three patients were included in this study. Their median age (range) was 11.9 (1.4 to 17) years and median post-transplant time 4.3 (1 to 11.7) years. Seventeen of the 33 patients had epicardial CAV (mainly peripheral obliterations or B1 and B2 lesions) and microvascular CAV. Epicardial CAV only was found in 4 patients and microvasculopathy only was present in only 1 patient. CFR was significantly reduced in patients with epicardial CAV and microvasculopathy when compared with patients without any signs of CAV: 206 +/- 53 vs 276 +/- 39 (p < 0.001) for the systemic application and 213 +/- 50 vs 271 +/- 45 (p = 0.004) for the intracoronary application. CONCLUSIONS: CFR and coronary vasoreactivity to adenosine are decreased in pediatric patients with CAV and correlate with histopathologic and angiographic evidence of microvascular disease. Measurement of CFR with intracoronary and systemic application of adenosine is comparable, while systemic application is necessary for non-invasive measurement of CFR in pediatric patients.

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.

Alpha2C-adrenoceptor polymorphism is associated with improved event-free survival in patients with dilated cardiomyopathy.

AIMS: The sympathetic nervous system plays a central role in cardiac growth but its overstimulation is associated with increased mortality in patients with chronic heart failure. Pre-synaptic alpha2-adrenoceptors are essential feedback regulators to control the release of norepinephrine from sympathetic nerves. In this study we tested whether a deletion polymorphism in the human alpha2C-adrenoceptor gene (alpha2CDel322-325) affects progression of heart failure in patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: We genotyped and phenotyped 345 patients presenting with DCM in the heart transplant unit of the German Heart Institute, starting in 1994. Patients were treated according to guidelines (99% ACEI, 76% beta-blockers) and were followed until December 2002 or until a first event [death, heart transplantation, or implantation of a left ventricular assist device (LVAD) for a life-threatening condition] occurred. Mean follow-up time was 249 weeks (4.9 years) in event-free patients and 104 weeks (2 years) in patients with events. During follow-up, 51% of the patients exhibited an event: death (18%), implantation of LVAD as bridging for transplantation (7%), or heart transplantation (25%). By Kaplan-Meier analysis, DCM patients with the deletion variant Del322-325 in the alpha2C-adrenoceptor showed significantly decreased event rates (P=0.0043). Cox regression analysis revealed that the presence of the deletion was associated with reduced death rate (relative risk: 0.129, 95% CI: 0.18-0.9441, P=0.044) and event rates (relative risk: 0.167, 95% CI: 0.041-0.685, P=0.012). CONCLUSION: Alpha2C-adrenoceptor deletion may be a novel, strong, and independent predictor of reduced event rates in DCM patients treated according to guidelines.