| BackgroundFor patients with intractable heart failure, cardiac transplantation has been the most effective long-term therapy. However, it is not unusual for a child listed as a heart transplant candidate to wait several months before an organ becomes available [1-2]. In order to assist the failing heart in infants and small children, mechanical circulatory support with a variety of devices has been routinely applied in pediatric patients with end-stage heart disease, aiming at bridge to transplantation or myocardial recovery. Current options for mechanical support in children include miniaturized intraaortic balloon pumps (IABP), extracorporeal membrane oxygenation (ECMO), centrifugal pumps, pulsatile VADs, and axial flow devices.ECMO [3-8] and centrifugal pumps [9] remain the most common forms of mechanical support available, and are the best option for acute decompensation. ECMO can provide total cardiopulmonary support, is relatively rapid, and allows the flexibility of peripheral and central cannulation. ECMO pumps, however, produce nonpulsatile flow and the circuit is complex. The incidence of medium and long-term bleeding and infectious complications is exceedingly high and neurological impairment with extended use is also common [10-14]. ECMO also restricts patient mobility, impairing physical rehabilitation [15-16].Ventricular assist devices (VAD) have potential advantages over ECMO and centrifugal pumps as a mechanical bridge. Pulsatile pumping results in better tissue perfusion and specifically provides better recruitment of the microcirculation of the brain, lungs, and kidneys during extracorporeal circulation. In addition to improving the patient's hemodynamic status and reversing end-organ dysfunction, VADs can be partially or fully implanted and allow for physical rehabilitation to improve the patient's overall condition and likelihood for successful transplantation. Although several adult-sized ventricular assist devices could be implanted in larger adolescent patients, they could not provide circulatory support in small children with weight less than 20 kg [17-18]. Specific concerns regarding“oversized”devices have been documented. Pumping large stroke volumes into a small aorta can perpetuate systolic hypertension and subsequent intracranial hemorrhage, stasis in the device can cause thromboembolic complications, and placement of multiple adult size cannulae in a limited pericardial space can be technically challenging.Current experience with the use of pediatric-specific VADs in children is limited, and previous studies were mostly based on either adult-sized VADs or a relatively small patient number [19-30]. Furthermore, for the pediatric population, classic guidelines for VAD implantation have not always been successful, since almost all of them were based on adult VAD patients, and these models might be largely unsubstantiated when applied to children [31].Additionally, despite the great improvement in VAD technology and growing clinical experience, a significant proportion of the left ventricular assist device (LVAD) recipients developed postoperative right heart failure, which has been proved to adversely affect outcomes [32-36]. For patients with severe right ventricular dysfunction refractory to standard medical therapy, additional right ventricular assist device (RVAD) implantation needs to be considered [37]. However, even with proper treatment, high mortality is still common in these patients [38]. Prior studies have shown that pre-planned implantation of biventricular assist device (BVAD) was associated with improved patient outcomes, as compared with delayed conversion of an LVAD to biventricular mechanical support, thus, highlighting the importance of preimplantation patient selection for BVAD insertion. Currently, although many risk factors for post-LVAD right ventricular dysfunction in adult VAD candidates have been identified [39-43], predictors for severe right heart failure and requirement for biventricular mechanical circulatory support in pediatric recipients have not been fully characterized.Left heart failure is considered as one of the most common causes of pulmonary hypertension (PH), which has an incidence of up to 70% in patients with chronic heart failure attributable to left ventricular dysfunction of systolic or diastolic origin, or by valvular diseases [44-45]. It adversely affects right ventricular function, exercise capacity, and patient survival. The pathogenesis of PH in left heart disease is complex. It is not solely caused by a "passive”congestive increase of pulmonary vascular pressures in response to elevated left atrial pressure, but is frequently aggravated by pulmonary endothelial dysfunction, pulmonary vasoconstriction and vascular remodeling, which causes a superimposed rise in pulmonary vascular resistance (PVR) [46]. This“reactive”elevation in PVR further increases right ventricular afterload and promotes right ventricular dysfunction, and thus, leads to poor prognosis of these patients [47]. However, the underlying pathomechanisms for PH owing to left heart disease are scarcely understood, and approved therapeutic strategies for the treatment of this disease are lacking.Previously, we have shown significant upregulation of mast cell genes and the perivascular accumulation of mast cells in rats with PH owing to left heart disease. Further study has showed that, in the mast cell deficient Ws/Ws rats with chronic heart failure induced by supracoronary aortic-banding, pulmonary hypertension, lung vascular remodeling, and right ventricular hypertrophy were largely attenuated, thus identifying a critical role for mast cells in PH owning to left heart disease.Therefore, in the first part of our study, we conducted a retrospective analysis by collecting the data of the patients with age < 18 years who were supported by Berlin Heart EXCOR Pediatric VADs at DHZB between 1999 and 2009. We reported the clinical results of pediatric VAD recipients and further analyzed the preoperative risk factors associated with postoperative mortality; in the second part of our study, we further analyzed predictors for the need of biventricular mechanical support in pediatric patients with advanced heart failure; in the third part of our study, we determined the potential therapeutic efficacy of the mast cell stabilizer (ketotifen) to prevent or even reverse pulmonary and right ventricular pathology in two rat models of established cardiogenic and non-cardiogenic PH.Objective1. To describe the recent 10-year the Deutsches Herzzenturm Berlin (DHZB) experience with long-term mechanical circulatory support in small children and young adolescents with intractable heart failure;2. To define the preoperative risk factors for in-hospital mortality in children with advanced heart failure;3. To determine the preoperative correlates of a need for BVAD use in children with advanced heart failure;4. To determine the potential therapeutic efficacy of the mast cell stabilizer (ketotifen) to prevent or even reverse pulmonary and right ventricular pathology in two rat models of established cardiogenic and non-cardiogenic PH.Methods1. We conducted a retrospective, non-randomized study by obtaining patient data from the ventricular assist device registry database of DHZB., all pediatric patients implanted with the Berlin Heart EXCOR pediatric ventricular assist device at the DHZB between 01/1999 and 12/2009 were included in this study. The following clinical data were collected and analyzed: (1) patient characteristics: age, sex, body surface area (BSA), body length, weight, body mass index (BMI), temperature, pulse oxygen saturation, causes of heart failure, prior sternotomy, history of comorbidities, VAD type, year of implantation; (2) medical and device therapy for heart failure: preimplantation cardiac pulmonary resuscitation, intravenous inotropes, vasopressor, vasodilators, diuretics, antiarrhythmic therapy, other mechanical circulatory support before EXCOR implantation; (3) measures of hemodynamic severity of heart failure: left ventricular ejection fraction (LVEF), blood pressure (systolic, diastolic, mean), heart rate, rhythm, pulse oxygen saturation, central venous pressure (CVP), pulmonary artery pressure (PAP, systolic, diastolic, mean), pulmonary capillary wedge pressure (PCWP), cardiac output and index; (4) laboratory data (< 24 hours before VAD implantation): serum sodium concentration, serum potassium concentration, serum glucose concentration, hemoglobin, white blood count, hematocrit, platelet count, international normalization ratio (INR), partial thromboplastin time (PTT), alanine and aspartate aminotransferase activity (ALT, AST), lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB),?-glutamyl transpeptadase (GGT), total bilirubin concentration, albumin concentration, total protein (TP), blood urea nitrogen (BUN), serum creatinine concentration, serum C-reactive protein (CRP); (5) clinical outcomes: duration of ventilation, period of ICU stay, duration of EXCOR support, causes of EXCOR explantation, cause of death, posttransplantation survival, and adverse events.2. To determine the predictors for the need of biventricular support, we retrospectively reviewed preimplantation patient characteristics, laboratory values, and hemodynamic data, and the differences between BVAD and LVAD recipients were further compared by univariate and multivariate analysis.3. First, we successfully setting up the aortic-banding and monocrotaline PH rat model; thereafter, the rats were given ketotifen treatment 5 weeks after surgery and 3 weeks after monocrotaline injection, accordingly. Hemodynamic and histological tests were conducted 9 weeks after surgery and 5 weeks after monocrotaline injection, accordingly.Results1. The etiology of end-stage myocardial failure included non-congenital (72%) and congenital heart disease (CHD) (27%); the median age at implantation was 4 years (12 days to 17 years), and the median support time was 59 days (1 to 432 days). Thirty-three patients were bridged to heart transplantation, 14 were explanted following myocardial recovery, 2 continued to receive support, and the other 24 died on support. The accurate rate of survival at 30 days and 1 year after EXCOR implantation was 80.3% and 55.5%, respectively. For the subset of 56 children listed for transplantation, 77% survived during the support period. No differences in clinical outcomes between small children with BSA < 1.2 m2 and larger children were observed, except that there was a higher incidence of stroke in small recipients. Patients supported with a biventricular assist device had significantly higher postimplantation mortality as compared to children with univentricular assist device (UniVAD). Lower postimplantation survival was also observed in patients with congenital cardiac disease compared with children with a non-congenital diagnosis. Our multivariate analysis revealed that congenital diagnosis and CVP > 17 mmHg were independent risk factors for survival after EXCOR implantation. For patients without any of these factors, the 30-day and 1-year survival after EXCOR implantation was 92.2%±4.4% and 75.9%±8.3%; for the combined group with at least 1 risk factor, it was 75.9%±8.3% and 29.7%±10.4%, respectively.2. Compared to children implanted with LVAD, patients receiving biventricular support had significantly higher postoperative mortality (p = 0.04). The multivariate logistic regression indicated that decreased milrinone use was the only preoperative factor independently associated with increased requirement for biventricular support (Odds ratio [OR] 0.19, 95% confidence interval [CI] 0.05-0.7, p = 0.01). Children treated with milrinone preoperatively had improved survival after implantation (p = 0.04).3. There are no differences in PAP, PVR, and remodeling between PH rats receiving ketotifen treatment and those did not.Conclusions1. The Berlin Heart EXCOR pediatric VAD provides efficient and reliable mechanical circulatory support in both small children and larger adolescents suffered from end-stage heart disease, with encouraging clinical outcomes comparable to those in adult VAD patients. The overall survival to transplantation, recovery of ventricular function, or ongoing device support for patients with CHD were also significantly lower than in children with a non-congenital diagnosis. Incidences of certain complications (such as cerebralvascular accident) in our study remained high (especially in small pediatric patients), which might emphasize the need of further improvement in anticoagulation therapy for children after VAD implantation.2. The presence of congenital heart disease and CVP > 17 mmHg were independent risk factors for postimplantation survival of children supported with EXCOR VAD. Further analysis demonstrated that the high-risk patient group was associated with significantly elevated mortality as compared to those recipients without any risk factor. Of note, age-dependent factors were not correlated with different patient survival outcomes after implantation, even in our initial univariate analysis, which supported our point that EXCOR can provide satisfactory support and has comparable clinical outcomes in both small children and larger adolescent patients.3. Pediatric patients needing biventricular support had significantly higher postoperative mortality. Preoperative milrinone use might decrease the risk of severe right ventricular failure requiring additional RVAD insertion, and improve postimplantation survival in children with advanced heart failure.4. Inhibition of mast cell degranulation by late ketotifen treatment does not prevent or reverse disease progression in established PH of cardiogenic or non-cardiogenic PH origin. Mast cells play a fundamental role predominantly in the initial stage of PH, while they do not seem critical for the progression of established PH. |
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