Cardiac surgery and congenital heart disease: reflections on a modern revolution.

The success of cardiac surgery has transformed the prospects of children with congenital heart disease with over 90% now surviving to adulthood. The early pioneering surgeons took on significant risk, whilst current surgical practice emphasises safety and consistency. In this article we review important British contributions to the field and consider challenges for the future, specifically how to better manage and reduce the adverse sequelae of congenital cardiac surgery by continuing to innovate safely.

Combined heart-lung transplantation from a donation after circulatory death donor.

Combined heart-lung transplantation is the optimal treatment option for many patients with end-stage heart failure and fixed severe pulmonary hypertension. It offers the only possibility of long-term survival and a return to a normal quality of life. Unfortunately, it is rarely performed because of donor organ allocation policies. We present the case of a critically ill 24-year-old man, who after waiting for >100 days in-hospital on the urgent transplant list, deteriorated further and underwent the first successful heart-lung transplant with organs from a donation after circulatory death.

Surgical technique for heart transplantation: a strategy for congenital heart disease.

The standard techniques for orthotopic heart transplantation often require certain adjustments when the procedure is carried out for complex congenital heart disease. This is because of both the unusual anatomy and possible distortions caused by previous surgery. Such technical adjustments have been described in various published reports over the years. Those reports, when combined, do cover the full spectrum of the technical difficulties that may be encountered, whether the defects are in their original form or altered by surgery, such that no cardiac malformation or distortion would prohibit transplantation. However, those reports are comprehensive only when combined. None of the individual reports addresses all the possible technical challenges. Consequently, the available information is somewhat fragmented. In addition, the generic aspect of the described technical strategies is not always given the emphasis that it deserves. Indeed, occasionally a technique may be presented as a specific solution for a specific malformation, without necessarily pointing out that the same technique may be applied to other hearts with different overall pathologies but which share that specific malformation. The aim of this review article was to combine all the available published information in one article in a manner that constructs a simple but comprehensive and generic system of decision-making that may be applied to any heart in order to determine the exact technical adjustments needed for transplantation in each case. Such a strategy is possible for two reasons. First, only a few anatomical sites are technically significant, namely the points of anastomosis between the donor's organ and the recipient. The rest of the intracardiac morphology does not affect the operation and may be ignored. Second, each of those anatomical sites can present difficulties in only a few ways, and each of those few difficulties has a well-described and published solution already. Therefore, the exact technical adjustments required in each case may be worked out by the sequential assessment of the anastomotic sites alone.

What are the predictors that affect the excellent long-term benefits of redo coronary artery bypass grafting?

OBJECTIVE: Recurrent angina refractory to medical therapy in patients having undergone prior coronary artery bypass grafting (CABG) is an indication for repeat surgical revascularisation. The primary aim of this retrospective study was to determine the benefit of redo surgery over the longer term with regards to survival and freedom from cardiac symptoms/events. Our secondary aim was to identify risk factors that compromise surgical efficacy of redo revascularisation. METHODS: Patients were identified through case note review. Survivors were interviewed by telephone according to a defined protocol. Actuarial freedom from cardiac symptoms/events and survival were determined. A composite outcome for cardiac symptoms/events was used and defined as angina class> or =2 or NYHA> or =2 or myocardial infarction or need for percutaneous intervention. Univariate and multivariate analysis was performed. Survival was assessed using a Kaplan-Meier method, and determinants of survival with the Cox proportional hazards model. RESULTS: Between January 1st, 1996 and February 1st, 2004, 101 consecutive patients underwent redo CABG at our institution under the care of a single surgeon. There were 91 men and 10 women, 64% (65/101) had an age> or =70 years. 30-Day mortality was 1.2% (2/101). Mean time to follow-up was 5.3+/-3.8 years. Poor left ventricular function and pre-operative NYHA> or =2 status were independent predictors of decreased survival with hazard ratios (HR) of 2.12 (1.042-4.31) and 3.98 (1.39-11.39) respectively. The use of a radial artery graft at re-operation was an independent predictor of peri-operative death OR=18 (1-346). Actuarial survival at 1, 5 and 8 years was 90.1%, 84.4% and 76.9% and freedom from cardiac symptoms/events was 100%, 95% and 68% respectively. CONCLUSION: This study shows acceptable short- and long-term survival and freedom from symptoms/events in patients undergoing redo coronary artery bypass grafting at a single institution. The apparent association between radial arterial grafts and impaired early clinical outcome warrants further investigation.

Deposition of C4d and C3d in cardiac transplants: a factor in the development of coronary artery vasculopathy.

BACKGROUND: Coronary artery vasculopathy (CAV) is the major life-limiting factor in cardiac transplantation, after 1 year. Antibody-mediated rejection (AMR) has been associated with development of both acute and chronic rejection. We analyzed endomyocardial biopsies for pathologic markers of AMR (C4d and C3d), from the first 2 years post-transplantation, to determine complement deposition in relation to the development of CAV. METHODS: A retrospective, matched-pair study was used. Group 1 subjects (n = 26) were CAV-negative at 8 years, and Group 2 (n = 26) had angiographically detectable CAV at 4 years. Biopsies from six time-points were studied (total = 282). Immunohistochemistry was performed for C4d, C3d and CD68. Biopsies were graded for rejection using ISHLT criteria. RESULTS: Although CAV was not significantly associated with C4d deposition, it was associated with C3d deposition (p = 0.043). Only 4% of C4d and 5% of C3d biopsies were completely negative. Group 1 had 6 AMR-positive biopsies, with Group 2 having 8. There was no significant relationship between acute cellular rejection or AMR events and CAV. CONCLUSIONS: This study demonstrates that complement deposition is a frequent occurrence in the first 2 years post-transplantation. Although acute rejection is a known risk factor for CAV, in this study the relationship was found not to be significant. No relationship was found with the development of CAV and histologic features of AMR, when assessed by C4d deposition alone. However, an association between C3d deposition and the development of CAV was determined in this study group, suggesting that complement activation may play a role in the pathogenesis of CAV.

Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection.

In 1990, an international grading scheme for the grading of pulmonary allograft rejection was adopted by the International Society for Heart and Lung Transplantation (ISHLT) and was modified in 1995 by an expanded group of pathologists. The original and revised classifications have served the lung transplant community well, facilitating communication between transplant centers with regard to both patient management and research. In 2006, under the direction of the ISHLT, a multi-disciplinary review of the biopsy grading system was undertaken to update the scheme, address inconsistencies of use, and consider the current knowledge of antibody-mediated rejection in the lung. This article summarizes the revised consensus classification of lung allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates, Grade A0 (none), Grade A1 (minimal), Grade A2 (mild), Grade A3 (moderate) and Grade A4 (severe), as previously. The revised (R) categories of small airways inflammation, lymphocytic bronchiolitis, are as follows: Grade B0 (none), Grade B1R (low grade, 1996, B1 and B2), Grade B2R (high grade, 1996, B3 and B4) and BX (ungradeable). Chronic rejection, obliterative bronchiolitis (Grade C), is described as present (C1) or absent (C0), without reference to presence of inflammatory activity. Chronic vascular rejection is unchanged as Grade D. Recommendations are made for the evaluation of antibody-mediated rejection, recognizing that this is a controversial entity in the lung, less well developed and understood than in other solid-organ grafts, and with no consensus reached on diagnostic features. Differential diagnoses of acute rejection, airway inflammation and chronic rejection are described and technical considerations revisited. This consensus revision of the working formulation was approved by the ISHLT board of directors in April 2007.

Acute leukaemoid reaction following cardiac surgery.

Chronic myelomonocytic leukaemia is an atypical myeloproliferative disorder with a natural history of progression to acute myeloid leukaemia, a complex and poorly understood response by the bone marrow to stress. Cardiac surgery activates many inflammatory cascades and may precipitate a systemic inflammatory response syndrome. We present a case of undiagnosed chronic myelomonocytic leukaemia who developed rapidly fatal multi-organ dysfunction following cardiac surgery due to an acute leukaemoid reaction.

Leiomyosarcoma of the retrohepatic vena cava treated by excision and reconstruction with an aortic homograft: a case report and review of literature.

Leiomyosarcoma of the retrohepatic inferior vena cava is a rare entity and presents a number of diagnostic and therapeutic challenges. Here such a case is presented in which the retrohepatic inferior vena cava was excised after full mobilization of the liver under venovenous bypass. The continuity of the vena cava was restored with cryopreserved aortic homograft. The technical details with regard to total vena caval clamping, venovenous bypass, hepatic inflow occlusion, techniques of reconstruction, including the use of cryopreserved aortic homograft, and a brief review of the literature on the surgical management of retrohepatic inferior vena caval tumors are discussed.

Is obliterative bronchiolitis in lung transplantation associated with microvascular damage to small airways?

BACKGROUND: Acute rejection, a vascular-based disorder, has been identified as the major risk factor for obliterative bronchiolitis (OB), an airway-based pathology. This study investigated the hypothesis that changes to the microvascular blood supply of small airways were associated with the development of OB, thus providing a possible link between an acute vascular insult (acute rejection) and chronic airway changes (OB). METHODS: Microvasculature of 695 small airways (99 patients) was assessed in post-mortem lung allograft specimens using monoclonal antibodies for von Willebrand factor and CD31. Group A consisted of 343 small airways from 58 patients with no evidence of OB. The remaining 41 patients had histological evidence of OB in some of their small airways and grouped as B, C, and D with some patients contributing to all three groups ie, their lung specimen had some small airways which were completely obliterated with OB, some airways which were partially obliterated and some small airways without any histological evidence of OB development. Thus group B consisted of 145 small airways (34 patients) without OB. Group C consisted of 171 small airways with partial luminal obstruction (36 patients). Group D consisted of 36 small airways (14 patients) with complete luminal obliteration. RESULTS: Airway circumference (mean +/- standard deviation) was 2.36 +/- 0.37, 2.41 +/- 0.51, 2.49 +/- 0.51, and 2.57 +/- 0.79 mm, respectively (p = 0.40). Mean number of blood vessels per unit length of airway circumference was 4.12 +/- 1.1, 1.58 +/- 0.61, 2.42 +/- 1.06, and 4.42 +/- 1.46 vessels/mm, respectively (p < 0.001). Blood vessels with circumference greater than 0.2 mm were present in 100%, 64%, 39%, and 7% of small airways, respectively (p < 0.001). Univariate and multivariate analyses (donor and recipient age, sex, and cytomegalovirus status, recipient pretransplant diagnosis, ischemic times, acute rejection and infective episodes, postoperative survival days, recipient group [A to D], blood vessels per unit length, and airway circumference) confirmed that reduction in blood vessels per unit length was associated with the development of OB and was time-independent. CONCLUSIONS: Obliterative bronchiolitis was preceded by a decrease in microvascular supply to the small airways (group B). The subsequent onset of airway scarring (groups C and D) was associated with an increased number of significantly smaller vessels, suggestive of neovascularization.

APT070 inhibits complement activation during in vitro cardiopulmonary bypass.

BACKGROUND: The proteins of the complement cascade play an important role in inflammation and the immune response. They have been shown to be activated during cardiopulmonary bypass (CPB), and may be responsible for the inflammatory response to CPB. We looked at the effect of APT070, an anti-complement agent, on human blood during in vitro CPB. MATERIALS AND METHODS: Four hundred millilitres of blood was venesected from healthy human volunteers and heparinised. To the blood was added either APT070 to a concentration of 50 microg/ml (n=5) or vehicle control (n=4). The blood was entered into an in vitro CPB circuit and circulated for 90 min. RESULTS: Our results showed that after 90 min of in vitro bypass APT070 significantly inhibited the activation of compliment as demonstrated by C3a (p=0.03) and sC5b-9 (p=0.01) levels, and reduced neutrophil stimulation as measured by CD11b expression (p=0.04 at 90 min). CONCLUSION: APT070 significantly inhibits complement and neutrophil activation. This result may have considerable implications, especially if it can be shown to decrease the inflammatory sequelae of CPB.

The cumulative effect of acute rejection on development of cardiac allograft vasculopathy.

BACKGROUND: Acute rejection increases the inflammatory burden of the transplanted organ and predisposes to cardiac allograft vasculopathy (CAV). In this study we aim to determine the magnitude of the association, and to differentiate between the effects of mild vs severe rejection episodes. METHODS: Between 1988 and 2003, 489 1-year survivors of heart transplantation underwent 1,435 angiograms. These patients were classified as having no CAV (0% stenosis), mild/moderate CAV (<70%) or severe CAV (>70%). Acute rejection was considered either mild (Grades 1A, 1B and 2 untreated) or moderate/severe (Grade 2 treated on a clinical basis and Grades 3A, 3B and 4). We used multi-state Markov models to examine risk factors for the onset of CAV. RESULTS: Expressed as relative risk, the onset of CAV was significantly increased by donor age (1.26 per 10 years, 95% confidence interval [CI] 1.12 to 1.42), male recipient (1.72, 95% CI 1.01 to 2.94), pre-transplant recipient ischemic disease (1.53, 95% CI 1.14 to 2.06) and cumulative number of moderate/severe rejections (1.10 per episode, 95% CI 1.03 to 1.18). Human leukocyte antigen (HLA) and cytomegalovirus (CMV) matching, donor gender, recipient age, smoking, cumulative CMV infections and mild rejections were not significant risk factors. Estimated annual onset rate of CAV was 11.3% for patients with no moderate/severe rejection, rising to 13.6% for those with two and 18.0% for those with five such rejections. CONCLUSIONS: Acute moderate/severe cellular rejection has a cumulative impact on CAV onset, whereas mild, untreated rejection is not associated with CAV.

The outcomes of lung transplantation in patients with bronchiectasis and antibody deficiency.

BACKGROUND: Lung transplantation is an established treatment for end-stage bronchiectasis. A proportion of patients with bronchiectasis have an associated antibody deficiency. This group benefits from immunoglobulin replacement therapy, but the outcome of lung transplantation is not known. METHODS: We conducted a retrospective observational study of all who received a transplant for bronchiectasis at our unit. We compared the survival after transplant, number of infective and rejection episodes, and the change in forced expiratory volume in 1 second (FEV1). RESULTS: Five of the 37 patients identified with bronchiectasis had an antibody deficiency that required immunoglobulin replacement therapy. Actuarial survival was similar in the 2 groups, being 81% at 12 months in the Bronchiectasis Group and 80% in the Antibody Deficiency Group. The FEV1 at 12 months after transplantation was similar in each group, with a predicted mean +/- SD FEV1 of 83.7% +/- 24.2% in those with bronchiectasis and 83.0% +/- 30.4% in those with antibody deficiency as well. The infection and rejection rates in the first year after transplantation were lower in the Antibody Deficiency Group. Infection episodes per 100 patient-days for bronchiectasis alone were 0.90 vs 0.53 and rejection episodes per 100 patient-days were 0.59 vs 0.24. CONCLUSIONS: There was no evidence that transplant recipients with bronchiectasis and antibody deficiency have a worse prognosis than those with bronchiectasis alone.

Does heart transplantation confer survival benefit in all risk groups?

BACKGROUND: Over 50,000 heart transplants have been performed in the last 3 decades. The global shortage of donor organs and the relaxation of candidate selection criteria over time has resulted in recent controversy about the benefits of heart transplantation for some risk groups. We assessed the survival benefit acquired in the Papworth Hospital heart transplant population overall, taking into account resuscitated marginal donors and high-risk recipients. METHODS: All heart transplant patients listed between 1979 and June 2002 were analyzed (n = 1,212). Of these, 931 cardiac transplantations were done, including the use of 126 marginal donors. High-risk recipients (n = 163) were defined as patients being in the hospital, on intravenous inotropic drugs, and/or with a high transpulmonary gradient (>15 mm Hg). Using Cox regression with transplantation as a time-dependent covariate, we assessed the survival benefit of transplantation. In our model we assumed that after transplantation the initial risk of death is high relative to continued waiting, followed by an exponential decline in risk. The crossover point (COP) is the time at which the risk of death after transplantation is equal to that of continued waiting (i.e., the relative risk is 1). The equity point (EP) determines the time at which the early post-operative risk is offset by the later period of lower risk and, therefore, the time at which transplantation has a survival advantage. RESULTS: Overall, the COP was at 54 days and EP at 141 days. In the marginal donor sub-group, COP was achieved at 32 days with EP at 72 days, indicating a survival benefit. The difference in the COP and EP between the borderline donor and normal donor sub-groups was not statistically significant. Post-transplant survival was not significantly different from recipients of normal cardiac allografts (p = .43). Likewise, for the high-risk recipient group, the COP and EP were at 72 and 203 days. Although post-op survival was significantly shorter than the normal-risk group, both groups achieved survival benefits. CONCLUSION: Heart transplantation provides survival benefit in these risk groups of recipients in our population. This is a reflection of our active donor management protocol and rigorous donor and recipient selection process.

Comparison of survival by allocation to medical therapy, surgery, or heart transplantation for ischemic advanced heart failure.

BACKGROUND: To ascertain survival of ischemic advanced heart failure patients by treatment allocation, we examined the outcome of transplant assessment patients allocated to medical therapy, high-risk conventional surgery, or transplantation. METHODS: Patients were identified from the Papworth transplant database and excluded if primary etiology was not ischemic. Grouping was undertaken according to treatment allocation at initial assessment, and analysis was performed by intention to treat. Survival was computed from the time of assessment and Cox regression used to stratify patients according risk with the Heart Failure Survival Score. RESULTS: From May 1993 to September 2001, a total of 755 patients were admitted for transplant assessment, with 348 (46.1%) identified as having heart failure of ischemic origin. Variables required for calculation of the Heart Failure Survival Score was available in 273 patients (78.4%), and 20 patients (7.3%) were lost to follow-up. Of the remaining 253 patients, 89 (35.2%) were allocated to medical therapy, 32 (12.6%) to surgery, and 132 (52.2%) to transplantation. The relative risk (95% confidence limit) of death compared with medical therapy was 0.62 (0.28, 1.40) for surgery and 0.38 (0.24, 0.61) for transplantation in medium- to high-risk patients. For low-risk patients, the relative risks for death compared with medical therapy were 1.87 (0.63, 5.60) for surgery and 1.97 (0.79, 4.96) for transplantation. CONCLUSIONS: Transplantation improved survival of medium- and high-risk patients compared with medical therapy. In the low-risk group, this was not evident. However, repeated assessment of risk is required because the hazard for death rises steadily after the third year in these patients.

Angiogenesis occurs within the intimal proliferation that characterizes transplant coronary artery vasculopathy.

BACKGROUND: Vascular remodeling is central to the development of transplant coronary artery vasculopathy (CAV). For remodeling to occur, a sustained blood and nutrient supply is essential. Here we report on the presence of angiogenesis within the neointima of coronary arteries from cardiac transplant recipients. METHODS: Coronary arteries from 57 cardiac transplant recipients with CAV were analyzed. Immunocytochemistry with antibodies raised against endothelial cells (CD31, CD34, and vWF), vascular smooth muscle cells (SmA), and activated endothelial cells (MHC 2, P-SEL, E-SEL, and VCAM-1) was performed. RESULTS: A total of 89% of patients had significant angiogenesis. These vessels appeared as endothelial lined channels and were present in a concentric circumferential pattern within the mid portion of the neointima. These new vessels were present at an interface between an area of intimal hyperplasia and below an area of fibrous regeneration. These 2 distinct zones were present in 64% of the cases, and were clearly demonstrated with an elastic van Gieson (EVG) stain and are distinctly different from that seen in native atherosclerosis. Endothelial activation markers were strongly expressed by the endothelial cells lining new vessels, suggesting that they are functional and may aid in the recruitment of inflammatory cells. CONCLUSIONS: These data suggest that angiogenesis is present within the intima of CAV lesions and may contribute to the continued obliteration of the vessel lumen. The vessels appear to originate in the intima and may represent the location of the donor endothelium before transplantation. Inhibition of endothelial damage may provide therapeutic options to prevent the progression of CAV.

Early mortality after cardiac transplantation: should we do better?

BACKGROUND: According to International Society for Heart and Lung Transplantation (ISHLT) data, the 30-day survival after heart transplantation has continually improved from 84% (1979-85) to 91% (1996-2001). This has probably been achieved by better donor/recipient selection, along with improved surgical technique and immunosuppressive therapy. On the other hand, the data concerning the early causes of death after cardiac transplantation is incomplete, because in 25% of cases, an unknown cause is listed. This study investigated the incidence and causes of 30-day mortality (determined by postmortem studies) after cardiac transplantation and assessed the possibility of improvements. METHODS: A retrospective study of all patients who underwent heart transplantation at Papworth Hospital from 1979 to June 2001 (n = 879) and who died within 30 days of surgery was carried out. Postmortem examination data were available for all patients. RESULTS: The mean (standard deviation) recipient and donor ages were 46 (12) and 31 (12) years, respectively. Overall, the 30-day mortality was 8.5% (n = 75), 12.1% for the 1979 to 1985 period and 6.9% for the 1996 to 2001 period. The primary causes of death were graft failure (30.7%), acute rejection (22.7%) (1.3% for the 1996-2001 era), sepsis (18.7%) gastrointestinal problems (bowel infarction and pancreatitis; (9.3%), postoperative bleeding (6.7%), and other (12%). CONCLUSIONS: Our 30-day mortality compares favorably with the data from the ISHLT registry, with great improvement in the early mortality. Acute rejection is no longer a major cause of early mortality. Further reduction may be achieved by a better protection of the donor heart against the effects of brainstem death and ischemic injuries. However, the quest to improve early outcome should not be at the expense of needy patients by being overselective.