N. de Jonge

Left Ventricular Hypertrophy: A Shift in Paradigm

Observational studies have identified left ventricular hypertrophy (LVH) as a strong, independent risk factor for the development of heart failure (HF), coronary heart disease and stroke. LVH develops in response to hemodynamic overload. Classical conceptualization has it that LVH would start as an adaptive, beneficial response in order to normalize wall stress. With progression of the disease, deterioration to maladaptive hypertrophy, and further on to HF could occur. Recent experiments in animal models of pressure-overload and myocardial infarction now challenge this concept by demonstrating that blunting the hypertrophic response is actually associated with preserved cardiac function, and with improved survival. These findings may have profound therapeutical implications.

Left ventricular assist device as a bridge to recovery in a young woman admitted with peripartum cardiomyopathy

Left ventricular assist devices (LVAD) are an effective therapeutic option for end-stage heart failure patients as a bridge to cardiac transplantation in those who deteriorate despite maximal therapy and when a donor heart is not ready available. In some patients, cardiac recovery has been reported while supported by an LVAD. In this case report, we describe a 29-year-old female who was admitted to our centre because of peripartum cardiomyopathy (PPCM). Despite intensive treatment with intravenous inotropes and intra-aortic balloon counter-pulsation she had a persisting low cardiac index and an LVAD was implanted. In the months following implantation the left ventricular systolic function improved and the left ventricular dimensions normalised. Eventually the LVAD could be ex-planted nine months after implantation. At this moment, three years after explantation, echo-cardiography shows a normal-sized left ventricle and almost completely recovered systolic function. (Neth Heart J 2008;16:426-8).

Guidelines for heart transplantation

Based on the changes in the field of heart transplantation and the treatment and prognosis of patients with heart failure, these updated guidelines were composed by a committee under the supervision of both the Netherlands Society of Cardiology and the Netherlands Association for Cardiothoracic surgery (NVVC and NVT).The indication for heart transplantation is defined as: ‘End-stage heart disease not remediable by more conservative measures’.Contraindications are: irreversible pulmonary hypertension/elevated pulmonary vascular resistance; active systemic infection; active malignancy or history of malignancy with probability of recurrence; inability to comply with complex medical regimen; severe peripheral or cerebrovascular disease and irreversible dysfunction of another organ, including diseases that may limit prognosis after heart transplantation.Considering the difficulties in defining end-stage heart failure, estimating prognosis in the individual patient and the continuing evolution of available therapies, the present criteria are broadly defined. The final acceptance is done by the transplant team which has extensive knowledge of the treatment of patients with advanced heart failure on the one hand and thorough experience with heart transplantation and mechanical circulatory support on the other hand. (Neth Heart J 2008;16:79-87.)

Left ventricular assist device: a functional comparison with heart transplantation.

AbstractBackground A growing number of patients with end-stage heart failure undergo implantation of ventricular assist devices as a bridge to heart transplantation.Objectives In this study we investigated whether functional and haemodynamic recovery after implantation is sufficient to warrant the use of them as long-term alternative to heart transplantation.Methods We compared peak VO2 of a group of patients three months after implantation of a ventricular assist device and three months after heart transplantation. Furthermore, we analysed the degree of haemodynamic recovery, by comparing plasma levels of BNP and creatinine before and after implantation of the device.Results After implantation of a ventricular assist device, exercise capacity improved considerably; three months after implantation peak VO2 was 20.0±4.9 ml/kg/min (52% of predicted for age and gender). After heart transplantation exercise capacity improved even further; 24.0±3.9 ml/ kg/min (62% of predicted for age and gender) (p<0.001). In the three months after implantation, BNP plasma levels decreased from 570±307 pmol/l to 31±25 pmol/l and creatinine levels decreased from 191±82 μmol/l to 82±25 μmol/l, indicating significant unloading of the ventricles and haemodynamic recovery.Conclusion With regard to functional and haemodynamic recovery, the effect of implantation of a ventricular assist device is sufficient to justify its use as an alternative to heart transplantation. (Neth Heart J 2008;16:41-6.)

T cells in Cardiac Allograft Vasculopathy Are Skewed to Memory Th-1 Cells in the Presence of a Distinct Th-2 Population

Cardiac allograft vasculopathy (CAV) in heart transplantation (HTx) patients remains the major complication for long‐term survival, due to concentric neointima hyperplasia induced by infiltrating mononuclear cells (MNC). Previously, we showed that activated memory T‐helper‐1 (Th‐1) cells are the major component of infiltrating MNC in coronary arteries with CAV. In this study, a more detailed characterization of the MNC in human coronary arteries with CAV (n = 5) was performed and compared to coronary arteries without CAV (n = 5), by investigating MNC markers (CD1a, DRC‐1, CD3, CD20, CD27, CD28, CD56, CD68, CD69, FOXP3 and HLA‐DR), cytokines (IL‐1A, 2, 4, 10, 12B, IFN‐γ, and TGF‐β1), and chemokine receptors (CCR3, CCR4, CCR5, CCR7, CCR8, CXCR3 and CX3CR1) by immunohistochemical double‐labeling and quantitative PCR on mRNA isolated from laser microdissected layers of coronary arteries. T cells in the neointima and adventitia of CAV were skewed toward an activated memory Th‐1 phenotype, but in the presence of a distinct Th‐2 population. FOXP3 positive T cells were not detected and production of most cytokines was low or absent, except for IFN‐γ, and TGF‐β. This typical composition of T‐helper cells and especially production of IFN‐γ and TGF‐β may play an important role in the proliferative CAV reaction.

Left ventricular assist devices: a kidney’s perspective

The left ventricular assist device (LVAD) has become an established treatment option for patients with refractory heart failure. Many of these patients experience chronic kidney disease (CKD) due to chronic cardiorenal syndrome type II, which is often alleviated quickly following LVAD implantation. Nevertheless, reversibility of CKD remains difficult to predict. Interestingly, initial recovery of GFR appears to be transient, being followed by gradual but significant late decline. Nevertheless, GFR often remains elevated compared to preimplant status. Larger GFR increases are followed by a proportionally larger late decline. Several explanations for this gradual decline in renal function after LVAD therapy have been proposed, yet a definitive answer remains elusive. Mortality predictors of LVAD implantation are the occurrence of either postimplantation acute kidney injury (AKI) or preimplant CKD. However, patient outcomes continue to improve as LVAD therapy becomes more widespread, and adverse events including AKI appear to decline. In light of a growing destination therapy population, it is important to understand the cumulative effects of long-term LVAD support on kidney function. Additional research and passage of time are required to further unravel the intricate relationships between the LVAD and the kidney.

Stem cell-derived cardiomyocytes after bone marrow and heart transplantation

Cardiomyocytes are a stable cell population with only limited potential for renewal after injury. Tissue regeneration may be due to infiltration of stem cells, which differentiate into cardiomyocytes. We have analysed the influx of stem cells in the heart of patients who received either a gender-mismatched BMT (male donor to female recipient) or a gender-mismatched cardiac transplant (HTX; female donor to male recipient). The proportion of infiltrating cells was determined by Y-chromosome in situ hybridization combined with immunohistochemical cell characterization. In BM transplanted patients and in cardiac allotransplant recipients, cardiomyocytes of apparent BM origin were detected. The proportions were similar in both groups and amounted up to 1% of all cardiomyocytes. The number of stem cell-derived cardiomyocytes did not alter significantly in time, but were relatively high in cases where large numbers of BM-derived Y-chromosome-positive infiltrating inflammatory cells were present. The number of Y-chromosome-positive endothelial cells was small and present only in small blood vessels. The number of BM-derived cardiomyocytes in both BMT and HTX is not significantly different between the two types of transplantation and is at most 1%.

Autoimmune markers are undetectable in end stage idiopathic dilated cardiomyopathy.

BACKGROUND: Autoreactive humoral and cellular immune responses may be involved in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). Certain human leucocyte antigens (HLA) could also be linked to the development of IDC. AIM: To determine whether various markers of autoimmunity are present in the final phase of the disease, to substantiate the role of an autoimmune process in IDC. METHODS: 37 patients with end stage IDC were studied, together with 39 patients with end stage heart disease of known aetiology who were included for comparison. Multiple myocardial tissue samples from the explanted heart of each patient were evaluated (immuno)histologically. An indirect immunofluorescence assay was used to screen patient serum samples for the presence of heart specific autoantibodies. HLA class I and II frequencies were determined in each group and compared with HLA frequencies from healthy blood donors. RESULTS: Only scanty small mononuclear cell infiltrates were present in myocardial tissue of seven patients with IDC and of 11 patients with heart disease of known cause. The majority of these inflammatory cells were negative for T cell markers. All blood specimens were negative for heart specific autoantibodies and there was no apparent association of IDC with particular HLA phenotypes. CONCLUSIONS: These findings suggest that an active autoimmune process is not involved in the end stage of IDC.

Donor-Specific Antibodies Are Produced Locally in Ectopic Lymphoid Structures in Cardiac Allografts

Cardiac allograft vasculopathy (CAV) is a transplant pathology, limiting graft survival after heart transplantation. CAV arteries are surrounded by ectopic lymphoid structures (ELS) containing B cells and plasma cells. The aim of this study was to characterize the antigenic targets of antibodies produced in ELS. Coronary arteries and surrounding epicardial tissue from 56 transplant recipients were collected during autopsy. Immunofluorescence was used to identify antibody‐producing plasma cells. Immunoglobulin levels in tissue lysates were measured by enzyme‐linked immunosorbent assay and analyzed for donor‐specific HLA antibodies by Luminex assay. Cytokine and receptor expression levels were quantified using quantitative polymerase chain reaction. Plasma cells in ELS were polyclonal and produced IgG and/or IgM antibodies. In epicardial tissue, IgG (p < 0.05) and IgM levels were higher in transplant patients with larger ELS than smaller ELS. In 4 of 21 (19%) patients with ELS, donor‐specific HLA type II antibodies were detected locally. Cytokine and receptor expression (CXCR3, interferon γ and TGF‐β) was higher in large ELS in the epicardial tissue than in other vessel wall layers, suggesting active recruitment and proliferation of T and B lymphocytes. ELS exhibited active plasma cells producing locally manufactured antibodies that, in some cases, were directed against the donor HLA, potentially mediating rejection with major consequences for the graft.

Assist devices in the new decade: from technical developments to political decisions

Although assist devices have successfully been used for 20 years as a bridge to heart transplantation, there is still an ongoing debate about the use of long-term mechanical circulatory support as an alternative to transplantation. Since the publication of the REMATCH study in 2001, there have been extensive discussions about the optimal treatment of end-stage heart failure. The REMATCH study is still unsurpassed in which patients, non-eligible for heart transplantation, were randomly assigned to optimal medical therapy or mechanical circulatory support with a pusherplate type of left ventricular assist device (LVAD), the HeartMate XVE (Thoratec, Inc., Pleasanton, CA, USA). After 1 year of follow-up, survival in the LVAD group was about twice that in the conservatively treated patients (52 vs. 25%). For the first time, it had been shown that long-term mechanical support was feasible and better than optimal medical treatment. This has led to FDA approval and reimbursement of the HeartMate XVE as a treatment option for end-stage heart failure. Despite high expectations, the number of implants, however, did not grow excessively. Part of this lack of widespread enthusiasm was certainly related to the bulky size of the device, and the very characteristic hissing noise from the device, hampering normal social contacts. Another major problem became evident in the 2-year follow-up, when almost all patients had died in both arms (survival 23% vs. 8%), the major problems in the LVAD group being device failure and device-related infections. None of the study patients lived for more than 3.5 years with their device. These poor long-term results from the REMATCH study shed new light on the cost-effectiveness of LVADs. If the majority of patients were to die within 2 years, LVADs would lack costeffectiveness, often defined as the yearly cost of haemodialysis. In the Netherlands and several other European countries, this has been a major reason for limiting reimbursement of LVADs to patients requiring a bridge to transplant. In 2006, Potapov et al. reported on the use of long-term circulatory support for over 4 years in a small group of non-transplant candidates, proving the feasibility of extended longevity of LVADs in individual patients. Since 2005, the worldwide focus has changed from bulky and noisy pusher-plate pumps to smaller and silent axial flow devices and centrifugal pumps, facilitating more widespread use. Although these continuous-flow pumps soon appeared to surpass the pulsatile-flow devices both in acceptability and longevity, until recently there were only case reports and registries to prove their superiority. In November 2009, the HeartMate DT study was published. This was a randomized study—again in patients unsuitable for heart transplantation—to compare event-free survival between the HeartMate XVE (a pulsatile flow device) and HeartMate II, a continuous flow pump. The primary endpoint was defined as survival free of major neurological complications and pump failure or pump exchange. After a 2-year follow-up, HeartMate II patients did about twice as well as patients on a HeartMate XVE, with an actuarial survival rate of 58 vs. 24%. The difference in the 2-year survival free from disabling stroke and reoperation for device repair or replacement was even more impressive, in favour of the continuous-flow pump compared with the pulsatile-flow device (46 vs. 11%). This difference was mainly driven by a lower rate of pump replacements (9 vs. 34%, respectively). Disabling stroke, both ischaemic and haemorrhagic, remains a real problem with both types of pumps, occurring in about 12% of patients. Quality of life and exercise capacity in uncomplicated LVAD patients are much better than in medically treated patients with end-stage heart failure and comparable with patients after heart transplantation. The lack of need for immunosuppressive therapy may even outweigh the physical limitations of an artificial pump, such as the need to wear batteries and limitations in taking a shower. However, no randomized studies have yet been performed to compare the quality of life of patients with an LVAD and those who have undergone heart transplantation. With respect to ‘longevity’, heart transplantation undoubtedly beats LVADs, with an average survival of about 11 years, although