Intra-aortic balloon pump in acute chest pain and cardiogenic shock - a long-term follow-up.

Objectives. Coronary revascularisation and intra-aortic balloon pump (IABP) has been considered the gold standard treatment of acute coronary syndrome with cardiogenic shock, recently challenged by the SHOCK II study. The aim of this non-randomised study was to investigate the long term prognosis after immediate IABP supported angiography, in patients with acute chest pain and cardiogenic shock, treated with percutaneous coronary intervention (PCI), cardiac surgery or optimal medical treatment. We assessed data from 281 consecutive patients admitted to our department from 2004 to 2010. Results. Mean (±SD) age was 63.8 ± 11.5 (range 30-84) years with a follow-up of 5.6 ± 4.4 (0-12.7) years. Acute myocardial infarction was the primary diagnosis in 93% of the patients, 4% presented with unstable angina pectoris and 3% cardiomyopathy or arrhythmias of non-ischemic aetiology. Systolic blood pressure at admittance was 85 ± 18 mmHg and diastolic 55 ± 18 mmHg. Thirty day, one- and five-year survival was 71.2%, 67.3% and 57.7%, respectively. PCI was performed immediately in 70%, surgery was done in 17%, and 13% were not eligible for any revascularisation. Independent variables predicting mortality were medical treatment vs revascularisation, out-of-hospital cardiac arrest, and advanced age. Three serious non-fatal complications occurred due to IABP treatment, i.e. 0.001 per treatment day. Conclusions. We report the use of IABP in patients with acute chest pain admitted for angiography. Long-term survival is acceptable and discriminating factors were no revascularisation, out-of-hospital cardiac arrest and age. IABP was safe and feasible and the complication rate was low.

Disturbed energy metabolism after lung and heart transplantation.

Overweight, in combination with other cardiovascular risk factors, reduces survival after transplantation. The aim of this prospective study was to observe leptin, adiponectin, and energy intake as predictors of body mass index (BMI) and body composition and as risk factors associated with metabolic syndrome after lung and heart transplantation. After pre-operative baseline investigations, 35 lung and 59 heart recipients were followed and re-investigated two, six, and 12 months after transplantation. Linear regressions were performed to predict BMI and body composition. The lung recipients had a substantial weight gain after transplantation. Leptin increased, especially in the lung recipients and positively predicted BMI. Energy intake predicted BMI before and at two months after transplantation, but not after 12 months. Percentage trunk fat increased and lean mass decreased. Before transplantation, the dominant determinant of lean mass was adiponectin (positively associated), while after it was leptin (negatively associated), controlled for possible confounding variables (including prednisolone). Metabolic syndrome 12 months after transplantation was associated with higher leptin, greater weight gain without increased energy intake. After transplantation, a disturbed energy metabolism is indicated, where adiponectin and especially leptin are involved and a disadvantageous body composition is favored with increased body fat and decreased lean mass.

Pregnancy in heart- and heart/lung recipients can be problematic.

OBJECTIVE: The first successful pregnancy after heart transplantation was reported in 1988. Worldwide experience with heart and heart/lung transplanted (H-HLTx) pregnant women is limited. To expand this knowledge the collaborating Nordic thoracic transplant centers wanted to collect information on all such pregnancies from their centers. DESIGN: Information was retrospectively collected on all H-HLTx pregnancies in the Nordic countries. RESULTS: A total of 25 women have had 42 pregnancies and all survived the gestation. Minor complications were increasing incidence of proteinuria, hypertension and diabetes. Major problems were two rejections (early post partum), two severe renal failures, seven pre-eclampsias and 17 abortions. Five women died two to 12 years after delivery. Of 25 live born children, one was born with cancer and one died early after inheriting the mother's cardiomyopathy. CONCLUSION: Pregnancy after H-HLTx can be successful for both mother and child. There are, however, many obstacles which should be addressed. Respecting the couple's desire for children the attitude should be carefully, not too optimistic, after proper pre-pregnant information and counseling. Delivery should preferably take place at the transplant center.

Osteoporosis is a prevalent finding in patients with solid organ failure awaiting transplantation - a population based study.

Post-transplant bone disease is common in solid organ recipients; however, there is limited information on their pre-transplant bone status. We aimed to compare bone mineral density (BMD) in different categories of patients with end-stage organ failure awaiting transplantation (Tx) in Norway. Overall 291 adult patients were enrolled, including 60, 84, 81 and 66 patients with end-stage lung, liver, kidney and heart failure, respectively. Mean age was 51 ± 12 yr with no significant differences between the groups. We measured BMD in lumbar spine, femur, proximal one third and ultra-distal radius by dual energy X-ray absorptiometry. Differences in T- and Z-scores between the groups were compared by ANOVA. Low bone mass was found in all four groups of patients. Both T- and Z-scores differed (p < 0.05) at all measured sites between the groups. Patients with lung failure had the highest prevalence of osteoporosis (67%) and lowest Z-scores, followed by patients with liver (31%), kidney (24%), and heart (23%) failure. Osteoporosis is prevalent in all groups of organ transplant candidates, and poor bone health is remarkably pronounced in patients with chronic lung disease. General practitioners and specialists who care for these patients before they are referred for transplantation should consider measures to prevent osteoporosis at an earlier stage.

Acute renal failure early after heart transplantation: risk factors and clinical consequences.

Limited information exists about acute renal failure (ARF) early after heart transplantation (HTx). We correlated pre-, per-, and post-operative patient and donor parameters to the risk of developing ARF. We also analyzed the consequences of ARF on kidney function after HTx, risk of later need for chronic dialysis or kidney transplantation, and mortality. In a retrospective study from 1983 to 2007, 145 (25%) of 585 HTx recipients developed ARF, defined as ≥ 26.4 micromol/L or ≥ 50% increase in serum creatinine from pre-operatively to the seventh day post-HTx and/or the need of early post-operative dialysis. Independent risk factors for ARF were intravenous cyclosporine immediately post-operatively (odds ratio [OR] 2.16, 95% CI 1.34-3.50, p = 0.02), donor age (OR 1.02, 95% CI 1.00-1.04, p = 0.02), and pre-operative cardiac output (OR 1.38, 95% CI 1.12-1.71, p = 0.003). The development of ARF was a predictor for short-term survival (≤ 3 months) ranging from 98% for patients who improved their creatinine after HTx vs. 79% for those in need of dialysis (p < 0.001). However, ARF did not predict subsequent end stage renal disease in need of dialysis or renal transplantation. ARF is a common complication post-HTx. As ARF is associated with short-term survival, post-operative strategies of preserving renal function have the potential of reducing mortality. Of avoidable risk factors, the use of intravenous CsA should be discouraged.

The prognostic importance of modifiable risk factors after heart transplantation.

BACKGROUND: It is well established that the treatment of modifiable risk factors can reduce cardiovascular mortality in the general population. However, there is limited data evaluating the importance of modifiable risk factors for survival following heart transplantation (HTx). Hence, we evaluated the prognostic importance of smoking, obesity, hyperglycemia and hyperlipidemia at 1 year after HTx for all-cause and cardiac mortality. METHODS: We evaluated 381 patients attending their first annual visit post-HTx. Data regarding modifiable risk factors was collected together with other clinical variables. Median follow-up time was 7.4 years. RESULTS: In total, there were 122 (32%) deaths and smoking and elevated total cholesterol were independent risk factors for all-cause mortality (adjusted HR 1.6 [P = .02] and 1.8 [P = .003], respectively). A significantly higher incidence of cardiac death was noted amongst smokers and patients with elevated total cholesterol. Elevated body mass index and hemoglobin A(1c) did not affect prognosis and elevated total cholesterol was not a risk factor once statin therapy commenced at the time of HTx was instituted as protocol. CONCLUSIONS: Smoking is a risk factor for all-cause and cardiac mortality, but elevated total cholesterol is a risk factor only in the absence of statin therapy being commenced at the time of HTx.

Intra-aortic balloon counterpulsation as a bridge to heart transplantation does not impair long-term survival.

AIMS: There are few studies of the use of intra-aortic balloon pump (IABP) treatment as a bridge to heart transplantation (HTx). This is the first study to compare long-term clinical and haemodynamic outcomes in IABP-treated HTx patients and electively transplanted patients. METHODS AND RESULTS: This was a retrospective study of all adult HTx recipients between 2001 and 2007. Thirty-two patients (aged 50 +/- 13 years) treated with IABP, as a bridge to HTx due to severe hypo-perfusion, were compared with 135 electively transplanted patients (aged 54 +/- 11 years). The mean time from onset of IABP to HTx was 21 +/- 16 days. Clinical condition improved during IABP treatment. Serum creatinine decreased from 128 +/- 56 to 102 +/- 29 micromol/L (P < 0.01), aspartate transaminase from 682 +/- 1299 to 63 +/- 89 U/L (P = 0.01), and ALAT from 483 +/- 867 to 126 +/- 284 U/L (P = 0.02). Intra-aortic balloon pump treatment related complications were few. Mortality was similar in the IABP and control groups at 30 days post-HTx (6.2 vs.3.7%, P = 0.54), at 1 year (9.4 vs.11.1%, P = 0.80), and beyond. Long-term clinical and haemodynamic indices were similar in the two groups. CONCLUSION: Intra-aortic balloon pump treatment stabilizes patients in end-stage heart failure, is safe, well tolerated, and is successful in bridging acutely decompensated patients to transplantation. Complications are few and manageable. Following IABP and HTx, short- and long-term survival, biochemical and invasive and non-invasive haemodynamic outcomes were similar to those in electively transplanted patients.

Prognostic importance of renal function 1 year after heart transplantation for all-cause and cardiac mortality and development of allograft vasculopathy.

BACKGROUND: Impaired renal function is associated with increased mortality among heart failure patients. Although a significant proportion of heart transplant (HTx) recipients have reduced renal function at 1 year post-HTx, no previous study has evaluated the associated risk for both all-cause and cardiac mortality. Hence, we assessed the relationship between glomerular filtration rate (GFR) at 1 year post-HTx and all-cause and cardiac mortality and development of cardiac allograft vasculopathy (CAV). METHODS: We evaluated 381 patients with a minimum survival of 1 year post-HTx and the Modification of Diet in Renal Disease Study formula was used to calculate estimated GFR. Mortality and angiographic CAV were defined as separate endpoints, and median follow-up was 7.4 and 4.0 years, respectively. RESULTS: During the follow-up period, 122 patients died and 154 patients developed CAV. Reduced GFR pre-HTx was not a risk factor for either endpoint. Overall, 193 (51%) patients had GFR <60 ml/min/1.73 m at one year post-HTx and this was an independent predictor of all-cause mortality with an adjusted hazard ratio of 1.7 (P=0.01) for a GFR between 30-60 and 3.2 (P=0.006) for GFR <30 ml/min/1.73 m. GFR <60 ml/min/1.73 m at 1 year post-HTx was also associated with a higher risk of cardiac mortality (HR=1.9; P=0.04) but did not predict the development of CAV. CONCLUSIONS: Renal impairment is evident in a majority of HTx recipients at 1 year post-HTx. It is an important risk factor for both all-cause and cardiac mortality but does not predict the development of angiographic CAV.

Probrain natriuretic peptide and C-reactive protein as markers of acute rejection, allograft vasculopathy, and mortality in heart transplantation.

BACKGROUND: N-terminal probrain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) are useful in risk stratification of patients with congestive heart failure. They could also be markers of distinctly altered hormonal and immunological milieus, but the combined prognostic value of these biomarkers in heart transplant (HTx) recipients has not been assessed previously. METHODS: We sought to assess the individual and combined value of NT-proBNP and CRP as markers of acute rejection, cardiac allograft vasculopathy (CAV) and all-cause mortality in HTx recipients. We evaluated 101 patients for acute rejection and 210 patients for CAV and all-cause mortality. Patients evaluated for rejection had serial endomyocardial biopsies and plasma sampling performed during the first year postHTx. All other patients had plasma samples taken upon inclusion at an annual visit. Median follow-up for CAV and all-cause mortality was 2.2 years and 5.4 years, respectively. RESULTS: Altogether, 1131 biopsy procedures were performed, and increased NT-proBNP and CRP levels were not useful markers of acute cellular rejection. In total, 78 (37%) patients developed CAV, and 39 (19%) patients died. Neither biomarker was a predictor of CAV, but both were independent predictors of mortality. When combining both biomarkers, elevated levels of both NT-proBNP and CRP identified patients at highest risk for CAV (HR 2.10, P=0.01) and all-cause mortality (HR 3.14, P=0.01). CONCLUSIONS: In HTx recipients, NT-proBNP and CRP are not useful as markers of acute cellular rejection during the first year postHTx, but combined analysis adds significantly to their predictive value for development of CAV and all-cause mortality.

Depressive symptoms and all-cause mortality after heart transplantation.

BACKGROUND: Several studies indicate that heart transplantation (HTx) is associated with depression and reduced quality of life. However, the impact of depression on the prognosis for HTx-patients has not yet been sufficiently established. The aim of the present study was to prospectively investigate the influence of depression on mortality in patients with HTx, adjusting for other known risk factors. METHODS: In a prospective, cross-sectional study with minimum 5-year follow-up, symptoms of depression were assessed in 147 HTx-patients using the Beck Depression Inventory (BDI). RESULTS: Mild to severe depressive symptoms (BDI > or =10) were observed in 36 patients (24.5%). Depressive symptoms on inclusion increased the risk of mortality during the follow-up period. The risk remained significant after adjusting for several somatic and lifestyle risk factors, and the adjusted relative risk associated with depression (risk ratio: 2.32; 95% CI: 1.13-4.79; P=0.02) was comparable to the adjusted relative risk associated with time since HTx. CONCLUSIONS: Symptoms of depression predict mortality independently of somatic and lifestyle risk factors in HTx patients, and this group of patients should be screened for depressive symptoms.

A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus.

BACKGROUND: Cytomegalovirus (CMV) infection in recipients of cardiac transplants is associated with higher rates of morbidity. A recent phase III trial showed highly significantly (P<0.001) lower CMV rates with the proliferation signal inhibitor everolimus compared to azathioprine (AZA). To better define this association, data on CMV risk factors were collected retrospectively and analyzed. METHODS: Data on CMV risk factors from a multicenter phase III trial on de novo heart transplant recipients (n=634) receiving a triple immunosuppressive regimen randomized to everolimus 1.5 mg/day (group 1), everolimus 3 mg/day (group 2), or AZA (group 3) were merged with prospectively collected CMV-related outcome data and analyzed. RESULTS: CMV-positive donors (D+) and CMV-negative recipients (R-) were evenly distributed across groups 1-3 at 36/209 (17.2%), 48/211 (22.7%), and 38/214 (17.8%), respectively. CMV prophylaxis had been given for a mean (SD) of 175 (127.8), 183 (137.1), and 177 (132.9) days, respectively. In the high-risk D+/R- subgroup with prophylaxis, the proportions of patients with CMV infection compared with group 3 (12/29 [41.4%]) were 3/25 (12.0%) in group 1 (P=0.031) and 6/36 (16.7%) in group 2 (P=0.049). In D+/R+ subgroups either with or without prophylaxis, the everolimus groups had less CMV disease (P<0.001). The incidence of CMV syndrome, organ involvement, and laboratory evidence was lower with everolimus use compared to AZA. CONCLUSIONS: Everolimus is associated with lower rates of CMV infection, syndrome, or organ involvement, suggesting an additional advantage from the use of everolimus in cardiac transplant recipients.

[Survival after heart transplantation in Norway]. / Overlevelse etter hjertetransplantasjon i Norge.

BACKGROUND: Heart transplantation has been a treatment option in Norway for selected patients with terminal congestive heart failure since 1983. The number of transplants is limited by donor availability. Few Norwegian doctors are aware of the challenges to be expected in taking care of heart transplant recipients. In the present paper we therefore present our experience so far. MATERIAL AND METHODS: We have followed individuals within our patient cohort for up to 22 years. The cohort consists of 522 patients (mean age 48.8 years +/- 13.6), somewhat unequally distributed from various parts of the country, reflecting the local referring practice. We have a complete overview of the patients who are partly followed up locally, but come to a control at least once a year at our hospital. RESULTS AND INTERPRETATION: Mean survival in these patients is 12 years. With an expected survival of less than one year without transplantation, these are strong results that compare well with international figures. Patients younger than 50 years at transplantation have the best prognosis regardless of donor age, while the combination of patients older than 50 years and donor above 35 years have the poorest chance of survival. However, patients are disposed to various severe complications. Initially after transplantation acute rejection, unspecific graft failure and infections are a threat; while complications such as chronic graft sclerosis, renal failure and cancer are complications that appear over time. To optimise results, life-long regular follow up is necessary.

[Self-assessed health and psychological symptoms after heart transplantation]. / Selvvurdert helse og psykiske symptomer etter hjertetransplantasjon.

BACKGROUND: The purpose of this study was to assess quality of life (QoL, self-reported health) and psychological adjustment in a sample of heart transplanted patients. MATERIAL AND METHODS: The sample comprised 147 (117 men) Norwegian heart transplanted patients (operated 1983 - 1999). Data on QoL and psychological adjustment were collected during annual routine follow-up controls between 1998 and 2000. The Short Form 36 (SF-36), the Symptom Checklist 90-Revised (SCL-90-R), and Beck Depression Inventory (BDI) were used. RESULTS: On average, heart transplant recipients reported significantly reduced QoL and increased levels of psychological symptoms compared to a normative population. Recently operated patients reported a generally good QoL compared to the norms, while there was a worsening after 3 years of both the patients' psychological symptoms and QoL, compared to patients who were transplanted less than 3 years ago. The clinical significance was underscored by the BDI; 30 % of the patients were classified as suffering from mild depression (BDI >/= 10) if transplanted more than 3 years ago, compared to 16 % in patients operated less than 3 years ago (p < .05). 62 % of the patients never returned to work and became/remained permanent disability pensioners. INTERPRETATION: This study demonstrates that heart transplanted patients have a reduced QoL and psychological problems after the transplantation and this seems to worsen with time. Detection and early intervention of psychological symptoms may assist heart transplant survivors in their return to everyday life. The cross-sectional nature of the study makes it difficult to infer causality from these results.

Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure.

BACKGROUND: Persistent inflammation appears to play a role in the development of heart failure (HF). Osteoprotegerin (OPG), the receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) are newly discovered members of the tumor necrosis factor superfamily that are critical regulators in bone metabolism but appear also to be involved in immune responses. We hypothesized that the OPG/RANK/RANKL axis could be involved in the pathogenesis of heart failure (HF), and this hypothesis was investigated in both experimental and clinical studies. METHODS AND RESULTS: Our main and novel findings were as follows: (1) In a rat model of postinfarction HF, we found persistently increased gene expression of OPG, RANK, and RANKL in the ischemic part of the left ventricle (LV) and, for OPG, in the nonischemic part that involved both noncardiomyocyte and in particular cardiomyocyte tissue. (2) Enhanced myocardial protein levels of OPG, RANK, and RANKL, in particular, were also seen in human HF, and using immunohistochemistry, we localized these mediators to cardiomyocytes within the LV in both experimental and clinical HF. (3) In human HF, we also found increased systemic expression of RANKL (T cells and serum) and OPG (serum), with increasing levels according to functional, hemodynamic, and neurohormonal disease severity. (4) RANKL increased total matrix metalloproteinase activity in human fibroblasts, which indicates a matrix-degrading net effect and suggests a potential mechanism by which enhanced RANKL expression in HF may contribute to LV dysfunction. CONCLUSIONS: These findings suggest a potential role for known mediators of bone homeostasis in the pathogenesis of HF and possibly represents new targets for therapeutic intervention in this disorder.

Decreased endomyocardial RANKL expression in transplant coronary artery disease.

Transplant-associated coronary artery disease (TxCAD) appears to be initiated by endothelial cell activation and inflammation involving inflammatory cytokines and chemokines. Osteoprotegerin (OPG) and receptor activator of nuclear Factor-kappaB ligand (RANKL) have been implicated in cardiovascular disease progression and we measured the expression of these mediators in serum and myocardial biopsies taken serially during the first year after heart transplantation (HTx), relating them to the development of TxCAD. Serum OPG as well as myocardial gene expression of RANK and OPG, but not RANKL, were highest early after HTx and declined progressively. Importantly, patients who develop TxCAD or experience episodes of acute rejection showed a lower myocardial RANKL expression throughout the first year after transplantation than patients without these complications. Our findings may suggest an unrecognized role RANKL in maintaining myocardial and/or endothelial integrity and suggest that RANKL should be further investigated as a parameter that may predict development of TxCAD.

N-terminal pro-B-type natriuretic peptide as an indicator of disease severity in a heterogeneous group of patients with chronic precapillary pulmonary hypertension.

N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) is well established as a predictor of prognosis in patients with left ventricular dysfunction. Although a similar prognostic significance has been suggested in 1 study of right ventricular failure and idiopathic pulmonary arterial hypertension, NT-pro-BNP has not been assessed as a marker of disease severity in a more heterogenous group of patients with chronic precapillary pulmonary hypertension (PH). Hence, this study assessed plasma NT-pro-BNP and other clinical variables in 61 consecutively recruited patients with various forms of chronic precapillary PH. Right-sided cardiac catheterization and cardiopulmonary exercise testing were performed at baseline, and the prognostic significance of NT-pro-BNP was investigated with a mean follow-up of 25 months. Compared with age-matched controls (n = 10), plasma NT-pro-BNP was significantly greater in those with idiopathic pulmonary arterial hypertension (n = 16), chronic precapillary PH associated with other diseases (n = 26), and chronic thromboembolic disease (n = 19) and was correlated with hemodynamic variables and functional capacity. In 17 medically treated patients, the significant decrease in NT-pro-BNP levels correlated with improved hemodynamics. During follow-up, 15 patients died from cardiopulmonary causes. Baseline NT-pro-BNP was an independent predictor of mortality. Kaplan-Meier survival analysis according to the median value of NT-pro-BNP (168 pmol/L) demonstrated a significantly higher mortality rate in those with supramedian values than in those with low plasma levels (p = 0.010). In conclusion, these findings suggest that in a heterogenous group of patients with chronic precapillary PH, plasma NT-pro-BNP can be used to determine the clinical severity of disease and is independently associated with long-term mortality.

[Treatment of cardiac failure with an intra-aortic balloon pump]. / Behandling av hjertesvikt med intraaortal ballongpumpe.

BACKGROUND: Cardiogenic shock is associated with high mortality. This retrospective study examined the effect of an intra aortic balloon pump (IABP) in patients with decompensated heart failure and hypotension, with or without cardiogenic shock. MATERIAL AND METHODS: 94 patients were treated with IABP from January 1998 to December 2002, at the Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway. The indications for use of IABP were decompensated heart failure with hypotension with or without cardiogenic shock in patients with acute myocardial infarction (n = 41), ventricular septal rupture or mitral insufficiency as a complication to acute cardiac failure (n = 23), severe heart failure waiting for heart transplant (n = 10), unstable angina pectoris (n = 8), myocarditis (n = 6) and miscellaneous (n = 6). RESULTS: Mortality after 30 days was 24 % for all patients, with little variation between the above-mentioned subgroups. Median duration for IABP was 96 hours. Systolic blood pressure and diuresis per hour increased significantly from before to after application of IABP (35 +/- 34 mL/hour versus 95 +/- 77 mL/hour, p < 0.001 and 90 +/- 20 mmHg versus 115 +/- 22 mmHg, p < 0.001). The rate of complications requiring treatment was low with use of IABP (5 out of 94 patients). INTERPRETATION: Treatment with IABP in patients with decompensated heart failure and hypotension is an efficient stabilising treatment and safe to use.

Soluble CD40 ligand in pulmonary arterial hypertension: possible pathogenic role of the interaction between platelets and endothelial cells.

BACKGROUND: Inflammatory processes seem to be involved in pulmonary arterial hypertension (PAH). CD40 ligand (L) may promote inflammation and thrombus formation, and we hypothesized that CD40L could be involved in the pathogenesis of PAH. METHODS AND RESULTS: Several significant findings were revealed when examining the possible role of CD40L in PAH. (1) Patients with primary (n=13) and secondary (n=11) PAH but not those with chronic thromboembolic pulmonary hypertension (n=8) had increased plasma levels of soluble (s) CD40L compared with control subjects (n=8). (2) PAH patients using warfarin had markedly lower sCD40L levels than those without such therapy. (3) sCD40L levels were higher in arterial (femoral artery) compared with mixed venous blood (pulmonary artery), suggesting enhanced release or reduced clearance in the pulmonary vasculature. (4) Platelets from PAH patients showed enhanced spontaneous and SFLLRN-stimulated release of sCD40L compared with control subjects. (5) In vitro, recombinant sCD40L induced monocyte chemoattractant protein (MCP)-1 and interleukin-8 gene expression in endothelial cells, and plasma levels of these chemokines were raised in all PAH groups, significantly correlated to sCD40L and hemodynamic parameters. (6) Although prostacyclin therapy (3 months) showed clinical benefit, this therapy had no effect on sCD40L and increased MCP-1 levels in PAH patients, and prostacyclin enhanced MCP-1 in CD40L-stimulated endothelial cells. CONCLUSIONS: Our findings suggest a role for CD40L in the pathogenesis of PAH, possibly operating through an interaction between platelets and endothelial cells involving chemokine-related mechanisms.

Elevated levels of activin A in heart failure: potential role in myocardial remodeling.

BACKGROUND: Although modulation of inflammatory processes has been suggested as a new treatment modality in heart failure (HF), our knowledge about abnormalities in the cytokine network during HF is still limited. On the basis of a previous cDNA array study examining peripheral blood mononuclear cells from HF patients, we hypothesized a role for activin A, a member of the transforming growth factor (TGF)-beta superfamily, in the pathogenesis of HF. METHODS AND RESULTS: This study had 4 main and novel findings. First, serum levels of activin A were significantly elevated in patients with HF (n=86) compared with healthy control subjects (n=20), with increasing levels according to disease severity as assessed by clinical, hemodynamic, and neurohormonal parameters. Second, compared with control subjects, HF patients, as determined by real-time quantitative reverse transcriptase polymer chain reaction, also had markedly increased gene expression of the activin A subunit activin betaA in T cells but not in monocytes. Third, in a rat model of HF, we demonstrated a concerted induction of the gene expression of activin betaA and activin receptors IA, IB, IIA, and IIB after myocardial infarction. Immunohistochemical analysis localized activin A solely to cardiomyocytes. Finally, activin A markedly increased gene expression of mediators involved in infarction healing and myocardial remodeling (ie, atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta1, and monocyte chemoattractant protein-1) in neonatal rat cardiomyocytes. CONCLUSIONS: Together with our demonstration of activin A-induced gene expression in neonatal cardiomyocytes of mediators related to myocardial remodeling, the expression pattern of activin A during clinical and experimental HF suggests an involvement of this cytokine in the pathogenesis of HF.

Plasma C-reactive protein as a marker of cardiac allograft vasculopathy in heart transplant recipients.

OBJECTIVES: This study was initiated to determine whether heart transplant recipients (HTRs) with cardiac allograft vasculopathy (CAV) have increased levels of high-sensitivity C-reactive protein (hsCRP) and to examine whether an increase in hsCRP after heart transplantation predicts the development of CAV. Furthermore, the effect of pravastatin on plasma levels of hsCRP in HTRs was investigated. BACKGROUND: The relationship between CAV and hsCRP, as well as the effect of statins on hsCRP in HTRs, has not been well established. METHODS: On referral for their annual angiographic control study, 150 consecutive HTRs (mean 6.5 years since transplantation) were included. Plasma levels of hsCRP were measured before angiography and compared with patients with (n = 52) and without (n = 98) CAV. In 49 of these patients, we additionally analyzed hsCRP in blood samples stored from their six-month visit after the transplantation procedure. Furthermore, in a randomized, crossover study, hsCRP was analyzed in 17 male HTRs before and after six weeks of treatment with 20 mg pravastatin. RESULTS: Median levels of CRP were elevated among patients with CAV compared with those with normal angiograms [3.86 (1.78 to 7.00) vs. 1.08 (0.72 to 2.13) mg/l, p < 0.001]. Prospectively evaluated hsCRP levels from six months to follow-up were significantly higher among those who developed CAV compared with those with normal angiograms [+2.76 (1.56 to 5.00) vs. +0.07 (-0.57 to 0.41) mg/l, p < 0.001]. On multivariate analysis, the increase in hsCRP was the only significant predictor of CAV. Six weeks of treatment with pravastatin significantly reduced hsCRP levels by 25%, without any relation to changes in lipid values. CONCLUSIONS: Elevated plasma levels of CRP are associated with angiographic evidence of CAV, and the increase in hsCRP is a strong predictor of development of CAV. Statin treatment reduces levels of hsCRP and should be used in HTRs, regardless of their lipid levels.