Prospective study of everolimus with calcineurin inhibitor-free immunosuppression after heart transplantation: results at four years.

BACKGROUND: Immunosuppression is necessary after transplantation but it is associated with distinct adverse side effects. These negative effects could at least partially be overcome with the mammalian target of Rapamycin (mTOR) inhibitor everolimus. Few studies have examined everolimus therapy with calcineurin inhibitor (CNI) withdrawal in maintenance heart transplant patients (HTx). METHODS: In this prospective, single-arm, single-center study, maintenance patients after HTx were converted from CNI to everolimus. They were followed for 48 months. Primary endpoints were kidney-function and arterial hypertension. RESULTS: Forty-eight patients were recruited (mean post-transplant time 5.4 ± 3.5 years). Of these, 36 were followed for the entire 4-year period. Median calculated glomerular filtration rate increased from 40.7 (32.4 to 59.1) mL/minute at baseline to 48.9 (29.7 to 67)) mL/minute at month 48 (p = not significant). Median systolic and diastolic blood pressure, triglycerides, and high-density lipoprotein and low-density lipoprotein cholesterol, did not change significantly in a comparison of the values at baseline and at 48 months. Early resolution of most non-renal CNI-related adverse events was sustained. Due to adverse events, CNI therapy had to be reintroduced in 6 patients (12.5%). No significant changes in cardiac function parameters were observed. CONCLUSIONS: Calcineurin inhibitor-free immunosuppression with everolimus is an effective and safe option in selected maintenance HTx patients. Most adverse effects under everolimus occurred early after conversion and in most cases resolved without intervention within a few weeks. Refining selection criteria may help both in identifying patients who will profit most from switching and in alleviating the need to reintroduce CNI therapy.

Concordance among pathologists in the second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II).

BACKGROUND: There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs). METHODS: We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades ≥2R merged because of small numbers). RESULTS: Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade ≥2R by at least one were assigned this grade by both. CONCLUSION: The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade ≥2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteria--EMB based or otherwise--that correspond better with the pathophysiology of the transplanted heart.

Effects of enzyme replacement therapy in adult patients with Fabry disease on cardiac structure and function: a retrospective cohort study of the Fabry Munster Study (FaMuS) data.

OBJECTIVE: Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism caused by deficient lysosomal α-galactosidase A activity. Progressive accumulation of globotriaosylceramide and related glycosphingolipids in vascular endothelial lysosomes of the heart, kidneys and brain is responsible for the main disease manifestations. The aim of our study was to assess short-term and long-term effects of enzyme replacement therapy (ERT) on cardiac mass and function. DESIGN: Retrospective cohort study. SETTING: Hospital outpatient clinic. PARTICIPANTS: 40 FD patients (21 men, 19 women) receiving agalsidase ß-ERT. OUTCOME MEASURES: The focus at baseline and follow-up examinations was on structural, functional (Doppler-echocardiography) as well as electrical changes (ECG) and blood pressure. RESULTS: In the Early Group, systolic and diastolic blood pressures significantly decreased. Left-ventricular (LV) also decreased; however, wall thickness and LV mass index showed no further increase. VE as an indicator for diastolic function significantly improved (64±21 vs 75±27 cm/s, p=0.038). There were no significant changes of ECG parameters. There were few relevant changes in the Late Group, albeit systolic blood pressure significantly decreased and QRS duration significantly increased. In conclusion, echocardiographic left-ventricular mass index, interventricular septum thickness, left-ventricular posterior wall, left-ventricular end-diastolic dimension) and diastolic function parameters are valuable for follow-up and guidance of therapy. CONCLUSIONS: The primary positive impact of ERT appears to be an early effect after the start of therapy, and early initiation of ERT should be recommended.

Elevated left ventricular end-diastolic pressure favours closure of foramen ovale.

OBJECTIVE: It has been described that prevalence of patent foramen ovale (PFO) declines with age. Our hypothesis was that persistent high pressures in the left atria (LA), may facilitate closure of PFO and age would not play a role. METHODS AND RESULTS: The prevalence of PFO was studied in 201 consecutive patients with suspicion of cardioembolic stroke by contrast transoesophageal echocardiography. Left ventricular end-diastolic pressures (LVEDP) were estimated non-invasively by transthoracic echocardiography. Patients with normal diastolic function (DF) or with diastolic dysfunction (DD) stage I were considered as having normal LVEDP whereas patients with DD stage II or III as having elevated LVEDP. Prevalence of PFO was 42.8% and it was smaller in patients with elevated LVEDP than in patients with normal LVEDP (21.2% vs. 51.7%, P < 0.01). There was a smaller prevalence of PFO in patients with DD stage II than in patients with DD stage I or normal DF (25% vs. 51 and 54%, both P < 0.05). Size of the LA was larger in patients without PFO [34.73 ml/m2 (24.14-40.84ml/m2) vs. 27.86 ml/m2 (21.37-34.68 ml/m2), P < 0.05]. Mean age was 64.2 years (57.38-75.77) with no difference between patients with PFO and without PFO. In multivariate analysis Eustachian valve, atrial septal aneurysm, elevated LVEDP and large LA remained significantly associated (P < 0.05) with PFO. CONCLUSION: Elevated LVEDP and enlargement of LA are negatively associated with PFO. The higher the LVEDP, the lower the prevalence of PFO. Age is not associated with PFO.

Prospective study of everolimus with calcineurin inhibitor-free immunosuppression in maintenance heart transplant patients: results at 2 years.

BACKGROUND: Few studies have examined everolimus therapy with calcineurin inhibitor (CNI) withdrawal in maintenance heart transplant patients. METHODS: In a prospective, single-arm, single-center study, CNI-treated heart transplant patients were converted to everolimus and were followed up for 24 months. The primary endpoints were kidney function and arterial hypertension at 12 and 24 months after conversion. RESULTS: Fifty-eight patients were recruited (mean time posttransplant 5.6±3.7 years), 55 of whom (91.7%) had renal impairment. Mean creatinine clearance increased from 43.6±21.1 mL/min to 49.5±21.2 mL/min at month 24 (P=0.02). Median blood pressure increased from 120/80 mm Hg at baseline to 122.5/80 mm Hg (P=0.008 and 0.006 for systolic and diastolic pressure, respectively). Lipid parameters did not change significantly over the 24-month follow-up. Early resolution of most non-renal CNI-related adverse events was sustained. CNI therapy was re-introduced at a mean of 309 days (range, 31-684 days) in eight patients after month 6 due to adverse events (n=13) or withdrawal of consent (n=2). No significant changes in cardiac function parameters were observed. CONCLUSIONS: CNI-free immunosuppression with everolimus is an effective and safe option in selected heart transplant maintenance patients. Most adverse effects under everolimus occurred early after conversion and generally resolved without intervention within a few weeks. Refining selection criteria may reduce the need to re-introduce CNI therapy.

Sex-specific pathways in early cardiac response to pressure overload in mice.

Pressure overload (PO) first causes cardiac hypertrophy and then heart failure (HF), which are associated with sex differences in cardiac morphology and function. We aimed to identify genes that may cause HF-related sex differences. We used a transverse aortic constriction (TAC) mouse model leading to hypertrophy without sex differences in cardiac function after 2 weeks, but with sex differences in hypertrophy 6 and 9 weeks after TAC. Cardiac gene expression was analyzed 2 weeks after surgery. Deregulated genes were classified into functional gene ontology (GO) categories and used for pathway analysis. Classical marker genes of hypertrophy were similarly upregulated in both sexes (alpha-actin, ANP, BNP, CTGF). Thirty-five genes controlling mitochondrial function (PGC-1, cytochrome oxidase, carnitine palmitoyl transferase, acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase) had lower expression in males compared to females after TAC. Genes encoding ribosomal proteins and genes associated with extracellular matrix remodeling exhibited relative higher expression in males (collagen 3, matrix metalloproteinase 2, TIMP2, and TGFbeta2, all about twofold) after TAC. We confirmed 87% of the gene expression by real-time polymerase chain reaction. By GO classification, female-specific genes were related to mitochondria and metabolism and males to matrix and biosynthesis. Promoter studies confirmed the upregulation of PGC-1 by E2. Less downregulation of metabolic genes in female hearts and increased protein synthesis capacity and deregulation of matrix remodeling in male hearts characterize the sex-specific early response to PO. These differences could contribute to subsequent sex differences in cardiac function and HF.

Quantitation of myocardial borderzone using reconstructive 3-D echocardiography after chronic infarction in rats: incremental value of low-dose dobutamine.

Myocardial remodeling determines the degree of left ventricular dysfunction and mortality after transmural chronic myocardial infarction (CMI). Noninvasive characterization and quantitation of myocardial borderzone and collagenous scar are therefore parameters of clinical interest. The aims of this study were (i) to measure accuracy of reconstructive 3-D echocardiography (3DE) in scar and myocardial borderzone size assessment and (ii) to investigate the incremental value of low-dose dobutamine stress. 3DE was performed in 14 immunodeficient rats (rnu-rnu, 180-200 g) with anterior CMI 25 d after coronary ligation. Briefly, consecutive parallel short-axis cineloops were obtained electrocardiogram-gated starting from base to the apex. Morphology (mass, surface) and function (contractility, contractile reserve) of different compartments were assessed and correlated with 3-D histomorphometry. Histology was done using picrosirius red for collagen staining. 3DE left ventricular mass correlated closely with histomorphometry (y = 0.89x + 155, p < 0.0001, r = 0.80). Hypo- and akinetic myocardial surface correlated well with borderzone myocardium (y = 0.34x + 17, p = 0.009, r = 0.62) and collagenous scar (y = 1.9x + 4.4, p < 0.0001, r = 0.79), respectively. Extent of abnormal wall motion was closely related to borderzone and scar tissue area (y = 0.82x + 7, p < 0.0001, r = 0.77). 3DE quantitation of borderzone myocardium, but not collagenous scar, was more closely correlated to histomorphometry during inotropic stimulation. Global contractile reserve is positively associated with the size of myocardial borderzone. Regional contractile reserve of borderzone myocardium is not negatively associated with its collagen content. 3DE allows precise quantitation of myocardial borderzone and identification of transmural scar tissue noninvasively. Assessment of contractile reserve improves characterization and estimation of myocardial borderzone after CMI.

Calcineurin inhibitor-free immunosuppression using everolimus (Certican) in maintenance heart transplant recipients: 6 months' follow-up.

BACKGROUND: Everolimus is a proliferation signal-inhibitor recently introduced in heart transplant recipients. To date, little is known about calcineurin inhibitor (CNI)-free immunosuppression using everolimus. This study reports the results of CNI-free immunosuppression using everolimus. METHODS: During a continuous 9-month period, 60 heart transplant recipients were enrolled. Reasons for switching to everolimus were side effects associated with prior CNI immunosuppression. All patients underwent standardized switching protocols and completed 6 months of follow-up. Blood was obtained for lipid status, renal function, routine controls, and levels of immunosuppressive agents. Echocardiography and a physical examination were performed on Days 0, 14, 28, and then every 3 months. RESULTS: After switching to everolimus, most patients recovered from the side effects associated with CNIs. Renal function improved significantly after 6 months (creatinine, 2.1 +/- 0.6 vs 1.5 +/- 0.9 mg/dl, p = 0.001; creatinine clearance, 42.2 +/- 21.6 vs 61.8 +/- 23.4 ml/[min x 1.73 m2], p = 0.018). Arterial hypertension improved after 3 months and remained decreased during the observation period. Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Adverse events occurred in 8 patients (13.3%), including interstitial pneumonia (n = 2), skin disorders (n = 2), reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3). CONCLUSION: Preliminary data suggest that CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance heart transplant recipients. Arterial hypertension and renal function improved significantly. CNI-induced side effects such as tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved in most patients.

Reversible pulmonary hypertension in heart transplant candidates: to transplant or not to transplant.

BACKGROUND: Pulmonary hypertension (PHT), defined as a pulmonary vascular resistance (PVR) greater than 2.5 Wood units [WU] and(or) transpulmonary gradient (TPG) greater than 12 mm Hg, is a risk factor for mortality in cardiac transplantation due to elevated postoperative right heart failure. Orthotopic heart transplantation is possible if PVR could be reversed below 2.5 WU and TPG below 12 mm Hg. We show the Muenster experience from the last 10 years. METHODS: From April 1996 to December 2005 all cardiac transplant recipients separated into patients with and without PHT were included. All patients with PHT had successful reduction (PVR < or = 2.5 WU and TPG < or = 12 mm Hg) using prostaglandin I2 or E1. Posttransplant early and late mortality and incidence of right heart failure were studied. RESULTS: Two hundred seventeen patients were included in this study. Of these, 168 had normal pulmonary pressures (non-PHT group), 49 (22.6%) had reversible PHT (rev-PHT group). Mean PVR was 1.6 +/- 1.1 WU vs 2.1 +/- 1.1 WU (p < 0.01; non-PHT vs rev-PHT) and mean TPG 8.0 +/- 1.9 mm Hg vs 10.6 +/- 4.1 mm Hg (p = not significant [NS]). Thirty-day survival after orthotopic cardiac transplantation was 85% vs 78% (p = 0.150) and 10 year survival 63% vs 61% (p = NS). Right heart failure during the first 30 days after transplantation occurred in 27% in the non-PHT group and in 64% in the rev-PHT group (p = 0.035). However, in patients transplanted after 2001 it did not appear. CONCLUSIONS: Cardiac transplant candidates with reversible PHT have still significantly elevated pulmonary pressures compared with patients without PHT. Despite a significantly higher risk of right heart failure, long-term survival after orthotopic cardiac transplantation was not affected.

Does continuous flow left ventricular assist device technology have a positive impact on outcome pretransplant and posttransplant?

BACKGROUND: Left ventricular assist devices (LVADs) with continuous flow properties are increasingly used to bridge heart failure patients to cardiac transplantation. Advantages in comparison with the pulsatile LVADs are smaller size, better endurance, and lower thromboembolic events. However, whether these new pumps have similar pre- and posttransplant outcomes is not clear. METHODS: Fifty patients with a continuous flow device (Micromed DeBakey, Houston, TX or InCor BerlinHeart, Berlin, Germany) were compared with an age-, disease-, and LVAD duration-matched control group (n = 80) supported with a pulsatile device (Novacor, WorldHeart, Oakland, CA or HeartMate, Thoratec Corp, Pleasanton, CA). RESULTS: Age (44.3 +/- 13.4 vs 46.1 +/- 11.1 years), disease (idiopathic dilated cardiomyopathy, 58% vs 65%), and LVAD duration (138 +/- 131 vs 128 +/- 106 days) were comparable in both groups. Successful bridging to transplantation was similar with continuous flow in comparison with pulsatile device support (52% vs 56%, p = not significant [NS]). Thirty-day mortality after cardiac transplantation in patients with continuous flow LVAD support was 21.7% vs 22.2% with pulsatile LVADs (p = NS). Reasons for death were similar among the different LVAD groups. Long-term survival was similar in both LVAD groups compared with patients without previous LVAD support. Interestingly, severe rejections were significantly more frequent in patients with a continuous flow LVAD (p < 0.001). CONCLUSIONS: The new generation of cardiac assist devices with continuous flow pattern has a similar rate of pre- and posttransplant mortality in comparison with pulsatile LVADs. However, the rate and severity of posttransplant rejection was significantly higher in the group with continuous flow devices. Further studies are warranted to explain the higher rate of severe rejections.

Left bundle branch block in chronic heart failure-impact on diastolic function, filling pressures, and B-type natriuretic peptide levels.

BACKGROUND: For patients with chronic heart failure (CHF), left bundle branch block (LBBB) is associated with impaired systolic function and increased morbidity and mortality, but data on diastolic function are scarce. In this patient population, we attempted to define the impact of LBBB on diastolic function, filling pressures, and brain natriuretic peptide and its circulating N-terminal precursor (NT-proBNP) levels. METHODS: A total of 94 patients with stable CHF (48 with complete LBBB, 46 without intraventricular conduction delay and normal QRS duration) underwent conventional 2-dimensional/Doppler echocardiography and Doppler tissue analysis of mitral annular velocities. As a measure of left ventricular filling pressures, the ratio of peak early mitral flow velocity to peak early diastolic mitral annular velocity was derived. NT-proBNP measurements were carried out on a bench-top analyzer (Elecsys-2010, Roche Diagnostics, Mannheim, Germany). RESULTS: Patients with or without LBBB did not differ with respect to the cause of CHF or ejection fraction, but in LBBB deceleration time was shorter (163 +/- 66 vs 205 +/- 95 milliseconds, P = .021) and a restrictive mitral filling pattern was more frequent (35% vs 11%, P = .005). In such patients, the ratio of peak early mitral flow velocity to peak early diastolic mitral annular velocity was higher (14.5 +/- 6.2 vs 10.6 +/- 5.2, P < .001) and NT-proBNP was elevated (3553 +/- 3725 vs 850 +/- 896 pg/mL, P < .01) as compared with patients without LBBB. CONCLUSION: For patients with CHF and comparable systolic performance, LBBB is associated with more severe diastolic dysfunction, elevated filling pressures, and higher NT-proBNP levels. These findings may contribute to increased morbidity and mortality of such patients.

Tissue Doppler imaging in patients with moderate to severe aortic valve stenosis: clinical usefulness and diagnostic accuracy.

BACKGROUND: Mitral annular velocities derived from tissue Doppler imaging (TDI) provide information about left ventricular (LV) long-axis function and allow for the assessment of LV filling pressures in selected subsets of patients. It was the aim of this study to assess the usefulness of TDI in patients with moderate to severe aortic valve stenosis (AS). METHODS: Twenty-three patients with moderate to severe AS (mean aortic valve area 0.8 +/- 0.4 cm2), in whom coronary artery disease had been ruled out, and 36 asymptomatic age-matched control subjects underwent assessment of ejection fraction, fractional shortening, and mitral inflow (E, A, E/A ratio). TDI velocities (S', E', A') were derived from the septal mitral annulus. In patients with AS, LV pressure before atrial contraction (LV pre-A pressure), LV end-diastolic pressure, and cardiac index were measured during cardiac catheterization. RESULTS: In patients with AS, systolic (S') and early diastolic mitral annular velocities (E') were significantly reduced in comparison to control subjects (systolic, 5.5 +/- 1.2 vs 8.3 +/- 1.3 cm/s; early diastolic, 5.6 +/- 1.6 vs 10.2 +/- 3.0 cm/s, P <.001 for both comparisons), but ejection fraction, fractional shortening, and cardiac index were normal. In patients with AS, LV pre-A pressures (14 +/- 4 mm Hg) and end-diastolic pressures were high (19 +/- 7 mm Hg). In such patients, the mitral E/E' ratio was significantly related to LV pre-A pressure (r = 0.75, P <.001) and to LV end-diastolic pressure (r = 0.78, P <.001). In patients with AS, an E/E' ratio > or =13 identified an LV end-diastolic pressure >15 mm Hg, with a sensitivity of 93% and a specificity of 88%. CONCLUSIONS: In patients with moderate to severe AS, TDI allows for a reliable, noninvasive estimation of filling pressures. In such patients, systolic long-axis function is impaired even in the presence of normal ejection fraction and cardiac index. Thus, TDI integrates information about systolic and diastolic performance and may be a useful addition in the echocardiographic workup and care of patients with AS.

Vasoactive peptides during long-term follow-up of patients after cardiac transplantation.

BACKGROUND: Vasoactive peptides are accepted indicators of the degree of heart failure and its progression or improvement following medical therapy. Normalization of cardiac hemodynamics by cardiac transplantation (HTx) may lead to normalization of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) plasma levels shortly after the procedure. METHODS: Long-term follow-up was done for 14 consecutive patients, 12 men and 2 women, 49 years of age (range 24 to 64 years). ANP and BNP were measured by radioimmunoassay (RIA) in central venous plasma samples (before breakfast, at steady state) at the following intervals after HTx: 7 to 30 (1), 31 to 60 (2), 61 to 90 (3), 120 to 180 (4) and 210 to 365 (5) days. RESULTS: During follow-up, ANP decreased significantly within 2 months after HTx and continued of this level, whereas BNP decreased continuously without reaching normal values. The mean ratio of ANP:BNP increased from 3.23 to 8.01 during follow-up. Whereas right atrial pressure (RAP), right ventricular pressure (RVP), right ventricular end-diastolic pressure (RVEDP) and pulmonary capillary wedge pressure (PCWP) did not change during follow-up, cardiac output (CO) improved slightly, but significantly from 5.21 liters/min to 5.9 liters/min (p = 0.035). CONCLUSIONS: Normalization of left ventricular function after orthotopic HTx does not induce an early diminution of ANP and BNP plasma levels to normal concentrations. Although elevated ANP concentrations showed only minimal changes within 1 year, BNP decreased significantly as early as 2 months after HTx, without reaching normal values during the year of follow-up. Also, the ratio of ANP and BNP increased significantly from 3.23 to 8.01. These results demonstrate the contribution of other factors beyond cardiac function that determine the levels of these peptides.

Left ventricular pressure and volume unloading during pulsatile versus nonpulsatile left ventricular assist device support.

BACKGROUND: Nonpulsatile axial or centrifugal pumps are the latest generation of left ventricular assist devices (LVAD). Whether left ventricular (LV) unloading and outcome in these devices is similar to pulsatile LVADs during long-term support has not been investigated. We compared LV unloading and mortality between different types of LVAD support (pulsatile versus nonpulsatile). METHODS: In 31 patients undergoing long-term LVAD implantation (nonpulsatile = 10, pulsatile = 21) preoperative and postoperative echocardiographic and hemodynamic assessment with right heart catheterization had been obtained. RESULTS: All patients had similar echocardiographic, hemodynamic, and clinical heart failure characteristics at baseline. The degree of LV pressure unloading was the same in both device types, caused by similar reduction of mean pulmonary pressure (18.6 +/- 5.1 versus 18.3 +/- 7.5 mm Hg) and pulmonary capillary wedge pressure (8.9 +/- 4.4 versus 8.0 +/- 7.0 mm Hg). Left ventricular volume unloading was pronounced with a pulsatile device owing to a statistically significant higher pump output (5.1 +/- 1.0 L/min) in comparison with nonpulsatile LVADs (3.6 +/- 0.9 L/min, p < 0.001). Echocardiographic-determined end-systolic indicators confirm this augmentation in pulsatile LVADs. Etiology or the time interval of hemodynamic reassessment had no impact in left ventricular pressure unloading, but LV volume unloading decreased between day 60 and 120 in patients with nonpulsatile LVADs. The preoperative and postoperative transplant mortality was comparable in both groups. CONCLUSIONS: Left ventricular pressure unloading is similar in patients with nonpulsatile as compared with pulsatile implantable long-term assist devices. Left ventricular volume unloading is pronounced in pulsatile LVADs.