Update on percutaneous mitral valve therapy: clinical results and real life experience.

Mitral regurgitation (MR) is a common valvulopathy worldwide increasing in prevalence. Cardiac surgical intervention, preferable repair, is the standard of care, but a relevant number of patients with severe MR do not undergo surgery because of high peri-operative risk. Percutaneous mitral valve repair with the MitraClip System has evolved as a new tool for the treatment of severe MR. The procedure simulates the surgical edge-to-edge technique, developed by Alfieri in 1991, creating a double orifice valve by a permanent approximation of the two mitral valve leaflets. Several preclinical studies, registries and Food and Drug Administration approved clinical trials (EVEREST, ACCESS-EU) are currently available. The percutaneous approach has been recently studied in a randomized controlled trial, concluding that the device is less effective at reducing MR, when compared with surgery, by associated with a lower adverse event rate. The patients enrolled in this trial had a normal surgical risk and mainly degenerative MR with preserved left ventricular function. On the other hand, results derived from the clinical "real life" experience, show that patients actually treated in Europe present a higher surgical risk profile, more complex mitral valve anatomy and functional MR in the most of cases. Thus these data suggest that MitraClip procedure is feasible and safe in this subgroup of patients that should be excluded from the EVEREST trial due to rigid exclusion criteria. Despite the promising results clinical experience is still small, and no data related the durability are currently available. Therefore, MitraClip device should be reserved now to high risk or inoperable patients.

Clinical impact and evolution of mitral regurgitation after TAVI using the new generation self-expandable valves.

BACKGROUND: Concomitant mitral regurgitation (MR) impaired prognosis in patients undergoing transcatheter aortic valve implantation (TAVI). It has been suggested that the use of first generation self-expandable valve in patients with significant MR is associated with worse outcome as compared with balloon expandable valve. However, the impact of newer generation transcatheter devices on MR has not been investigated so far. We aim to assess the prognostic impact of MR in patients undergoing TAVI with the first-generation vs. the latest generation of self-expandable valves. METHODS: We analyzed 2964 consecutive patients who underwent TAVI. Patients were classified into 4 groups according to the degree of baseline MR and the generation of self expandable valve implanted. RESULTS: Of 1234 patients with moderate or severe MR, 817 were treated with first generation and 417 patients with second generation valves. Whereas, of 1730 patients with no or mild MR, 1130 were treated with first generation and 600 patients with second generation valves. Although, concomitant moderate-severe MR was found to be an independent predictor of mortality after TAVI, the use of newer generation self expandable valves was associated with higher survival rate at 1 year irrespective of the degree of preprocedural MR. At multivariable analysis the use of newer generation valve was associated with MR improvement throughout 1 year follow-up. CONCLUSION: Baseline moderate-severe MR is associated with an increase in mortality after TAVI. However, the degree of preprocedural MR doesn't impact survival when a second generation self expandable valve is used.

Reduction of mitral valve regurgitation with Mitraclip® percutaneous system.

Mitral regurgitation (MR) is the second most common heart valve disease worldwide and the current gold-standard treatment is surgical repair or replacement. Nevertheless, many patients do not undergo surgical intervention due to several comorbidities. Percutaneous "edge-to-edge" mitral valve repair using the MitraClip System is an emerging and effective option to this subset of patients. This device has been used to treat both functional and degenerative mitral valve regurgitation and has been compared to surgery in the Endovascular Valve Edge-to-Edge Repair Study II (EVEREST II) randomized trial. Although the field of percutaneous management of MR is at an early stage, it has been demonstrated that percutaneous approaches can reduce MR, suggesting there is a great deal of potential for clinical benefit to patients with MR.

Possible role for increased C4b-binding-protein level in acquired protein S deficiency in type I diabetes.

In this study, total protein S (PS) immunological levels, free-PS and C4b-binding-protein (C4bBP) concentrations, and PS functional activity were investigated in insulin-dependent (type I) diabetic patients and compared with nondiabetic subjects. Mean total PS antigen concentration was not different between diabetic patients and nondiabetic subjects, whereas free-PS levels and PS functional activity were significantly reduced in diabetic patients. C4bBP was increased in diabetic patients and correlated with HbA1 levels. This study shows that type I diabetic patients have depressed free PS and PS activity despite the presence of normal total PS concentration and suggests that this phenomenon is probably linked to the increase of circulating C4bBP.

The HLA class I-CML association revisited taking into account the two forms of gene fusion in the Philadelphia chromosome. A multicenter study.

CML patients possess either a b3-a2 or a b2-a2 fusion between the BCR and ABL genes. Depending on the type of fusion, two different series of non-self potentially immunogenic peptides may be produced. If they are presented by HLA class I molecules and recognized by cytotoxic CD8 lymphocytes, individuals could be more susceptible or resistant to leukemic cells bearing one or the other form of fusion according to their HLA class I phenotype. To test this point, the frequencies of HLA-A and HLA-B alleles were compared between b3-a2 and the b2-a2 CML patients. In essence, no difference was found whose significance could withstand correction for multiple comparisons.

Transcatheter Aortic Valve Implantation Experience with SAPIEN 3.

Based on randomized trials with first generation devices, transcatheter aortic valve replacement (TAVI) has been included into the treatment strategy for high-risk and inoperable patients with severe aortic stenosis. Procedural complications remain a concern with TAVI, including stroke, vascular complications, paravalvular leak (PVL) and conduction disturbances. Addressing these limitations will support TAVI use in lower risk populations. This review discussed features and most recent clinical evidence of the new balloon-expandable THV (SAPIEN 3, Edwards Lifescience, Irvine, CA, USA).

Prevention and therapy of experimental venous thrombosis in rabbits by desmin 370.

Desmin 370 (D370), a low molecular weight dermatan sulfate, has been shown to reduce the size of preformed thrombi in rats, via a mechanism largely independent of its anticoagulant activity. In the present study we investigated the therapeutic efficacy of D370 in rabbits with experimental jugular vein thrombosis. Experiments performed to evaluate the antithrombotic dosages in rabbits indicated that D370 prevented the formation of venous thrombi (Wessler model) in a dose-dependent manner with complete inhibition at 20 mg/kg. When injected to rabbits bearing a 30 min aged thrombus, D370 caused a time- and dose-dependent reduction in thrombus weight. Thrombi harvested 2 h after injection of 50 mg/kg of D370 were 71% smaller than thrombi from saline-treated rabbits and 50% smaller than pretreatment thrombi, suggesting a double effect of the drug: inhibition of thrombus accretion and reduction of the existing thrombus. Interestingly, pretreatment with the fibrinolytic inhibitor EACA (1 g/kg), significantly attenuated the therapeutic efficacy of D370, suggesting a possible involvement of the fibrinolytic system. Heparin (50 and 200 U/kg) was less active as therapeutic agent, the maximal decrease in thrombus weight, as compared to untreated rabbits, amounting to 38%. Heparin, moreover, caused a more pronounced prolongation of APTT than comparable antithrombotic dosages of D370. Our present data extend previous results on the therapeutic efficacy of D370 and underscore its potential as an alternative antithrombotic drug.

Desmin 370, a low molecular weight dermatan sulfate, reduces the weight of preformed thrombi in rats made afibrinogenemic by ancrod.

Desmin 370 (D370), a low molecular weight dermatan sulfate, has been shown to induce a marked reduction of the weight of preformed venous thrombi in rats and rabbits by mechanisms that appeared largely independent of inhibition of thrombus accretion. In order to provide further support for such a mechanism, we exploited the defibrinating capacity of ancrod to obtain a thrombosis model characterized by the lack of thrombus growth and thus sensitive only to agents promoting thrombus lysis. Thrombus formation in anesthetized rats was induced by vena cava ligature. Injection of ancrod (5 U/kg) 5 h after induction of venous stasis caused a more than 95% reduction in plasma fibrinogen and prevented thrombus accretion as indicated by the lack of thrombus weight increase during the 3 h experimental period (12.2 +/- 0.6 vs 14.5 +/- 1 as compared to 12.6 +/- 0.6 vs 19.6 +/- 0.8, p < 0.01, in control rats) and by the almost complete (> 90%) inhibition of 125I-fibrin(ogen) binding to thrombi. Moreover, when ancrod was given 1 h before vena cava ligature, no thrombi were formed within 2 h whereas at the same time interval visible thrombi were present in all control rats. Administration of D370 (10 mg/kg) to thrombus bearing rats, 1 h after induction of afibrinogenemia, resulted in a significant reduction in thrombus weight (43% after 2 h, p < 0.01) which was only slightly lower than that recorded in normofibrinogenemic rats (54%). Enhancement of plasma fibrinolytic activity by ancrod had no influence on thrombus lysis and was not all affected by administration of D370.(ABSTRACT TRUNCATED AT 250 WORDS)

Therapeutic effect of a low molecular weight dermatan sulphate (Desmin 370) in rat venous thrombosis--evidence for an anticoagulant-independent mechanism.

We evaluated the capacity of a low molecular weight dermatan sulphate (D370) to prevent thrombus formation and to induce a reduction of a stabilized thrombus in a rat venous thrombosis model. Injection of D370, 10 min before induction of venous stasis (prevention model), prevented thrombus formation in a dose-dependent way (ED50: 2.3 mg/kg). When given to rats 6 h after induction of venous stasis (therapeutic model), D370 caused a time- and dose-dependent reduction in thrombus size (60% to 70% reduction 2 h after injection of 10 mg/kg). At comparable antithrombotic dosages (i.e. minimum dose giving complete inhibition of thrombus formation), heparin (0.5 mg/kg) only caused 40% reduction of a preformed thrombus while hirudin (1 mg/kg) was virtually ineffective (less than 10% reduction in weight). All three compounds inhibited 125I-fibrin(ogen) deposition on 6-h aged thrombi by more than 85%, suggesting that D370 and, to a lesser extent, heparin reduce thrombus size via mechanisms other than inhibition of thrombus accretion. The involvement of a fibrinolysis-mediated mechanism in the D370-induced effect is suggested by the following. EACA (1 g/kg), when given to thrombus-bearing control animals, did not influence thrombus weight. However, when administered before D370 treatment, it prevented the expected reduction in thrombus weight by more than 80%, without influencing the effect of D370 on 125I-fibrin(ogen) accumulation onto preexisting thrombi. D370 injection caused neither an enhancement of fibrinolytic activity nor a reduction of PAI in plasma. In vitro, D370 (200 microns/ml) was unable to potentiate the spontaneous or PA-induced lysis of 125I-fibrinogen labelled blood, plasma, or purified fibrin clots.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein C deficiency in insulin-dependent diabetes: a hyperglycemia-related phenomenon.

In 30 insulin-dependent diabetic patients protein C (PC) antigen and PC activity were significantly lower than those of matched control healthy subjects. An inverse correlation between fasting plasma glucose and both PC concentration and activity was present in diabetics, while a direct correlation between PC concentration and PC activity was observed. Induced hyperglycemia in diabetic and normal subjects was able to decrease both PC antigen levels and PC activity, and heparin reversed in part this effect. In diabetic patients euglycemia obtained by insulin infusion restored to normal the depressed PC levels. Heparin did not alter both the basal PC concentration and activity in healthy controls. These data stress the major role of hyperglycemia in determining PC decrease in diabetics, and suggest that PC reduction is probably associated to hyperglycemia-enhanced thrombin formation.

Peripheral blood stem cell collection from G-CSF-stimulated unrelated donors for second transplant.

Peripheral blood stem cells (PBSCs) collected following stimulation with cytokines are commonly used for autologous haematopoietic transplants. Currently, PBSCs are being used for syngeneic or allogeneic transplants from matched or haploidentical donors. However, many issues are still unanswered regarding the early or late side-effects cytokines have on recipients and on healthy donors. The aims of this paper were to evaluate the experience acquired worldwide in this field, to define the acceptability of stem cell donation by G-CSF-stimulated apheresis from unrelated donors after the failure of a first donation, and to assess side-effects of G-CSF on unrelated donors. The use of PBSCs has increased tremendously over the last few years and in the near future PBSCs will probably become the most relevant source of stem cells. Studies conducted so far have definitely concluded that G-CSF is safe and well tolerated. Results observed in transplants utilizing marrow stem cells compared with results obtained in transplants utilizing PBSCs have shown that patients undergoing this latter procedure recover earlier, require a lower number of transfusions and spend fewer days in hospital with a consequent decrease in costs. We concluded that a second transplant by G-CSF-stimulated apheresis from an unrelated donor is definitely acceptable and we designed a prospective study to better define all controversial aspects. Donors will be given 10 microg/kg/day of G-CSF subcutaneously for 5 days. One or two PBSC collection procedures will be performed: the first on day 5 and the second, if necessary, on day 6. Donors will be surveyed and blood counts monitored in a standardized manner during the process.

Alternative donor transplants for patients with advanced hematologic malignancies, conditioned with thiotepa, cyclophosphamide and antithymocyte globulin.

Preparative regimens without total body irradiation (TBI) have been reported for alternative donor hemopoietic stem cell transplants (HSCT). Between 7 September 1994 and 7 June 1999 48 patients with advanced hematologic malignancies were conditioned with thiotepa (THIO) 15 mg/kg, cyclophosphamide (CY) 150 mg/kg and antithymocyte globulin (ATG). Donors were HLA mismatched family members (1-2 antigens) (FAM) (n = 24, median age 31 years) or HLA matched unrelated donors (UD) (n = 24, median age 34 years). GVHD prophylaxis was cyclosporine and methotrexate. Stem cell source was peripheral blood (n = 8) or bone marrow (n = 40). Hematologic recovery was seen in 42/46 (91%) evaluable patients and complete chimerism in 31/37 patients (85%). Acute GVHD grades III-IV were seen in 10/46 patients surviving 10 days (21%) and extensive chronic GVHD in 2/36 patients surviving 100 days (5%). Twenty-six patients died (54%), eight of recurrent disease (17%) and 18 of transplant-related complications (37%): main causes of TRM were GVHD (15%), infections (15%) and graft failure (4%). Twenty-two patients (46%) survive with a median follow-up of 877 days (287-1840). The actuarial 3-year survival is 49% for FAM and 42% for UD transplants. Results obtained with this regimen in unrelated grafts for advanced CML (n = 15) were not significantly different when compared to 21 concurrent UD grafts for advanced CML prepared with CY-TBI. In conclusion, the combination of THIO-CY-ATG allows engraftment of alternative donor hemopoietic stem cells. Results are similar when using unrelated matched donors or partially mismatched family donors, and not significantly different when compared to patients conditioned with CY-TBI.

Bone marrow transplantation for chronic myeloid leukemia (CML) from unrelated and sibling donors: single center experience.

This is a report on 60 consecutive patients with chronic myeloid leukemia (CML) who received an allogeneic bone marrow transplant (BMT) in this Unit. Donors were HLA-identical siblings (SIB) (n = 36) or unrelated donors (MUD) (n = 24) matched by serology for HLA A and B and by molecular biology for HLA DR. All patients were prepared with cyclophosphamide 120 mg/kg and fractionated total body irradiation 10-12 Gy. GVHD prophylaxis consisted of cyclosporin A (CsA) starting on day -7 and short-course methotrexate. Bone marrow was unmanipulated in all cases. Cytomegalovirus prophylaxis consisted of acyclovir for SIBs and foscarnet for MUDs. When compared to SIB transplants, MUD patients were younger (29 vs 36 years; P = 0.002), had younger donors (31 vs 39; P = 0.001), had a longer interval between diagnosis and BMT (1459 vs 263 days; P < 0.001) and received a smaller number of nucleated cells at transplant (3.3 vs 4.4 x 10(8)/kg; P = 0.003). More MUDs had advanced disease (50 vs 17%, P = 0.005). The median day to 0.5 x 10(9)/l neutrophils was similar in both groups (18 days for SIBs vs 17 days for MUDs; P = 0.06); the median platelet count on days +30, +50, +100 was significantly (P < 0.01) higher in SIB than in MUD patients (122 vs 38, 113 vs 50 and 97 vs 45 x 10(9)/l, respectively). Acute GVHD was scored as absent-mild, moderate, or severe, in 36, 58 and 6% of SIBs vs 25, 42 and 33% in MUD patients (P = 0.01). Chronic GVHD was comparable (P = 0.1). The actuarial risk of CMV antigenemia at 1 year was 60% in both groups. There were six deaths in SIB patients (two leukemia, two infections, one GVHD, one pneumonitis) and four deaths in MUD patients (three acute GVHD and one infection). Fifty patients survive with a median follow-up of 656 days for SIBs and 485 for MUDs. The actuarial 3-year transplant-related mortality is 12% in SIBs and 17% in MUDs (P = 0.5); the actuarial relapse is 18% in SIBs vs 6% in MUDs (P = 0.4) and 3-year survival 78% in SIBs vs 82% in MUDs (P = 0.7). This study suggests that survival of CML patients after marrow transplantation from unrelated or sibling donors is currently similar, provided the former are well matched. The increased incidence of GVHD in MUD patients is possibly compensated by a lower risk of relapse.

Unrelated donor marrow transplantation: initial experience of the Italian bone marrow transplant group (GITMO).

From 1 September 1988 to 30 September 1993, a search for an unrelated donor (URD) was started for 633 Italian patients. Eighty-five of them (13%) were transplanted. Despite the introduction of more strict criteria for the selection of compatible donors, the percentage of patients who reached transplant increased significantly after December 1992. For patients who started a search before and after January 1993, respectively the probability of transplant by 8 and 16 months from search activation was 4 and 10%, compared to 22 and 37% (P = 0.0001). The average intervals between search activation and graft were 15 and 8 months respectively, for the first and second group (P = 0.0001). Data of 75 consecutive transplants performed up to March 1994 were analyzed. Actuarial 2-year survival was 15% for patients grafted before 1992 and 40% for those grafted after January 1992. In this latter period, survival of patients with malignant and non-malignant disorders was 32 and 67%, respectively. In univariate analysis, patients younger than 16 years (P = 0.01), patients grafted after 1992 (P = 0.01) and patients receiving the marrow from a 6-antigen matched donor (P = 0.01) showed a higher survival probability. Multivariate analysis did not show any difference, probably due to the low number of patients and to short follow-up. The adoption of stricter and more accurate HLA-matching criteria and the consequent reduction of deaths related to acute GVHD were the main reasons for the improvement of survival observed in patients grafted after 1992.

Antithrombotic activity of a glycosaminoglycan (sulodexide) in rats.

Glycosaminoglycans extracted from various sources are extensively utilized in the treatment of occlusive vascular disease. These products have shown to possess antithrombotic activity in some experimental thrombosis (1,2). Our purpose was to study the activity of Sulodexide, an heparin-like compound (3,4), on rat model of arterial thrombosis and to study its interaction with platelets.

Thrombolysis enhancing activity of a low molecular weight dermatan sulfate (Desmin 370) in experimental pulmonary embolism in rats.

The effect of Desmin 370 (D370), a low molecular weight dermatan sulfate, on the extent of lysis of radiolabelled pulmonary emboli in rats was evaluated. 125I-fibrin labelled blood clots were embolized into the lungs via a jugular vein, and the degree of lysis was calculated, at predetermined intervals, by the residual radioactivity in the lungs. A single i.v. injection of D370 (50 mg/kg) caused a significant increase in the rate of lysis, which was visible at 30 min and persisted for the whole experimental period (2 h). This effect was prevented by epsilon-aminocaproic acid (1 g/kg). At comparable antithrombotic dosages, heparin (2 mg/kg) also produced a significant enhancement of thrombolysis while hirudin (2 mg/kg) was totally ineffective. Heparin, however, produced a much more pronounced anticoagulant effect than D370. No changes in the plasma levels of plasminogen activator and plasminogen activator inhibitor activities were observed after treatment with D370. Moreover, the dermatan sulfate failed to enhance the blood fibrinolytic activity measured by a solid phase 125I-fibrin assay. These results extend previous data indicating that D370 may be efficient also in the therapy of thrombosis and provide direct evidence that this effect occurs, at least in part, via degradation of thrombus associated fibrin.

Pharmacology of desmin (low molecular weight dermatan sulphate) in healthy volunteers following intravenous bolus administration of different dosages (200, 400, 800 mg).

Eight healthy volunteers (6 males, 2 females, mean age 31.6 yrs), were administered--on three separate days--200, 400 and 800 mg of a new low molecular weight Dermatan sulphate (Desmin), given as a single i.v. bolus (2 min.) injection. Before each administration and 10, 20, 30 min., 1, 2, 4, 8, 12, 24 hours after, blood samples were drawn and the following coagulative assays performed: aPTT (activated Partial Thromboplastin Time), TT (Thrombin Time), anti Xa (Xa Factor inhibition), Heptest, Stachrom D.S.. Furthermore, a kinetic analysis was performed on the activity curves calculated on the Heptest and Stachrom data. Plasma peak values and half lives of the parameters checked showed a clear dose-effect relationship. aPTT and TT showed very short-lasting variations and the inhibition of Factor Xa was moderate, but significant. The most evident and specific effects of Desmin were those on Heptest and Stachrom D.S.: both tests were influenced in a clear-cut and dose-dependent way, mainly as a consequence of the action of Desmin on HCII, with partially different kinetic patterns. A series of in vitro experiments proved an anti Xa effect of Desmin, mediated by antithrombin III, well above the possible interference of the small (< 1%) heparin contaminants in Desmin. An even more marked anti Xa activity was seen in the in vivo study, an observation so far unrecognized for this type of drug: some possible interpretations of this fact are discussed.

Pharmacodynamic effects of single and repeated doses of oral sulodexide in healthy volunteers. A placebo-controlled study with an enteric-coated formulation.

Eight male and 8 female healthy volunteers, aged on average 32 +/- 6 years, underwent a randomized, crossover study, aimed at comparing the activity on some fibrinolysis and coagulation parameters of 100 and 200 mg/day of oral sulodexide, administered as enteric-coated tablets. After the single and the repeated (for 7 days) administration of the two daily dosages, the Fibrin Plates test, the Heptest, the Plasminogen Activator Inhibitor test (as to both activity and antigen level) and the activated Partial Thromboplastin Time were checked during the first 6 hours after administration. The pro-fibrinolytic and antithrombotic activity of sulodexide was confirmed to be significant with both dosage schemes and potentiated by repeated administrations. On the other hand, the absence of any influence on aPTT confirmed the lack of interference of the drug, after oral administration, on the intrinsic pathway of coagulation. No adverse reactions or events were observed.

[The Italian Registry of Bone Marrow Donors]. / Il Registro Italiano dei Donatori di Midollo Osseo.

Following a synthetic statement of the scientific, genetic and practical assumptions of the bone marrow transplantation (BMT) from marrow unrelated donor (MUD), which, in turn, have represented the basis for the establishment of the Italian Bone Marrow Donor Registry (IBMDR), the paper reports the registry activity on 30 November 1998. At that date, Italian volunteers were 232,876, number which put the IBMDR as the fourth registry all over the world and as the third in Europe. The mean age of the donors is 34 years, and this means that IBMDR is one of the youngest among international registries. Using Italian donors, 426 BMT, altogether, have been performed, (248 for Italian patients and 178 for foreign patients). Donor search activations performed by national and international transplant centres have been, at the same date, 5729 (1821 for Italian patients and 3908 for foreign patients). Operating standards and guidelines for all centres participating in the IBMDR are reported in this issue.

[Genetic analysis of Italian hematologic patients candidates for bone marrow transplantation from unrelated donors]. / Analisi genetica di pazienti ematologici italiani candidati al trapianto di midollo osseo da donatore non consanguineo.

Frequencies of HLA-A, -B and -DR antigens and haplotypes were determined in 1945 Italian patients suffering from hematologic diseases and requiring bone marrow transplantation from unrelated donors. These frequencies were compared with those obtained from the Italian bone marrow donor population. No significant differences were found when considering the number of comparisons made, suggesting that the genetic structure of the Italian patients is not different from that of the Italian donor population.