A Randomized Clinical Trial of Trimetazidine, a Partial Free Fatty Acid Oxidation Inhibitor, in Patients With Heart Failure
Gabriele Fragasso, Altin Palloshi, Patrizia Puccetti, Carmen Silipigni, ...Alessandra Rossodivita, Mariagrazia Pala, Giliola Calori, Ottavio Alfieri, Alberto Margonato
We assessed whether the addition of trimetazidine to conventional therapy in patients with heart failure (HF) could improve New York Heart Association (NYHA) functional class and left ventricular function. Fifty-five HF patients were randomly allocated in an open-label fashion to either conventional therapy plus trimetazidine or conventional therapy alone. Compared with those on conventional therapy only, NYHA functional class and ejection fraction (EF) improved in patients on trimetazidine. These benefits contrast with the natural history of the disease, as shown by the decrease in EF when on conventional therapy only. The question of whether these benefits could translate into decreased morbidity and mortality needs further investigation.
This study sought to assess whether the long-term addition of trimetazidine to conventional treatment could improve functional class, exercise tolerance, and left ventricular function in patients with heart failure (HF).
Previous small studies have shown that trimetazidine may be beneficial in terms of left ventricular function preservation and control of symptoms in patients with post-ischemic HF.
Fifty-five patients with HF were randomly allocated in an open-label fashion to either conventional therapy plus trimetazidine (20 mg three times daily) (28 patients) or conventional therapy alone (27 patients). Mean follow-up was 13 ± 3 months. At study entry and at follow-up, all patients underwent exercise testing and two-dimensional echocardiography. Among the others, New York Heart Association (NYHA) functional class and ejection fraction (EF) were evaluated.
In the trimetazidine group, NYHA functional class significantly improved compared with the conventional therapy group (p < 0.0001). Treatment with trimetazidine significantly decreased left ventricular end-systolic volume (from 98 ± 36 ml to 81 ± 27 ml, p = 0.04) and increased EF from 36 ± 7% to 43 ± 10% (p = 0.002). On the contrary, in the conventional therapy group, both left ventricular end-diastolic and -systolic volumes increased from 142 ± 43 ml to 156 ± 63 ml, p = 0.2, and from 86 ± 34 ml to 104 ± 52 ml, p = 0.1, respectively; accordingly, EF significantly decreased from 38 ± 7% to 34 ± 7% (p = 0.02).
In conclusion, long-term trimetazidine improves functional class and left ventricular function in patients with HF. This benefit contrasts with the natural history of the disease, as shown by the decrease of EF in patients on standard HF therapy alone.
Infections and autoimmunity have been implicated in the pathogenesis of atherosclerosis. Cytomegalovirus has been shown to contribute to the disease. Autoantibodies against human heat-shock protein ...(HSP) 60 are present in most atherosclerotic patients, and their titre correlates with disease severity, suggesting that anti-HSP60 might be implicated in disease pathogenesis. We postulated that cytomegalovirus infection might induce antibodies able to bind human HSP60 and to cause endothelial-cell damage.
We studied 180 patients with coronary-artery disease, raised high sensitivity C-reactive protein concentrations, and presence or absence of traditional risk factors; 90 patients with coronary-artery disease, normal values for high sensitivity C-reactive protein, and no traditional risk factors; and 98 controls. Individual sera were used to define the relevant epitope of HSP60 by ELISA. Affinity purified IgGs were used to identify endothelial cell-surface ligands by western blot and to induce apoptotic cell death.
We identified an 11 aminoacid sequence of HSP60 that was recognised by most patients with coronary-artery disease. This peptide shares homology with cytomegalovirus-derived proteins UL122 and US28. The same patients' sera recognised UL122-derived and US28-derived peptides. Purified IgGs against HSP60 and the viral peptides bound non-stressed human endothelial cells and induced endothelial-cell apoptosis by interaction with cell-surface molecules.
During cytomegalovirus infection, antibodies against the virus can arise that are able to crossreact with human HSP60 and cause apoptosis of non-stressed endothelial cells, which is judged a primary event in the pathogenesis of atherosclerosis.
Heart failure may promote metabolic changes such as insulin resistance, in part through neurohumoral activation, and determining an increased utilization of non-carbohydrate substrates for energy ...production. In fact, fasting blood ketone bodies as well as fat oxidation have been shown to be increased in patients with heart failure. The result is depletion of myocardial ATP, phosphocreatine and creatine kinase with decreased efficiency of mechanical work. A direct approach to manipulate cardiac energy metabolism consists in modifying substrate utilization by the failing heart. To date, the most effective metabolic treatments include several pharmacological agents that directly inhibit fatty acid oxidation. The results of current research are supporting the concept that shifting the energy substrate preference away from fatty acid metabolism and toward glucose metabolism could be an effective adjunctive treatment in patients with heart failure. Trimetazidine is the most studied drug in this context. Several small studies have evidenced the usefulness of such additional therapeutic tools for heart failure. More specifically, recent meta-analyses and a multicenter retrospective study have shown that additional use of trimetazidine in patients with heart failure, along with symptoms and cardiac function improvement, also provides a significant protective effect on all-cause mortality, cardiovascular events and hospitalization due to cardiac causes. Nevertheless, the exact role of metabolic therapy in heart failure is yet to be established, and a large multicenter randomized trial is necessary.
To relate therapeutic issues, comorbidities and functional parameters to mortality/morbidity of mild/moderate heart failure patients.
From our heart failure clinic, 372 heart failure patients (269 ...men, aged 66 ± 11 years), with stable heart failure and ejection fraction 45% or less were recruited. Survival curves were estimated according to the Kaplan-Meier method. Associations of protective/risk factors with cardiovascular mortality/morbidity were also evaluated.
One hundred and two patients (27%) died (aged 70 ± 10 years at diagnosis, 76 ± 10 at death) during follow-up (overall mortality at 60 months: 19.2%; mean follow-up period: 67 ± 44 months). Cardiovascular deaths were 64 (63% of total deaths, 44 men, age at diagnosis 70 ± 9). Cardiovascular mortality at 60 months was 12%; standardized mortality ratio was 5.9 for women and 6.8 for men. The remaining 38 patients (37% of total deaths, 30 men, age at diagnosis 70 ± 10) died of noncardiovascular causes. Overall, noncardiovascular mortality at 60 months was 7.2%; mean survival time from diagnosis to death was 63 ± 69 months (median 42, Q1 = 27.5, Q3 = 77.7). Average cardiovascular admission rate was 1.63 ± 1.84 admissions/patient. At multivariate analysis, only previous history of myocardial infarction hazard ratio: 3.62 (1.70-7.73), class of ejection fraction at diagnosis hazard ratio: 0.36 (0.32-0.60), acute cardiac decompensation at any time hazard ratio: 1.55 (1.32-1.84), implanted defibrillator hazard ratio: 0.11 (0.01-0.83) and use of statins hazard ratio: 0.08 (0.007-0.42) were independently associated with cardiovascular mortality. Factors associated to higher annual cardiovascular morbidity were age at diagnosis, chronic renal failure, diabetes, cardiac decompensation at any time, female sex and diuretic therapy. Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin-receptor-blockers reduced annual cardiovascular morbidity.
Survival in mild/moderate heart failure patients has consistently improved. Further improvements are warranted in terms of morbidity reduction.
Non-compaction of the ventricular myocardium (NCVM) is a rare disorder of myocardial morphogenesis usually diagnosed in paediatric age associated with high mortality rates. Among reported cases, NCVM ...has been described in only six patients > or = 70 years. We describe the case of a 74-year-old male with NCVM involving the left ventricle, representing one of the oldest patients ever reported in the literature. Of note, this case was characterized by late appearance of NCVM and rapid deterioration of clinical conditions. The wide age range of symptom onset from prenatal to geriatric age supports the hypothesis that NCVM is a multifactorial rather than a simple congenital disorder.
Two ligands widely used for
111In labelling of human platelets, oxine and tropolone, were compared as to the degree of their influence on platelet function. The labelling efficiency was assessed as a ...function of experimental variables. A good preservation of platelet function as evaluated by
ex vivo aggregation was obtained with both techniques. The extent of tracer detached from platelets was evaluated
in vitro and
in vivo: in normal subjects
111In was virtually all bound to platelets. A significant reduction in radiolabelling efficiency and a decreased percentage of
111In bound to platelets
in vivo was observed in patients with platelet counts < 150,000/mL.
Despite treatment with intensive chemotherapy, acute myelogenous leukemia (AML) remains an aggressive malignancy with a dismal outcome in most patients. We found that AML cells exhibit an unusually ...rapid accumulation of the repressive histone mark H3K27me3 on nascent DNA. In cell lines, primary cells and xenograft mouse models, inhibition of the H3K27 histone methyltransferase EZH2 to decondense the H3K27me3-marked chromatin of AML cells enhanced chromatin accessibility and chemotherapy-induced DNA damage, apoptosis, and leukemia suppression. These effects were further promoted when chromatin decondensation of AML cells was induced upon S-phase entry after release from a transient G
arrest mediated by CDK4/6 inhibition. In the
-null KG-1 and THP-1 AML cell lines, EZH2 inhibitor and doxorubicin cotreatment induced transcriptional reprogramming that was, in part, dependent on derepression of H3K27me3-marked gene promoters and led to increased expression of cell death-promoting and growth-inhibitory genes.In conclusion, decondensing H3K27me3-marked chromatin by EZH2 inhibition represents a promising approach to improve the efficacy of DNA-damaging cytotoxic agents in patients with AML. This strategy might allow for a lowering of chemotherapy doses, with a consequent reduction of treatment-related side effects in elderly patients with AML or those with significant comorbidities. SIGNIFICANCE: Pharmacological inhibition of EZH2 renders DNA of AML cells more accessible to cytotoxic agents, facilitating leukemia suppression with reduced doses of chemotherapy.
.
Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity and mortality. In an uncontrolled study published in 2005, administration of CMV-specific hyperimmune globulin to ...pregnant women with primary CMV infection significantly reduced the rate of intrauterine transmission, from 40% to 16%.
We evaluated the efficacy of hyperimmune globulin in a phase 2, randomized, placebo-controlled, double-blind study. A total of 124 pregnant women with primary CMV infection at 5 to 26 weeks of gestation were randomly assigned within 6 weeks after the presumed onset of infection to receive hyperimmune globulin or placebo every 4 weeks until 36 weeks of gestation or until detection of CMV in amniotic fluid. The primary end point was congenital infection diagnosed at birth or by means of amniocentesis.
A total of 123 women could be evaluated in the efficacy analysis (1 woman in the placebo group withdrew). The rate of congenital infection was 30% (18 fetuses or infants of 61 women) in the hyperimmune globulin group and 44% (27 fetuses or infants of 62 women) in the placebo group (a difference of 14 percentage points; 95% confidence interval, -3 to 31; P=0.13). There was no significant difference between the two groups or, within each group, between the women who transmitted the virus and those who did not, with respect to levels of virus-specific antibodies, T-cell-mediated immune response, or viral DNA in the blood. The clinical outcome of congenital infection at birth was similar in the two groups. The number of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13% vs. 2%).
In this study involving 123 women who could be evaluated, treatment with hyperimmune globulin did not significantly modify the course of primary CMV infection during pregnancy. (Funded by Agenzia Italiana del Farmaco; CHIP ClinicalTrials.gov number, NCT00881517; EudraCT no. 2008-006560-11.).
PDF
