Levosimendan for the treatment of acute heart failure syndromes: time to identify subpopulations of responding patients.
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Cardiotonic Agents↗
Biomedical subjects
Dimitrios Farmakis
Publications and source records attributed to Dimitrios Farmakis.
Effects of levosimendan on right ventricular function in patients with advanced heart failure.
Right ventricular (RV) dysfunction frequently complicates advanced left ventricular heart failure and contributes to an unfavorable prognosis. Levosimendan is a novel inodilator that beneficially affects hemodynamics and left ventricular systolic and diastolic function in patients with advanced heart failure. However, its effects on RV function have not yet been properly assessed in these patients. In this randomized trial, the impact of levosimendan or placebo on various echocardiographic parameters of RV systolic and diastolic function was investigated in 54 patients with advanced heart failure due to left ventricular systolic dysfunction. Tissue Doppler imaging maximal systolic tricuspid annular velocity (S wave) increased significantly only in the levosimendan group (8.2 +/- 3.2 vs 9.0 +/- 3.0 cm/s, p <0.03). Tissue Doppler imaging RV early diastolic velocity (E wave) and the ratio of early to late diastolic velocities (E/A) also increased significantly after levosimendan administration (p <0.01 and p <0.05, respectively). Systolic pulmonary arterial pressure decreased significantly (54 +/- 11 vs 43 +/- 11 mm Hg, p <0.01) in the levosimendan-treated patients. Levosimendan beneficially modulated neurohormonal and inflammatory status by decreasing B-type natriuretic peptide levels (p <0.05) and by altering the ratio of interleukin-6 to interleukin-10 in favor of the latter (p <0.05). In conclusion, levosimendan could offer further therapeutic advantages in patients with advanced heart failure by improving systolic and diastolic RV function.
Blood Pressure↗
Endothelial function and arterial stiffness in sickle-thalassemia patients.
BACKGROUND: Homozygous sickle-cell anemia and beta-thalassemia are characterized by impaired endothelial function, while data on arterial stiffness have hitherto been conflicting. We sought to investigate aortic elastic properties and endothelial function in sickle-thalassemia, which combines molecular and clinical features of the above conditions. METHODS AND RESULTS: Forty-seven sickle-thalassemia patients, younger than 45 years, with preserved left ventricular (LV) function and no history of smoking, systemic or pulmonary hypertension, diabetes mellitus, dyslipidemia or thyroid disease, along with 40 healthy controls were studied. Aortic strain, distensibility and stiffness index were calculated by echocardiographically-obtained aortic root diameters. Brachial artery endothelial function was assessed by ultrasonographic evaluation of flow-mediated dilatation (FMD) and nitrate-mediated dilatation (NMD). Left ventricle was assessed by echocardiography. Patients had an impaired FMD (4.2+/-2.9% versus 9.2+/-3.8% in controls, p<0.001) with a preserved NMD (16.9+/-5.6% versus 15.2+/-4.8% in controls, p>0.05). Aortic strain and distensibility were lower and aortic stiffness index was higher in patients compared to controls (8.1+/-4.6 versus 5.8+/-2.9, p<0.01). Indexed LV diameters and mass were higher in patients. Systolic LV function was preserved, while 14.9% of patients had an impaired relaxation transmitral inflow pattern. Patients' LV mass index and diastolic mitral E wave deceleration time were positively correlated with aortic stiffness index (p<0.001). CONCLUSION: Sickle-thalassemia is characterized by a complex vasculopathy, consisting of endothelial dysfunction and increased arterial stiffness, with a global effect on cardiovascular function.
Adult↗
Effects of levosimendan versus dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure.
A single levosimendan administration has recently been shown to result in clinical and hemodynamic improvement in patients with decompensated heart failure (HF), but without survival benefits. In this study, the effects of levosimendan and dobutamine on plasma levels of proinflammatory and proapoptotic mediators in decompensated HF were compared and correlated with the concomitant effects on cardiac function and prognosis. Sixty-nine patients were randomized to received 24-hour intravenous infusions of levosimendan (n = 23), dobutamine (n = 23), or placebo (n = 23). Echocardiographic, hemodynamic, and biochemical assessments were performed at baseline, immediately after treatment, and 48 hours later. Patients were subsequently followed for 4 months for disease progression. End-systolic wall stress, the left ventricular ejection fraction, pulmonary capillary wedge pressure, and cardiac index were significantly improved in the levosimendan group but remained practically unaffected in the other groups. Plasma N-terminal-pro-B-type natriuretic peptide, tumor necrosis factor-alpha, and soluble Fas ligand levels were significantly decreased only in the levosimendan group (from 1,900 +/- 223 to 1,378 +/- 170 pg/ml, 13.4 +/- 1.0 to 12.3 +/- 1.2 pg/ml, and 68.2 +/- 3.7 to 59.8 +/- 3.6 pg/ml, respectively; p <0.05 for all); interleukin-6 was also borderline reduced (p = 0.051). Levosimendan-induced reduction in end-systolic wall stress was significantly correlated with respective decreases in N-terminal-pro-B-type natriuretic peptide (r = 0.671, p <0.01), tumor necrosis factor-alpha (r = 0.586, p <0.01), soluble Fas (r = 0.441, p <0.05), and soluble Fas ligand (r = 0.614, p <0.01). Event-free survival was significantly longer in the levosimendan group (p <0.05). In conclusion, the superiority of levosimendan over dobutamine in improving central hemodynamics and left ventricular performance in decompensated HF seems to be related to its anti-inflammatory and antiapoptotic effects.
Aged↗
Advanced stage clear-cell epithelial ovarian cancer: the Hellenic Cooperative Oncology Group experience.
PURPOSE: Ovarian clear-cell carcinomas (OCCC) are known to be possibly resistant to platinum-based chemotherapy and to have a poorer prognosis with respect to other subtypes of epithelial ovarian cancer (EOC). This study was undertaken to compare response and survival to platinum-based chemotherapy between patients with advanced stage III and IV OCCC and serous EOC (sEOC). PATIENTS AND METHODS: A retrospective analysis was performed in patients with advanced stage of OCCC treated with first-line platinum-based chemotherapy in the context of several study protocols of the Hellenic Cooperative Oncology Group (HeCOG) between 1/2/1987 and 31/10/2003. The outcome was compared to that of patients with sEOC treated according to the same protocols during the same study period. RESULTS: One hundred and five patients (35 stage III and IV OCCC, 70 stage III and IV sEOC) treated with platinum-based chemotherapy were analyzed. The overall response rate for OCCC was 45% (complete response 25%) (95% CI, 23.1% to 68.5%) and 81% (complete response 46%) (95% CI, 67.4% to 91.1%) for sEOC. The overall response rate was significantly higher for sEOC (P = 0.008). In the subgroup of stage III patients, the rate of complete responders was higher among sEOC patients (P = 0.023). After a median follow-up of 61.1 months, median survival and time to tumor progression were not significantly different between the two groups (25.1 months [95% CI 11.7 to 38.5 months] versus 49.1 months [95% CI 36.5 to 61.6 months], P = 0.141, 12.0 months [95% CI 6.5 to 17.3 months] versus 18.0 months [95% CI 14.7 to 21.6 months], P = 0.384, respectively). CONCLUSION: Patients with OCCC have significantly lower response to platinum-based first-line chemotherapy compared to patients with sEOC. This low response to platinum-based chemotherapy was not translated in significantly shorter survival. The current study outcomes are provocative and suggest that a new strategy for chemotherapy in OCCC should be adopted, possibly one that focuses on new agents without cross-resistance to platinum agents.
Adenocarcinoma, Clear Cell↗
Levosimendan therapy in decompensated chronic heart failure: favourable haemodynamic and neurohormonal effects but for how long?
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C-Reactive Protein↗
Aortic valve replacement in a patient with thalassemia intermedia.
Pseudoxanthoma elasticum-like diffuse elastic tissue defects and hypercoagulability are two well-established features in beta-thalassemia, which play a key role in the development of a spectrum of collateral complications in these patients. We present here a middle-aged thalassemia intermedia patient with severe aortic stenosis caused by heavy calcification of the valve, a hallmark of pseudoxanthoma elasticum. The patient underwent a successful replacement of the valve, which is the first such operation ever reported in these patients. However, rapid thrombosis leaded to failure of the mechanical valve, despite proper antithrombotic therapy.
Aortic Valve Stenosis↗
Extramedullary hematopoiesis-related pleural effusion: the case of beta-thalassemia.
BACKGROUND: Thalassemia intermedia has a later clinical onset and a milder anemia than thalassemia major, characterized by high output state, left ventricle remodeling, and age-related pulmonary hypertension. Bone deformities, extramedullary hematopoiesis (EMH), and spleen and liver enlargement are the consequences of hypoxia and enhanced erythropoiesis. The EMH-related pleural effusion is rarely referred to in the literature of thalassemia. METHODS: We reviewed the thalassemia patients' medical records hospitalized for pleural effusion in our Department, within the last 6 years. RESULTS: Eight (4 men) thalassemia intermedia patients admitted for symptomatic pleural effusion were identified. Common clinical findings on admission were dyspnea and apyrexia. Their mean hemoglobin level was 7.15 +/- 0.64 g/dL. Radiology revealed intrathoracic EMH and pleural effusion in all patients: exudative in seven patients and massive hemothorax in one. Cytologic fluid analysis was negative for malignancy. Fluid and serum cultures, antibodies, and stains were negative for viral, bacterial, and fungal infection. The hemothorax case was successfully treated with repeated aspirations, transfusions, and hydroxyurea. Although repeated thoracentesis and radiation could not control the effusions in the rest of the cases, pleurodesis was successful in 5 patients, without serious adverse events. Treatment was further accomplished with hydroxyurea. No relapses were observed in the mean 30 month follow-up period. CONCLUSIONS: Afebrile, EMH-related pleuritis represents a potentially life-threatening complication in thalassemia. Therapy should be individualized and treatment is emerging. Pleurodesis seems to be an effective and safe therapeutic option for exudative effusions, while transfusion-chelation therapy combined with hydroxyurea may be helpful in suppressing increased erythropoiesis.
Adult↗
Functional electrical stimulation improves endothelial function and reduces peripheral immune responses in patients with chronic heart failure.
BACKGROUND: Previous studies have shown beneficial effects of functional electrical stimulation (FES) on muscle performance and exercise capacity of patients with chronic heart failure. This study evaluates the impact of FES on endothelial function and peripheral markers of immune activation in patients with moderate to severe heart failure. METHODS: Twenty-four patients with a left ventricular ejection fraction of less than 40% and New York Heart Association class II-III symptoms, undergoing optimized drug therapy, were randomly assigned (2 : 1) to a 6-week training programme of FES (n=16) or served as controls (n=8). Endothelial function was assessed by Doppler flow-mediated dilatation (FMD) of the brachial artery before and after the training programme. Peripheral pro-inflammatory/anti-inflammatory markers such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cell adhesion molecule (sVCAM)-1 and IL-10 were also measured before and after training. RESULTS: A significant improvement on the 6-min walk test (7.5+/-3.3%), Minnesota Living Score (18.2+/-8.6%) and FMD (38.5+/-15.1%) was observed only in the FES-treated group. FES also causes a significant reduction of TNF-alpha (-11.5+/-8.9%), sICAM-1 (-13.1+/-9.8%), and sVCAM-1 (-10.6+/-6.6%), as well as a respective increase in the ratio IL-10/TNF-alpha (37.1+/-29.4%). In the FES group, the percentage improvement in the Minnesota Living Score was significantly correlated with respective changes in circulating TNF-alpha (r=0.624, P<0.01), sVCAM-1 (r=0.665, P<0.001) and the ratio IL-10/TNF-alpha (r=-0.641, P<0.01). CONCLUSION: FES is an exercise training programme that improves endothelial function in patients with chronic heart failure, and also has anti-inflammatory effects.
Blood Flow Velocity↗
Tissue Doppler imaging analysis at pre-cardioversion time predicts recurrent atrial fibrillation: a 12-month follow-up study.
INTRODUCTION: Tissue Doppler imaging (TDI) has been extensively used in several clinical settings. We aimed to investigate whether TDI can predict recurrent atrial fibrillation (AF). METHODS AND RESULTS: Seventy-four consecutive patients (aged 62.6 +/- 11.7 years) with AF (>48 hours and <6 months of duration) who underwent successful external electrical direct current cardioversion and 20 healthy individuals were enrolled. Conventional echocardiography and TDI were prospectively performed before cardioversion. Based on a cutoff point of 5.43 cm/sec for the negative systolic wave velocity (NSWV), derived by the normal controls (mean + 2 SD), patients were divided into Group I (36 patients) with a NSWV >5.43 cm/sec and Group II (38 patients) with NSWV 48 hours; all patients were in AF at 12 months. In Group II, all patients were in sinus rhythm at 12 months. However, those patients presenting with a NSWV less but near to 5 cm/sec had frequent episodes of asymptomatic paroxysmal AF lasting for <48 hours. CONCLUSION: One year after successful direct current cardioversion, TDI analysis at pre-cardioversion time may be a useful marker to identify a subgroup of patients with increased risk for AF recurrence.
Aged↗
Exchange blood transfusions for the treatment of leg ulcerations in thalassemia intermedia.
Thalassemia intermedia is a heterogeneous, transfusion-independent form of b-thalassemia, with a clinical course dominated by multi-organ effects of chronic tissue hypoxia, in which hemoglobin F percentage seems to play an important role. We describe the case of a transfusion-independent thalassemia intermedia patient (total hemoglobin 10.7 g/dl) with high hemoglobin F percentage (70%), who presented with persistent leg ulcerations. The patient was successfully treated with one-year exchange blood transfusions, which reduced hemoglobin F percentage to 35%.
Adult↗
Effects of levosimendan on markers of left ventricular diastolic function and neurohormonal activation in patients with advanced heart failure.
In this randomized, placebo-controlled study, it was found that a 24-hour levosimendan infusion improves echocardiographic markers of abnormal left ventricular diastolic function (transmitral flow patterns and mitral annulus velocities, as assessed by transthoracic pulse-wave Doppler and tissue Doppler imaging, respectively) and reduces substances of excessive neurohormonal activation (plasma B-type natriuretic peptide and interleukin-6) in patients with advanced heart failure. Moreover, levosimendan-treated patients had fewer events and longer progression-free survival during a 5-month follow-up compared with those who received placebo. Thus, levosimendan seems to be effective in improving left ventricular diastolic function and reducing neurohormonal activation in patients with severe heart failure.
Aged↗
Myelodysplastic syndrome associated with multiple autoimmune disorders.
The association between myelodysplastic syndromes (MDS) and autoimmune manifestations is not uncommon. As a rule, autoimmune abnormalities follow the diagnosis of MDS. We describe here a patient with MDS who developed a striking spectrum of diverse autoimmune disorders, including dermatitis, polyarthritis, and vasculitis, which preceded the clinical appearance of MDS.
Aged↗
Anti-inflammatory effects of levosimendan in decompensated heart failure: impact on weight loss and anemia.
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Anemia↗
The role of neoadjuvant chemotherapy in the treatment of advanced ovarian cancer.
Primary cytoreductive surgery followed by chemotherapy represents the current standard treatment for patients with advanced ovarian cancer. Neoadjuvant chemotherapy followed by interval debulking surgery has been proposed as an alternative approach for the initial management of bulky ovarian cancer, aiming at the improvement of surgical efficiency and patients' quality of life. According to the hitherto published studies, consisting mainly of retrospective observations, neoadjuvant chemotherapy followed by interval cytoreduction appears to improve the prognosis and quality of life in selected groups of patients. The survival outcome in these patients is similar to that of the conventional approach, or even better in some of the cases. Moreover, patients undergoing debulking surgery after having received neoadjuvant chemotherapy had a reduced perioperative morbidity compared to patients undergoing primary cytoreduction. Concurrently, neoadjuvant chemotherapy provides preoperative knowledge of tumor chemosensitivity, hence allowing the surgeon to choose appropriately aggressive treatment. However, until the results of prospective randomized trials become available, neoadjuvant chemotherapy followed by interval surgery should be applied only to individual cases and primarily in the context of clinical trials.
Chemotherapy, Adjuvant↗
Cardiovascular effects of splenomegaly and splenectomy in beta-thalassemia.
Splenomegaly is common in beta-thalassemia, bearing some particular hemodynamic features, while splenectomy is an established therapeutic intervention in these patients. Their effects, however, on systemic hemodynamics and thalassemia heart disease have not yet been assessed. The study included 32 consecutive patients, 13 with thalassemia major (TM) and 19 with thalassemia intermedia (TI), aged 23.4+/-4.2 years, requiring splenectomy. Assessment was performed before and 6 months after splenectomy and included hematological profile and resting echocardiography; total blood volume was also measured in 10 of 32 cases. Preoperative echocardiographic data were compared with those of 34 controls. Preoperative left ventricular diameters and mass, cardiac index, and systolic pulmonary artery pressure were all significantly higher in patients compared to controls (p<0.001), but did not differ significantly between TM and TI patients. Postoperatively, the mean hemoglobin level increased from 8.1+/-0.6 to 9.1+/-0.4 g/dl (p<0.001), total blood volume index declined from 2847+/-332 to 2310+/-276 ml/m(2) (p<0.001), blood transfusions were discontinued in 80% of TI patients and mean 6-monthly transfusion requirements in TM patients were reduced from 28+/-5 to 22+/-4 units (p<0.001). However, cardiac parameters were not significantly modified. It seems that left ventricular remodeling, high output state, and increased pulmonary artery pressure characterize both TM and TI patients who require splenectomy. Although these abnormalities remain unchanged after splenectomy, the removal of the spleen may contribute to the prevention of further cardiac damage by ameliorating the patients' hematological status and reducing their transfusion needs.
Adult↗
Diagnostic value of bone remodeling markers in the diagnosis of bone metastases in patients with breast cancer.
Metastatic spread to bone is common in patients with breast cancer and its early detection is required for the better management of these patients. Several biochemical markers of bone remodeling have been recently developed, in order to assess metastatic bone disease with non radiologic methods. The pyridinolin cross-linked amino-terminal telopeptide of type I collagen (NTx) has been measured in serum and urine as a specific marker of bone collagen breakdown, while the bone-isoform of alkaline phosphatase (BAP) has been used to determine bone formation activity. Thirty-three consecutive ambulatory patients with metastatic breast cancer and bone metastases and 31 with extraskeletal metastases only, matched for age and menopausal status, were studied. Serum levels of NTx and BAP were measured by enzyme-linked immunosorbent assays. The diagnostic accuracy of both markers was evaluated by receiver operating characteristic (ROC) analysis. Patients with bone metastases had significantly higher levels of NTx (37.0+/-36.9 nM BCE versus 23.5+/-21.0 nM BCE, P<0.05) and BAP (57.8+/-31.7 U/L versus 36.5+/-28.5 U/L, P<0.01) compared to those without bone metastases. NTx was positively correlated with BAP (R=0.340, P<0.01). The area under the ROC curve was 0.671 for NTx and 0.755 for BAP. Using a cut-off value of 29.7 nM BCE for NTx, specificity and sensitivity were 87.1% and 45.5%, respectively; in the case of BAP, using a cut-off value of 50.6 U/L, the specificity and sensitivity were 90.3% and 54.5%, respectively. In patients not receiving concomitant hormonal treatment, the area under the ROC curve was 0.724 for NTx and 0.822 for BAP; in this subgroup of patients, using a cut-off value of 30.0 nM BCE for NTx, the specificity and sensitivity were 96.2% and 47.1%, respectively, while using a cut-off value of 50.0 U/L for BAP, the corresponding percentages were 92.3% and 70.6%. Although serum NTx and BAP are quite specific, they are not sensitive enough to diagnose bone metastases in patients with advanced breast cancer. Their diagnostic accuracy, however, is considerably enhanced in patients not receiving hormonal therapy.
Aged↗
Recent advances in conventional-dose salvage chemotherapy in patients with cisplatin-resistant or refractory testicular germ cell tumors.
Testicular germ cell tumors represent the most frequent malignancy in young males aged 20-35 years. Despite the considerably high cure rates provided by platinum-based chemotherapy, 20-30% of cases with advanced disease do not achieve a long-term disease-free survival with first-line chemotherapy. These patients are candidates for conventional-dose or high-dose salvage chemotherapy. The current conventional-dose salvage regimens of reference are the vinblastine-ifosfamide-cisplatin or etoposide-ifosfamide-cisplatin combinations, which are expected to cure approximately 25% of non-seminomatous germ-cell tumour patients. Paclitaxel has also been proved effective both as monotherapy in heavily-pretreated cases and as part of first-line salvage regimens; the combination of paclitaxel-ifosfamide-cisplatin, followed or not by high-dose chemotherapy, induced a favorable long-term disease-free survival rate, especially in patients with good prognosis. Newer cytotoxic drugs, such as gemcitabine and oxaliplatin have also been proved effective, while other agents, such as temozolamide, or targeted therapies, such as trastuzumab in cases over-expressing HER2/neu (20% of relapsing germ-cell tumors) are currently under evaluation. Seminomas have generally a better prognosis than non-seminomatous tumors and salvage therapy is expected to cure about 50% of all cases.
Adult↗