Levosimendan for the treatment of acute heart failure syndromes: time to identify subpopulations of responding patients.
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Cardiotonic Agents↗
Biomedical subjects
John T Parissis
Publications and source records attributed to John T Parissis.
Effect of levosimendan on ventricular arrhythmias and prognostic autonomic indexes in patients with decompensated advanced heart failure secondary to ischemic or dilated cardiomyopathy.
Positive inotropes used for the treatment of heart failure have been arrhythmogenic. Levosimendan is a novel calcium sensitizer with vasodilating properties and a complex mechanism of action. Its effect on ventricular arrhythmias and 24-hour Holter electrocardiographically derived prognostic autonomic nervous system-related markers, because it occurs in parallel with changes in cardiac function and neurohormonal response, has not been systematically assessed. Forty-five patients (mean age 65 +/- 1.3 years) with heart failure refractory to conventional therapy and a mean ejection fraction of 23 +/- 1.2%, randomized to levosimendan or placebo, were studied. After Holter electrocardiographic recording, 1 drug was infused for 24 hours (levosimendan at a dose of 0.1 mug/kg/min). During this period, another Holter recording was performed to assess changes in ventricular arrhythmogenesis, 24-hour heart rate variability indexes, QTc, QT variability, and QT/RR slope. Clinical evaluation, echocardiography, and B-type natriuretic peptide measurements were performed at baseline and after treatment. After levosimendan, clinical and echocardiographic improvement was observed, associated with beneficial neurohormonal modulation (mean B-type natriuretic peptide level after levosimendan 668 +/- 108 vs 1,009 +/- 122 pg/ml at baseline, p <0.05). Episodes of nonsustained ventricular tachycardia increased with levosimendan (21.9 +/- 9.6 vs 3.0 +/- 1.2, p <0.05). Levosimendan and placebo exerted a neutral effect on all autonomic markers assessed. In conclusion, levosimendan at low doses increases nonsustained ventricular arrhythmias, without affecting Holter-derived, prognostically significant autonomic markers. At the same time, it is associated with improvements in cardiac function and neurohormonal response. These findings may have important clinical and prognostic implications.
Aged↗
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↗
Depression in coronary artery disease: novel pathophysiologic mechanisms and therapeutic implications.
Depression is a common comorbid condition in patients with coronary artery disease and a well-documented risk factor for recurrent cardiac events and mortality. The exact mechanisms underlying the interplay between depression and ischemic heart disease remain poorly understood and the same is true for the most effective depression treatment for cardiac patients. This review summarizes current knowledge regarding the prognostic role of depression in patients with coronary artery disease, the pathophysiologic pathways involved, and the effects of antidepressant therapy on cardiovascular disease outcomes. With recent evidence suggesting that selective serotonin reuptake inhibitors may improve survival after myocardial infarction in patients with depression, diagnosis and treatment of this co-morbidity may be essential for the clinical management of coronary artery disease.
Antidepressive Agents↗
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↗
Levosimendan therapy in decompensated chronic heart failure: favourable haemodynamic and neurohormonal effects but for how long?
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C-Reactive Protein↗
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↗
Selective serotonin re-uptake inhibitors for the treatment of depression in coronary artery disease and chronic heart failure: evidence for pleiotropic effects.
Depression is a common co-morbidity in patients with cardiovascular diseases such as chronic coronary artery disease, acute coronary syndromes, post by-pass surgery and chronic heart failure. There is a significant body of evidence suggesting that the presence of depression is independently associated with a decline in health status and an increase in the risk of hospitalization and death for patients with coronary artery disease or congestive heart failure. Novel treatment modalities such as selective serotonin re-uptake inhibitors (SSRIs) may improve depressive symptoms and prognosis of post-myocardial infarction and heart failure patients interacting with the common pathophysiologic mechanisms of depression and cardiovascular disease. This review summarizes current experimental and clinical evidence regarding the pleiotropic effects of SSRIs on platelet functions, immune and neurohormonal activation, and cardiac rhythm disturbances in patients with cardiovascular disease. These bio-modulatory properties of SSRIs may be translated into improvement of patient clinical outcomes beyond their anti-depressant action.
Blood Platelets↗
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↗
An atypical left atrial myxoma causing intracavitary pressure gradient and typical diastolic transmitral flow of severe mitral stenosis.
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Aged↗
A rare case of large mediastinal germ cell tumor detected by echocardiography.
We describe a rare case of a large mediastinal germ cell tumor detected by modified views of transthoracic echocardiography. CT scanning and histological findings after tumor resection confirmed diagnosis. This case demonstrates the clinical importance of echocardiography in diagnosis of extra-cardiac masses.
Adult↗
Anti-inflammatory effects of levosimendan in decompensated heart failure: impact on weight loss and anemia.
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Anemia↗
Levosimendan reduces plasma B-type natriuretic peptide and interleukin 6, and improves central hemodynamics in severe heart failure patients.
BACKGROUND: Plasma B-type natriuretic peptide (BNP) and interleukin 6 (IL-6) levels have recently been demonstrated as significant neurohormonal markers associated with the progression of chronic heart failure (CHF). Additionally, clinical studies have shown that the calcium sensitizer, levosimendan, beneficially affects the central hemodynamics of CHF patients and improves their long-term prognosis. This study investigates whether levosimendan-induced hemodynamic improvement of CHF patients is related to the respective changes of NT-proBNP and IL-6 levels. METHODS: Circulating levels of NT-pro BNP and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA) in 12 patients with decompensated advanced CHF at baseline, immediately after the end of a 24-h levosimendan infusion and 72 h after the initiation of treatment. Hemodynamic parameters of patients (pulmonary wedge and pulmonary artery pressure (PAP), systemic and pulmonary vascular resistance (PVR), stroke volume, and cardiac output and index) were also monitored during the same period. RESULTS: NT-proBNP and IL-6 levels were significantly reduced in severe CHF patients within 72 h after the initiation of levosimendan treatment (p<0.01 and p<0.05, respectively). A significant reduction of pulmonary wedge (p<0.01) and artery pressure values (p<0.05) was also found during the same period. A good correlation between the levosimendan-induced changes in NT-proBNP levels and the respective reduction of pulmonary wedge pressure (r(s)=0.65, p<0.05) was observed. CONCLUSIONS: Our results indicate that changes of NT-pro BNP and IL-6 levels may be useful biochemical markers related with the levosimendan-induced improvement in central hemodynamics and the clinical status of decompensated advanced CHF patients.
Aged↗
Growth hormone-induced reduction of soluble apoptosis mediators is associated with reverse cardiac remodelling and improvement of exercise capacity in patients with idiopathic dilated cardiomyopathy.
OBJECTIVE: Recent experimental and clinical data indicate that abnormal inflammatory and apoptotic processes contribute to the progression of chronic heart failure (CHF). We sought to study the effects of growth hormone (GH) on circulating soluble apoptosis mediators, and to investigate whether these GH-induced anti-apoptotic effects are associated with the reduction of left ventricular (LV) volumes and attenuation of exercise intolerance in idiopathic dilated cardiomyopathy (IDC) patients. METHODS: Plasma tumour necrosis factor-alpha (TNF-alpha), its soluble receptors sTNFRI and sTNFRII, and plasma apoptosis mediators soluble Fas (sFas) and sFas Ligand (sFAsL) were measured (enzyme-linked immunosorbent assay) in 12 IDC patients (NYHA III; LVEF: 24+/-2%) before and after a 3-month subcutaneous administration of GH 4 IU every other day (randomized, crossover design). Peak oxygen uptake (VO2max), as well as LV volume indices, wall thickness, and end-systolic wall stress (ESWS) were also determined at the same period. RESULTS: Treatment with GH produced a significant reduction in plasma TNF-alpha (7.8+/-1.1 versus 5.5+/-0.9 pg/ml, P<0.02), sTNFRI (4.0+/-0.4 versus 3.3+/-0.3 ng/ml, P<0.05), sTNFRII (2.8+/-0.3 versus 2.4+/-0.2 ng/ml, P<0.05), sFas (4.7+/-0.7 versus 3.3+/-0.5 ng/ml, P<0.05) and sFasL (33.5+/-9.7 versus 20.2+/-6.2 pg/ml, P<0.01). A significant reduction in ESWS (841+/-62 versus 634+/-48 g/cm, P<0.01), LV end-systolic volume index (LVESVI, 128+/-12 versus 102+/-12 ml/m, P<0.001) and LV end-diastolic volume index (LVEDVI, 228+/-16 versus 200+/-18 ml/m, P<0.01) as well as a significant increase in VO2max (15.3+/-0.7 versus 17.1+/-0.9 ml/kg per min, P<0.01) were also observed in the patient population after GH administration. Significant correlations were found between the GH-induced decrease of sTNFRII and sFasL and respective reduction of LVESVI. CONCLUSION: Growth hormone administration reduces circulating TNF system and soluble apoptosis mediators in patients with IDC. These GH-induced anti-apoptotic effects may be associated with the improvement in exercise capacity as well as with the reverse of LV remodelling in patients with CHF and IDC.
Apoptosis↗
Depression in chronic heart failure: novel pathophysiological mechanisms and therapeutic approaches.
Depression is four to five times as common in chronic heart failure (CHF) patients as in the general population, may confer a higher risk of developing CHF in susceptible populations, and is significantly related to higher hospital readmission rates and increased mortality in established CHF. This effect may be mediated via the pathophysiological mechanisms that are shared between CHF and depression, including increased hypothalamic-pituitary-adrenal function, sympathoadrenal hyperactivity, diminished heart-rate variability and excessive pro-inflammatory cytokine activation. Each of these pathways of linkage represents a potential therapeutic target to improve outcome in CHF. This paper reviews the recent investigational observations that clarify the direct effects of antidepressants on immune functions, as well as the indirect effects of anticytokine pharmacological agents on depressive symptoms in CHF. With recent evidence suggesting that selective serotonin re-uptake inhibitors improve survival after myocardial infarction in patients with depression, diagnosis and treatment of this comorbidity may beneficially affect the functional capacity and prognosis of CHF patients.
Antidepressive Agents↗
Levosimendan for the treatment of acute heart failure syndromes.
Levosimendan is a novel calcium-sensitising agent that has been shown to have beneficial inotropic, metabolic and vasodilatory effects in the treatment of acute and advanced chronic heart failure. Levosimendan binds to troponin-C in cardiomyocytes and, thereby, improves cardiac contractility without disturbing the metabolic status of the heart and increasing myocardial oxygen demand or provoking fatal cardiac arrhythmias. Levosimendan also opens ATP-sensitive potassium channels, causing peripheral arterial and venous dilatation, and increasing coronary flow reserve. When it is given as a short-term therapy, levosimendan enhances cardiac output, reduces systemic vascular resistance and lowers pulmonary capillary wedge pressure. Clinical outcomes were significantly reduced in decompensated or postmyocardial infarction heart failure patients who received levosimendan, compared with those on dobutamine or placebo. Recent investigations focusing on the anti-inflammatory and antiapoptotic actions of levosimendan in the failing heart indicate that improvement of cardiac contractile performance is closely related with the drug-induced reduction of circulating pro-inflammatory cytokines and apoptosis inducers. The most common adverse effects of levosimendan treatment are hypotension and headache. Overall, levosimendan represents an effective and safe option for the treatment of decompensated heart failure patients.
Acute Disease↗
Anti-inflammatory and anti-apoptotic effects of levosimendan in decompensated heart failure: a novel mechanism of drug-induced improvement in contractile performance of the failing heart.
Recent experimental and clinical observations indicate that over-expression of pro-inflammatory cytokines is actively implicated to chronic heart failure progression through their cytotoxic and negative inotropic effects. Calcium-sensitizing agents, such as levosimendan, promotes inotropy by stabilizing troponin C in a configuration that enhances the calcium sensitivity of cardiac myofilaments, preserving also diastolic relaxation. Levosimendan also opens ATP-dependent potassium channels in peripheral vessels, leading to vasodilatation. Large scale randomized clinical trials have shown that levosimendan administration in patients with severe heart failure due to left ventricular systolic dysfunction results in favorable hemodynamic changes, symptomatic benefit, and a reduction in short-term morbidity and mortality. This review describes current knowledge about novel cellular mechanisms associated with beneficial effects of levosimendan on cardiac contractile performance, focusing mainly on its immunomodulatory and anti-apoptotic properties. Levosimendan-induced improvement in contractile reserve and clinical status of severe heart failure patients, seems to be related with the reduction of major pro-inflammatory cytokines (TNF-alpha, IL-6) and soluble apoptosis signaling molecules Fas/Fas Ligand. Modulation of pro-inflammatory and pro-apoptotic pathways into the failing heart by levosimendan may be an additional pathophysiologic mechanism that prevents further clinical and hemodynamic consequences of abnormal immune responses in decompensated heart failure and beneficially affects the progression of the syndrome.
Animals↗
Comparison of circulating proinflammatory cytokines and soluble apoptosis mediators in patients with chronic heart failure with versus without symptoms of depression.
This clinical study compared the expression of circulating proinflammatory (tumor necrosis factor-alpha [TNF-alpha] and interleukin-6) and anti-inflammatory (interleukin-10) cytokines and soluble apoptosis mediators (Fas/Fas ligand) between patients with stable chronic heart failure and depressive symptoms (as estimated by the Zung Self-Rating Depression Scale) (n = 15) and those without these symptoms (n = 20). Patients with depressive symptoms exhibited significantly higher levels of TNF-alpha and soluble Fas ligand, as well as significantly lower levels of interleukin-10, than patients without emotional distress. A disregulated cytokine network and activated apoptosis signaling molecules may be actively implicated in the pathophysiology of chronic emotional distress and depressive symptoms in patients with heart failure.
Aged↗