Levosimendan in Acute and Advanced Heart Failure: an Expert Perspective on Posology and Therapeutic Application.

Levosimendan, a calcium sensitizer and potassium channel-opener, is widely appreciated by many specialist heart failure practitioners for its effects on systemic and pulmonary hemodynamics and for the relief of symptoms of acute heart failure. The drug's impact on mortality in large randomized controlled trials has been inconsistent or inconclusive but, in contrast to conventional inotropes, there have been no indications of worsened survival and some signals of improved heart failure-related quality of life. For this reason, levosimendan has been proposed as a safer inodilator option than traditional agents in settings, such as advanced heart failure. Positive effects of levosimendan on renal function have also been described. At the HEART FAILURE 2018 congress of the Heart Failure Association of the European Society of Cardiology, safe and effective use levosimendan in acute and advanced heart failure was examined in a series of expert tutorials. The proceedings of those tutorials are summarized in this review, with special reference to advanced heart failure and heart failure with concomitant renal dysfunction. Meta-analysis of clinical trials data is supportive of a renal-protective effect of levosimendan, while physiological observations suggest that this effect is exerted at least in part via organ-specific effects that may include selective vasodilation of glomerular afferent arterioles and increased renal blood flow, with no compromise of renal oxygenation. These lines of evidence require further investigation and their clinical significance needs to be evaluated in specifically designed prospective trials.

The role of cardiorenal biomarkers for risk stratification in the early follow-up after hospitalisation for acute heart failure.

CONTEXT: Cardiorenal biomarkers (CBs) predict outcome in acute heart failure (AHF). OBJECTIVE: To evaluate CBs in early follow-up prognostication. METHODS: In 124 AHF patients, levels of CystatinC, NT-proBNP and TroponinI measured five weeks from admission (W5) and relative change from day 2 (D2) were assessed for 6-month prognosis (mortality/HF hospitalization). RESULTS: The combined end-point occurred in 33 patients (27%). D2-, W5-cystatin≥ median, and lack of ≥30%decrease in NT-proBNP were independent predictors of outcome. Additionally, a risk score established from W5 CBs identified patients with very high event rate. CONCLUSIONS: CBs at early follow-up of AHF may guide risk stratification.

Cystatin C, NT-proBNP, and inflammatory markers in acute heart failure: insights into the cardiorenal syndrome.

BACKGROUND: Inflammation is thought to be a mediator in the pathophysiology of the cardiorenal syndrome. We evaluated the interactions between kidney function, cardiac stress, and various inflammatory cytokines in patients with acute heart failure (AHF). The effect on 1-year mortality was also assessed. METHODS AND RESULTS: Plasma levels of cystatin C, NT-proBNP, and inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-α [TNF-α], IL-10) were measured in consecutive patients (n = 465) hospitalized for AHF. After adjustment for demographic characteristics and comorbidities, TNF-α had the strongest relation with renal function (ß = 0.39, P < 0.0001). Elevated TNF-α levels were seen in patients with high cystatin C, irrespective of NT-proBNP. Levels of IL-6 (ß = 0.26, P < 0.0001) and IL-10 (ß = 0.15, P < 0.01), but not TNF-α, were associated with NT-proBNP. Moreover, the most elevated levels of IL-6 were seen in patients with combined high NT-proBNP and high cystatin C. Cox regression analysis found IL-6 above median to be independently predictive of mortality (hazard ratio 1.9; 95% CI 1.2-2.9, P = 0.003). TNF-α was not significantly associated with prognosis in the overall population after adjustment for multiple covariates, but improved risk stratification in the subgroup with low cystatin C and NT-proBNP. CONCLUSION: Levels of TNF-α in AHF are related to kidney function, but not to NT-proBNP. IL-6 seems to be more associated with cardiac stress. Patients with severe dual organ dysfunction have the highest levels of IL-6 and TNF-α. Different relations of inflammatory cytokines to renal function and cardiac stress need to be considered when evaluating heart--kidney interactions.

The hemodynamic and pharmacokinetic interactions between chronic use of oral levosimendan and digoxin in patients with NYHA Classes II-III heart failure.

OBJECTIVE: Levosimendan is a calcium-sensitizing drug for the treatment of heart failure. The aim of this exploratory study was to assess the hemodynamic and pharmacokinetic interactions between digoxin and oral levosimendan as well as the proarrhythmic potential of this combination in patients with chronic heart failure. MATERIALS: Male or female patients (n = 24) with chronic heart failure of NYHA Classes II-III. METHODS: A randomized, placebo-controlled, double-blind, parallel-group trial. After a 1-week digoxin-free washout period, the patients were randomized to receive either digoxin and levosimendan (digoxin + levosimendan), or digoxin and placebo (digoxin) orally for 14 +/- 2 days. The levosimendan dose was 1 mg 3 times daily, and the digoxin dose was 0.125-0.25 mg once daily. Systolic time intervals, electrocardiography (ECG), magneto-cardiography (MCG) and 24-h ambulatory ECG were performed at baseline and at the end of each treatment period. Pharmacokinetic variables of levosimendan and digoxin were calculated in both treatment periods. Steady-state concentrations of the active metabolites OR-1855 and OR-1896 were determined at baseline at Visit 2. RESULTS: There tended to be a greater shortening of QS2i (suggesting trend to positive inotropy) in the digoxin + levosimendan group (-14ms) compared with the digoxin group (-5ms), although the difference was not statistically significant (p=0.359). However, the change from baseline in QS2i after digoxin + levosimendan was of statistically borderline significance (p=0.05). The change from baseline in the digoxin group was not statistically significant. ECG and MCG repolarization measures and occurrence of nonsustained ventricular tachycardia showed no substantial differences. After 2 weeks of digoxin + levosimendan treatment, mean area under the curve (AUC) of levosimendan increased approximately by 49% (p<0.01). The maximum plasma concentration (Cmax) of levosimendan increased from 17 to 23 ng/ml. The mean concentrations of the metabolites OR-1855 and OR-1896 in plasma were 4.3 and 8.3 ng/ml, respectively. CONCLUSIONS: The addition of oral levosimendan to digoxin therapy produced only a modest statistically nonsignificant additive inotropic effect. In contrast to the earlier data with intravenous levosimendan, the results indicate a pharmacokinetic interaction between levosimendan and digoxin. Data obtained from repolarization analyses and ambulatory ECG did not indicate any possible proarrhythmic effects of the combination.

Plasma levels of haemostatic factors in patients with pulmonary embolism on admission and seven months later.

INTRODUCTION: With the exception of D-dimer, not much is known about the plasma levels of haemostatic factors during acute venous thromboembolism (VTE) compared to their basic levels in a stable phase. The goal of this study was to examine how plasma levels of factor V, VIII, XIIIa, von Willebrand factor antigen (vWF:Ag), fibrinogen, thrombomodulin evolve from the point of diagnosis of acute VTE to the end of standard treatment period. METHODS: Sixty-three consecutive patients (mean 57, range 18-86 years, 33 females) with acute pulmonary embolism (PE) were included. Laboratory samples were collected upon arrival (acute phase) and seven months later (stable phase). Fifteen similar aged individuals served as controls. RESULTS: Plasma levels of factor XIIIa (87.5% vs 117.7%, P < .001) and soluble thrombomodulin (36.6 vs 47.5 ng/L, P < .001) were lower, whereas plasma levels of vWF:Ag (2.66 vs 2.01 IU/mL, P < .001) and fibrinogen (4.3 vs 3.9 g/L, P < .05) were higher on admission compared to the stable phase. In the stable phase, vWF:Ag (2.01 vs 1.43 IU/mL, P < .01) and soluble thrombomodulin (47.5 vs 38.0 ng/mL, P < .05), but not FXIIIa levels, were higher in PE patients compared to healthy controls. CONCLUSION: This study confirms the concept of FXIIIa consumption during acute phase of VTE by showing its intraindividual normalization during the follow-up. vWF:Ag, known to be associated with the risk of VTE, was constantly elevated in the majority of the patients. Soluble thrombomodulin levels were lower in acute phase compared to stable phase, a finding which significance needs to be evaluated in the future.

Levosimendan meta-analyses: Is there a pattern in the effect on mortality?

BACKGROUND: Levosimendan is an inodilator developed for treatment of acute heart failure and other cardiac conditions where the use of an inodilator is considered appropriate. Levosimendan has been studied in different therapeutic settings including acutely decompensated chronic heart failure, advanced heart failure, right ventricular failure, cardiogenic shock, septic shock, and cardiac and non-cardiac surgery. This variety of data has been re-analysed in 25 meta-analyses from 15 different international research groups, based on different rationales to select the studies included. METHODS: We here review all previously published meta-analyses on levosimendan to determine any common denominators for its effects on patient mortality. In addition, we also perform a comparative meta-analysis of the six phase II and III randomized double-blind trials which were taken into consideration by the regulatory authorities for the purpose of introducing levosimendan into the market. RESULTS: Irrespective of clinical setting or comparator, all meta-analyses consistently show benefits for levosimendan, with lower relative risk (or odds ratio) for patient mortality. In 3/25 of the meta-analyses these beneficial trends did not reach statistical significance, while in 22/25 significance was reached. The relative risk is consistent overall, and very similar to that obtained in our own meta-analysis that considered only the 'regulatory' studies. CONCLUSION: The existing meta-analyses, now based on a population of over 6000 patients, provide the general message of significant benefits for levosimendan in terms of patient mortality. The weight of evidence is now clearly in favour of usefulness/efficacy of levosimendan, with data from multiple randomized trials and meta-analyses.

Myosin heavy chain mRNA transform to faster isoforms in immobilized skeletal muscle: a quantitative PCR study.

A quantitative polymerase chain reaction (PCR) method was used to measure the quantities of type I, IIa, IIx, and IIb myosin heavy chain (MHC) mRNA in total RNA preparations of the soleus, gastrocnemius, and plantaris muscles of normal and hindlimb-immobilized rats. Type IIx and even type IIb MHC mRNA were demonstrated at extremely low levels in normal soleus, 2.1 +/- 0.4 x 10(5) and 5.0 +/- 0.2 x 10(5) molecules of mRNA per microgram total RNA, respectively. Immobilization for 1 wk significantly altered the gene expression of MHC isoforms. In soleus, both type IIx and IIb MHC genes became significantly upregulated, 24-fold (P < 0.005) and 2.6-fold (P < 0.05), respectively. In gastrocnemius, the level of type IIa MHC mRNA decreased by 51% (P < 0.01) and the level of type IIx MHC mRNA increased by 140% (P < 0.05). In plantaris, the level of type IIa MHC mRNA decreased by 58% (P < 0.005). In conclusion, immobilization changed the MHC mRNA profile in three different types of skeletal muscle toward faster isoforms. The quantitative results permit reliable evaluation of changes in mRNA levels.

The effect of catechol-O-methyl transferase inhibition by entacapone on the pharmacokinetics and metabolism of levodopa in healthy volunteers.

We studied the effect of inhibiting the enzyme catechol-O-methyltransferase (COMT) by a novel COMT inhibitor, entacapone, on the pharmacokinetics and metabolism of levodopa in 12 healthy male volunteers. Single increasing oral doses of entacapone (50-400 mg) were administered concomitantly with a single oral dose of levodopa/carbidopa (100/25 mg). The subjects were treated with carbidopa (100 mg t.i.d.) for 1 day prior to the administration of study drugs. Plasma concentrations of levodopa; its metabolites 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA); as well as carbidopa and entacapone were determined for pharmacokinetic calculations. Entacapone dose-dependently increased the area under the plasma concentration-time curve (AUC) of levodopa; the increase was 65% after the 400 mg dose of entacapone. Neither Cmax nor Tmax of levodopa was statistically significantly influenced by entacapone. Entacapone dose-dependently decreased the AUC of 3-OMD, maximally by 58%. The AUC of DOPAC was statistically significantly increased but no change in the AUC of HVA was observed after entacapone. No drug-related adverse events or hemodynamic effects were observed. The in vivo biochemical effects of entacapone indicate that it is an orally active COMT inhibitor and that it may improve the therapeutic efficacy of levodopa in Parkinson's disease.

Observations and warning signs prior to cardiac arrest. Should a medical emergency team intervene earlier?

BACKGROUND: The Medical Emergency Team (MET) has evolved in some hospitals as a means of delivering effective treatment early enough to prevent cardiac arrests. Our aim was to analyze the effectiveness of observation practice to detect abnormalities in vital signs prior to cardiac arrest and to determine the need for a MET system in Finnish hospitals. METHODS: The charts of patients who suffered cardiac arrest during 18 months in four hospitals were reviewed. The vital signs, symptoms and interventions during 8 h prior to arrest were recorded and analyzed against trigger criteria of the MET. RESULTS: During the study period, 110 patients suffered cardiac arrest in hospitals, and 56 (51%) of the arrests occurred on the wards. Of those patients, 30 (54%) had an abnormal vital sign fulfilling the MET criteria, documented on average 3.8 h prior to the arrest. During this period, 13 patients did not receive any intervention (e.g. supplemental oxygen or medication), eight received intervention within 1 h and nine received intervention after more than 1 h. Response to the first intervention was not attained in any patient; nevertheless re-interventions took place in one patient only. CONCLUSION: Significant physiological deterioration seems to be common in the hours before a cardiac arrest on the wards of Finnish hospitals, suggesting that implementation of a MET-system may be worthwhile. However, the practice of vital sign observation by the nursing staff should be improved before maximal benefit of a MET can be achieved.

The effect of androgen status on skeletal muscle myosin heavy chain mRNA and protein levels in rats recovering from immobilization.

Immobilization rapidly alters skeletal muscle. The aim of the present study was to determine whether testosterone administration or, in contrast, hypogonadism affects the recovery of muscle mass and myosin heavy chain (MHC) profile at both the mRNA and protein level, after 1 week of immobilization. Male rats were assigned to one of five groups: control (C), hindlimb-immobilized (IMM), and recovery (REC; where animals were allowed 2 weeks of free cage-activity after immobilization). The recovery group was further divided to eugonadal (REC-C), castrated (REC-GDX), and a testosterone-treated (REC-T). In all groups except REC-T, the body masses after immobilization were smaller than in C, although after immobilization the body mass in REC-T recovered at a slower rate than in the other two REC groups. The gastrocnemius mass and the amount of type IIa MHC mRNA decreased during immobilization, but the control levels were regained after recovery. The amount of type IIb mRNA was reduced in REC-GDX compared to C and IMM. The changes in the relative distribution of MHC mRNA were in line with these results. After recovery, the proportion of type IIx MHC protein increased and type IIb protein decreased, although in REC-T the changes were not statistically significant. The proportion of type IIa MHC protein increased only in REC-GDX. In summary, during recovery from immobilization it seems that muscle mass increases and the MHC mRNA and protein profile tend to change toward a slower phenotype, primarily as a result of the decrease in type IIb MHC. However, these changes occur rather independently of the testosterone status.

Association of Stomatococcus mucilaginosus with cholangitis.

The first case of cholangitis in which Stomatococcus mucilaginosus was cultured from bile is reported. A 64-year-old male became icteric and was shown to have gallstones in the gallbladder and a common bile duct stone which was removed endoscopically. As the patient remained icteric for a month thereafter the gallbladder with stones was removed. No common bile duct stone was shown by cholangiography perioperatively. The liver biopsy revealed cholangitis and Stomatococcus mucilaginosus was grown from the bile. The patient was cured by cholecystectomy without any antimicrobial therapy.

Report of four cases of Yersinia pseudotuberculosis septicemia and a literature review.

Yersinia pseudotuberculosis is a rare cause of disease in humans, the most common manifestation being mesenteric lymphadenitis accompanied by abdominal pain and fever. A septicemic form of Yersinia pseudotuberculosis infection has been reported only rarely. It is usually seen in patients with underlying disorders such as diabetes, hepatic cirrhosis or iron overload. Fifty-four cases of septicemic infection were found in the literature. The earlier published cases are reviewed, and four cases occurring in Finland during the period February to June 1992 are reported.

A clinical study of beta-haemolytic groups A, B, C and G streptococcal bacteremia in adults over an 8-year period.

All of the 88 episodes of beta-haemolytic streptococcal bacteremia (2.9% of all bacteremias) in adult patients during the years 1987-94 in a university hospital were reviewed. 38 bacteremias (43%) were caused by group A, 24 (27%) by group B, 3 (4%) by group C, and 23 (26%) by group G beta-haemolytic streptococcal. There was a statistically significant increase in group A and decrease in group C and G bacteremias (p < 0.02) compared to an earlier 8-year period in the same hospital, although the total number of streptococcal bacteremias remained the same. The most common T types of group A streptococcal strains were T11 (26%), T28 (14%), T6 and T1 (11% each), and T12 (8%). Cardiovascular disease, skin lesions, malignancy, and alcohol abuse were the most common underlying conditions. The most usual types of infection were skin (47%) and respiratory tract infections (23%). The overall mortality was 16%. It was highest in group A (24%) and lowest in group C (0%), 38% of patients with pneumonia died. All streptococcal strains were sensitive to penicillin, vancomycin, and cephalosporins. 11% of group A and 12% of all the strains had decreased sensitivity to erythromycin, 14 and 38% to tetracycline, and 0 and 2% to clindamycin, respectively.

Preservation of venous valve function after catheter-directed and systemic thrombolysis for deep venous thrombosis.

OBJECTIVES: The aim of the study was to assess venous reflux and the obstruction pattern after catheter-directed and systemic thrombolysis of deep iliofemoral venous thrombosis. PATIENTS: Thirty-two patients treated either with systemic (16) or catheter-directed local thrombolysis (16) for massive iliofemoral thrombosis were identified from the hospital registry. METHODS: Clinical evaluation at follow up was based on the CEAP classification and disability score. Reflux was assessed by colour duplex ultrasonography and standardised reflux testing. A vascular surgeon blinded to treatment established the clinical status of the lower limb following the previous DVT. RESULTS: Valvular competence was preserved in 44% of patients treated with catheter-directed thrombolysis compared with 13% of those treated with systemic thrombolysis (p=0.049, Chi squared). Reflux in any deep vein was present in 44% of patients treated by catheter-directed lysis compared with 81% of patients receiving systemic thrombolysis (p=0.03, Chi squared). Reflux in any superficial vein was observed in 25% vs. 63% of the patients, respectively (p=0.03, Chi squared). There were significantly more patients with venous insufficiency of classes C0-1 in the group treated with catheter-directed thrombolysis. CONCLUSION: In this clinical series venous valvular function was better preserved after iliofemoral DVT when treated with catheter-directed thrombolysis.

Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial.

BACKGROUND: Levosimendan, a novel calcium sensitiser, improves myocardial contractility without causing an increase in myocardial oxygen demand. We compared the effects of levosimendan and dobutamine on haemodynamic performance and clinical outcome in patients with low-output heart failure. METHODS: Patients were recruited into a multicentre, randomised, double-blind, double-dummy, parallel-group trial. Under continuous haemodynamic monitoring, an initial loading dose of levosimendan of 24 microg/kg was infused over 10 min, followed by a continuous infusion of 0.1 microg kg(-1) min(-1) for 24 h. Dobutamine was infused for 24 h at an initial dose of 5 microg kg(-1) min(-1) without a loading dose. The infusion rate was doubled if the response was inadequate at 2h. The primary endpoint was the proportion of patients with haemodynamic improvement (defined as an increase of 30% or more in cardiac output and a decrease of 25% or more in pulmonary-capillary wedge pressure) at 24 h. Analyses were by intention to treat. FINDINGS: 103 patients were assigned levosimendan and 100 dobutamine. The primary haemodynamic endpoint was achieved in 29 (28%) levosimendan-group patients and 15 (15%) in the dobutamine group (hazard ratio 1.9 [95% CI 1.1-3.3]; p=0.022). At 180 days, 27 (26%) levosimendan-group patients had died, compared with 38 (38%) in the dobutamine group (0.57 [0.34-0.95]; p=0.029). INTERPRETATION: In patients with severe, low-output heart failure, levosimendan improved haemodynamic performance more effectively than dobutamine. This benefit was accompanied by lower mortality in the levosimendan group than in the dobutamine group for up to 180 days.