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.

Left ventricular ejection fraction as therapeutic target: is it the ideal marker?

Heart failure (HF) consists the fastest growing clinical cardiac disease. HF patients are categorized on the basis of underlying left ventricular ejection fraction (LVEF) into HF with preserved EF (HFpEF), reduced LVEF (HFrEF), and mid-range LVEF (HFmrEF). While LVEF is the most commonly used surrogate marker of left ventricular (LV) systolic function, the implementation of two-dimensional echocardiography in estimating this parameter imposes certain caveats on current HF classification. Most importantly, LVEF could fluctuate in repeated measurements or even recover after treatment, thus blunting the borders between proposed categories of HF and enabling upward classification of patients. Under this prism, we sought to summarize possible procedures to improve systolic function in patients with HFrEF either naturally or by the means of pharmacologic and non-pharmacologic treatment and devices. Therefore, we reviewed established pharmacotherapy, including beta-blockers, inhibitors of renin-angiotensin-aldosterone axis, statins, and digoxin as well as novel treatments like sacubitril-valsartan, ranolazine, and ivabradine. In addition, we assessed evidence in favor of cardiac resynchronization therapy and exercise training programs. Finally, innovative therapeutic strategies, including stem cells, xanthine oxidase inhibitors, antibiotic regimens, and omega-3 polyunsaturated fatty acids, were also taken into consideration. We concluded that LVEF is subject to changes in HF after intervention and besides the aforementioned HFrEF, HFpEF, and HFmrEF categories, a new entity of HF patients with recovered LVEF should be acknowledged. An improved global and refined LV function assessment by sophisticated imaging modalities and circulating biomarkers is expected to render HF classification more accurate and indicate patients with viable-yet dysfunctional-myocardium and favorable characteristics as the ideal candidates for LVEF recovery by individualized HF therapy.

The diagnostic yield of transesophageal echocardiography in patients with cryptogenic cerebral ischaemia: a meta-analysis.

BACKGROUND AND PURPOSE: The diagnostic utility of transesophageal echocardiography (TEE) in patients with cryptogenic ischaemic stroke (IS) or transient ischaemic attack (TIA) remains controversial. METHODS: A systematic review and meta-analysis was performed according to PRISMA guidelines to estimate the pooled prevalence of potential cardioembolic causes detected by TEE in prospective observational studies of cryptogenic IS/TIA. Cardiac conditions causally associated with cerebral ischaemia were considered to be intramural thrombi and intracardiac tumors according to ASCO phenotyping of IS. RESULTS: Thirty-five eligible studies, comprising 5772 patients (mean age 53.6 years, 56.9% men) were identified. The most common TEE finding was ascending aorta and/or aortic arch atheroma [51.2% (27.4%-74.5%)], followed by patent foramen ovale (PFO) [43.2% (36.3%-50.4%)]. Complex aortic plaques and large PFOs were reported in 14% (10.2%-18.9%) and 19.5% (16.6%-22.8%) of TEE evaluations. The prevalence of atrial septal aneurysm was 12.3% (7.9%-18.7%) and was significantly higher in conjunction with PFO presence (risk ratio 2.04, 95% confidence interval 1.63-2.54, P < 0.001). The prevalence of left atrial thrombus [3.0% (1.1%-8.3%)] and spontaneous echo contrast [3.8% (2.3%-6.2%)] was low. The prevalence of intracardiac tumors was extremely uncommon [0.2% (0%-0.7%)]. Significant heterogeneity was identified (I(2) > 60%) in the majority of analyses. Heterogeneity was not affected by cryptogenic stroke definition (TOAST versus alternative criteria). After dichotomizing available studies using a cut-off of 50 years, PFO was significantly (P = 0.001) more prevalent in younger than in older patients. CONCLUSION: Routine TEE in patients with cryptogenic IS/TIA commonly identifies abnormal findings. However, the prevalence of cardiac conditions considered to be causally associated with cerebral ischaemia (intracardiac thrombi and tumors) is low.

The diagnostic approach and management of hypertension in the emergency department.

Hypertension urgency and emergency represents a challenging condition in which clinicians should determine the assessment and/or treatment of these patients. Whether the elevation of blood pressure (BP) levels is temporary, in need of treatment, or reflects a chronic hypertensive state is not always easy to unravel. Unfortunately, current guidelines provide few recommendations concerning the diagnostic approach and treatment of emergency department patients presenting with severe hypertension. Target organ damage determines: the timeframe in which BP should be lowered, target BP levels as well as the drug of choice to use. It's important to distinguish hypertensive emergency from hypertensive urgency, usually a benign condition that requires more likely an outpatient visit and treatment.

The heart failure pandemic: The clinical and economic burden in Greece.

BACKGROUND: The objective of this study was to identify the epidemiological and clinical characteristics of heart failure (HF) patients in Greece as well as the economic burden and the distribution of costs for the management of the disease. METHODS: Eight Greek secondary and tertiary cardiology centres from different cities have participated in a prospective, observational survey, the ESC HF Pilot Survey. 307 patients with HF, 177 hospitalised and 130 outpatients, have been recruited and monitored for 12months. Clinical and epidemiological data, along with data on mortality, hospitalisations and health care resources used have been collected. The economic evaluation was conducted from the social security system perspective. RESULTS: The annual mortality rate was 24.3% for the hospitalised patients vs 7.7% for the outpatients (P<0.001) and the annual rehospitalisation rate was 42.9% vs 19.2% respectively (P<0.001). Kaplan-Meier analyses revealed that patients with kidney dysfunction, S3 gallop and higher NYHA class have a significantly worse survival. The mean annual economic burden of the social security system per HF patient was estimated at €4411±4764. About two thirds of this cost is due to in-patient care. CONCLUSIONS: Despite the progress in the management of the disease, about one in four hospitalised patients dies and four in ten are rehospitalised in less than one year. Moreover, the disease imposes a significant economic burden for the social security system and national economy. Their findings suggest that there is still need of more effective drug treatment and efficient disease management programs focused in the reduction of the hospital admissions.

A simple score for early risk stratification in acute heart failure.

INTRODUCTION: The use of many acute heart failure (AHF) risk scores is cumbersome. We therefore developed a simple AHF risk score (AHFRS) for early risk stratification. METHODS: The study consisted of a prospective derivation cohort (PDC; N=104; age, 77[21] years; LVEF (%), 35[29]) and a retrospective validation cohort (RVC; N=141; age, 76[15] years; LVEF (%), 35[25]). Clinical, echocardiography and laboratory assessment was performed at admission. The study end-point was death from any cause or HF-rehospitalization at 1year. RESULTS: In the PDC 46 (44.2%) patients experienced the end-point. Independent prognostic factors of outcome were hypertension (HTN) history, myocardial infarction (MI) history, and admission red cell distribution width (RDW). Multivariate logistic regression indicated 8-, 4-, and 3-times higher odds ratio for development of study end-point in patients without a HTN history, with MI history, and RDW≥15% (median) respectively. Thus in AHFRS, 2 points were assigned for absence of HTN history, 1 point for presence of MI history, and 1 point for RDW values ≥15% (0 best possible, whereas 4 worst possible score). The AHFRS identified patients who developed the end-point in the PDC with an area under the ROC curve (AUC) of 0.80 [95% C.I.: (0.71, 0.87)] denoting a high discriminative ability. These findings were confirmed in the RVC, in which the endpoint occurred in 52 (36.9%) patients and the AUC for the AHFRS was 0.82 [95% C.I.: (0.73, 0.89)]. CONCLUSIONS: AHFRS is easily obtained at admission and accurately risk stratifies AHF patients.

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.

Detection of microsatellite instability in sporadic cardiac myxomas.

OBJECTIVE: Microsatellite instability (MIN) is an early event in DNA repair-deficient associated diseases and reflects an elevated mutation rate in the genome of neoplastic cells. Sporadic cardiac myxomas are the most common primary heart tumours and their aetiopathology remains obscure. This study investigates the incidence of MIN in sporadic cardiac myxomas as a possible genetic mechanism of tumour pathogenesis. METHODS: Eleven surgically excised sporadic cardiac myxomas were assessed for MI using twenty-two highly polymorphic microsatellite markers, located on a wide range of chromosomal arms. DNA was extracted from myxoma tissue specimens as well as the respective normal tissue and subjected to polymerase chain reaction. RESULTS: The microsatellite analysis revealed that seven myxoma specimens (64%) exhibited MIN in at least one marker. One tumour specimen exhibited evidence of MIN in four microsatellite markers, while the most frequently affected marker was D17S855 (27%), located on chromosome 17q. DISCUSSION: We have detected a considerable incidence of MIN in sporadic cardiac myxomas indicating that decreased fidelity in DNA replication and repair is common in these tumours. To the best of our knowledge this is the first report describing MIN in sporadic cardiac myxomas, as a possible pathogenetic mechanism of these rare neoplasms.

Pharmaco-economics of levosimendan in cardiology: a European perspective.

INTRODUCTION: Heart failure places a significant economic burden on health care. Acute heart failure requires hospitalization and often frequent re-hospitalization in expensive wards where vasoactive rescue therapy is often added on top of standard medications. In these lean times, there is a growing need for cost-effective therapeutic options that supply superior support and in addition shorten the length of stay in hospital and reduce re-hospitalization rates. The inodilator levosimendan represents the latest addition to the vasoactive treatments of acute heart failure patients, and it appears to meet these expectations. Our aim was to answer the question whether the treatment efficacy of levosimendan - when selected as therapy for patients hospitalized for acute heart failure - brings savings to hospitals in various European countries representing different economies. METHODS AND RESULTS: We took a conservative approach and selected some a fortiori arguments to simplify the calculations. We selected seven European countries to represent different economies: Italy, Spain, Greece, Germany, Sweden, Finland and Israel. Data on the costs of medications and on the cost per day were collected and fed in a simple algorithm to detect savings. These saving varied from country to country, from a minimum of €0.50 in Germany to a maximum of €354.64 in Sweden. CONCLUSIONS: The use of levosimendan as a therapy for patients hospitalized for acute heart failure provides a net saving to hospitals driven by a reduction in the length of hospital stay. This finding is true in each of the countries considered in this study.

Combined transarterial targeting locoregional immunotherapy-chemotherapy for patients with unresectable hepatocellular carcinoma: a new alternative for an old problem.

The prognosis for patients with advanced (stage III and IV) hepatocellular carcinoma (HCC) remains poor. Liver resection and liver transplantation have limited effects on overall survival. Our study was carried out to assess a novel therapeutic approach, which includes transarterial locoregional chemotherapy and in vivo locoregional dual immunostimulation, in patients with unresectable HCC. A group of 20 patients with stage III and IV hepatocellular carcinoma had 10 courses (once per day) of transarterial targeted locoregional immunotherapy with interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), emulsified in a Lipiodol-Urografin mixture. The target organs were the spleen and the liver tumor itself. One course of intrahepatic locoregional targeting transarterial chemotherapy was given 10 days after completion of immunotherapy (mitomycin C, carboplatin, Farmorubicin, Leucovorin, 5-fluorouracil, and IFN-gamma). This was followed after 2 months by another course of transarterial targeted locoregional immunotherapy-chemotherapy. All patients survived the operation and had a mean survival time of 18 months (4-22 months). There was a decrease in the tumor size of 14 of the 20 patients. Serum alpha-fetoprotein (AFP) levels declined in 14 patients, reaching normal levels in 12 patients. These preliminary results indicate that combined locoregional immunotherapy-chemotherapy is a promising therapeutic approach in patients suffering from advanced nonresectable HCC and merits further evaluation.

Correlation of interleukin-6 gene expression to immunologic features in patients with cardiac myxomas.

Cardiac myxomas, the most common primary heart tumors in adults, show a variety of clinical manifestations and laboratory findings correlated with elevated interleukin-6 (IL-6) serum concentration. The aim of this study was to determine the expression of IL-6 mRNA in myxoma tissue as a cause to frequent immunologic abnormalities in patients with such tumors. In our centers, we analyzed 17 surgically resected myxomas using the polymerase chain reaction (PCR) and found increased IL-6 mRNA expression in 14 of 17 cases. The serum IL-6 levels of the 14 patients, detected by enzyme-linked immunosorbent assay (ELISA) with mouse antihuman monoclonal antibody (mAb), were high preoperatively (> 6 pg/ml) and decreased to normal postoperatively (< or = 6 pg/ml). These same 14 patients exhibited significant autoimmune disorders preoperatively. The other 3 patients had normal serum levels of IL-6 (< or = 6 pg/ml) and did not present any serious signs and symptoms, and molecular analysis did not show overexpression of IL-6 mRNA in neoplasmic tissue. These results suggest that IL-6 is overproduced in myxoma tissue and secreted into the systemic circulation as a stimulator of the immunoregulatory system. Furthermore, this study indicates the promising role of molecular biology techniques in the research of pathophysiologic mechanisms of cardiac myxomas.

Serum profiles of granulocyte-macrophage colony-stimulating factor and C-C chemokines in hypertensive patients with or without significant hyperlipidemia.

The present study investigates the differences in serum activity of granulocyte-macrophage colony-stimulating factor, macrophage chemoattractant protein-1, and macrophage inflammatory protein-1alpha between hypertensive patients with and without significant hyperlipidemia before receiving any medical treatment. The serum activity of the studied inflammatory factors is more elevated in hypertensive patients with significant hyperlipidemia and may be associated with atherosclerotic inflammatory process induced by the coexistence of 2 major cardiovascular risk factors.

Clinical and neurohormonal correlates of circulating granulocyte-macrophage colony-stimulating factor in severe heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

In this report, we showed for the first time that granulocyte-macrophage colony-stimulating factor plasma levels are elevated in patients with severe heart failure, and these levels are correlated well with neurohormonal activation and hemodynamic deterioration characterizing this syndrome.

A glossary of circulating cytokines in chronic heart failure.

Recent studies have emphasized the importance of biologically active molecules, termed cytokines, in the development and progression of the syndrome of chronic heart failure. This article summarizes a glossary of major cytokines and other cytokine-related inflammatory factors implicated in the pathophysiology of chronic heart failure, describing the source of their synthesis and factors regulating their secretion and analyzing their biologic effects on the cardiovascular system.

A primary cardiac leiomyosarcoma with mutation at H-ras codon 12.

The presence of activating ras mutations in a cardiac leiomyosarcoma which occurred in the right atrium of the heart of a female patient was examined. The tumor had the appearance of leiomyosarcoma in rutine histopathological examination and the definite diagnosis was confirmed by a positive immunohistochemical reaction to smooth muscle actin. Molecular analysis by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) technique showed a point mutation of H-ras gene at codon 12. To the best of our knowledge, this is the first report describing ras gene mutation in a cardiac leiomyosarcoma implying a role for the ras oncogenes in the development of this tumor.

Resection versus resection combined with adjuvant pre- and post-operative chemotherapy--immunotherapy for metastatic colorectal liver cancer. A new look at an old problem.

Forty patients with metastatic liver disease from colorectal carcinoma are presented in this study. Patients were randomly assigned to two groups: Group A (20 patients) who had liver resection and Group B (20 patients) who had liver resection combined with post-operative locoregional immuno- therapy + chemotherapy. Thus, during the first year following surgery, they have four courses of targeted locoregional transarterial chemotherapy-immunotherapy, two courses during the second year and one course during the third year. Two patients died, one in each group, during the first 30 postoperative days. Survival in Group A (19 surviving patients) ranged from 4 to 25 months, mean 11 months. Eight (8) patients had intrahepatic recurrence of the disease and 11 are still alive and free of disease. Of those with intrahepatic recurrence, three (3) patients died 15, 15 and 17 months following surgery of causes related to the disease. In Group B (19 surviving patients), survival ranged from 3 to 30 months, mean 20 months. At present, all 19 patients are alive and free of disease (p < 0.001). None has had intrahepatic recurrence (p < 0.001). On the basis of present results, liver resection supplemented with postoperative targeted transarterial locoregional immunotherapy-chemotherapy is associated with optimal results. It is highly recommended as the procedure of choice in dealing with patients operated upon for metastatic liver disease due to colorectal carcinoma.

Combined immunopharmaceutical therapy of patients with unresectable pancreatic carcinoma.

BACKGROUND/AIMS: This paper presents the results of a prospective randomized study of targeting locoregional chemotherapy and targeting locoregional immunostimulation therapy implemented in 36, out of 66, patients with a histological diagnosis of pancreatic duct carcinoma seen by our group from 1991 to Sept. 1994. METHOD AND MATERIALS: Sixty-six patients with unresectable pancreatic duct carcinoma were separated into two groups. The first group received laparotomy (n = 30), with palliative gastric bypass (n = 8) or with palliative biliary bypass (n = 18). The second group received laparotomy (n = 36), with palliative gastric bypass (n = 9) or with palliative biliary bypass (n = 20), supplemented with locoregional immunostimulation and locoregional chemotherapy. This therapy consisted of ten days of infusion with Proleukin (IL2) and Imukin (gamma-IFN), emulsified in Lipidiol-Urographin. This infusion was performed five days trans-splenically and five days trans-tumorally. Fifteen days later, targeting locoregional chemotherapy was administered, again emulsified in Lipidiol-Urographin. RESULTS: All the patients in the first group are dead, with a mean survival of 4.5 months, as of November 1995. Presently, 47% (n = 17) of the second group have achieved a positive objective response, with a mean survival of 14.1 months. During re-exploration, eight patients became tumor free after pancreatic resection, which became feasible after our therapy and six are alive and have remained tumor free to date. CONCLUSION: Targeting locoregional immunotherapy, combined with locoregional chemotherapy appears to be a promising therapy, meriting further consideration for clinical application in patients with unresectable pancreatic ductal carcinoma.

Repetitive use of levosimendan for treatment of chronic advanced heart failure: clinical evidence, practical considerations, and perspectives: an expert panel consensus.

BACKGROUND: The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. METHODS AND RESULTS: A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. CONCLUSIONS: The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.