Apostolos Karavidas

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)-α, 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 ± L3.3%), 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-α (−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-α (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-α (r = 0.624, P<0.01), sVCAM-1 (r = 0.665, P<0.001) and the ratio IL-10/TNF-α (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.

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.

Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial

The aim of this study was to determine whether intermittent ambulatory treatment with levosimendan would improve functional capacity, quality of life, and event‐free survival in patients with advanced heart failure.

Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension

CONTEXT Aldosterone (ALD) secretion is regulated mainly by angiotensin II, K(+), and adrenocorticotropic hormone (ACTH). Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA). OBJECTIVE We tested whether chronic stress-related ACTH-mediated ALD hypersecretion and/or zona glomerulosa hypersensitivity could be implicated in the pathogenesis of essential hypertension (ESHT). PATIENTS AND METHODS One hundred thirteen hypertensives without PA and 61 normotensive controls underwent an ultralow-dose (0.03-μg) ACTH stimulation and a treadmill test. Patients with ALD hyper-response according to the cutoffs obtained from controls received treatment with MRAs and underwent genomic DNA testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs. RESULTS Based on the cutoffs of ALD and aldosterone-to-renin ratio (ARR) post-ACTH stimulation obtained from controls, 30 patients (27%) exhibited an ALD but not cortisol (F) hyper-response (HYPER group). This group had no difference in basal ACTH/renin (REN) concentrations compared with controls and the 83 patients with hypertension (73%) without an ALD hyper-response to ACTH stimulation. Patients in the HYPER group demonstrated significantly higher ALD concentrations, ARR, and ALD/ACTH ratio (AAR) in the treadmill test. Treatment with MRAs alone produced normalization of blood pressure in these patients whereas patients with hypertension with neither PA nor ALD hyper-response to ACTH stimulation who served as a control group failed to lower blood pressure. Also, two novel germline heterozygous KCNJ5 mutations were detected in the HYPER group. CONCLUSIONS A number of patients with hypertension without PA show ACTH-dependent ALD hyper-secretion and benefit from treatment with MRAs. This could be related to chronic stress via ACTH hyper secretion and/or gene-mutations increasing the zona glomerulosa responsiveness to excitatory stimuli.

Functional Electrical Stimulation is More Effective in Severe Symptomatic Heart Failure Patients and Improves Their Adherence to Rehabilitation Programs

BACKGROUND Functional electrical stimulation (FES) improves exercise capacity and quality of life in chronic heart failure (CHF) patients. However, there is no evidence regarding the effectiveness of this treatment modality according to the severity of CHF. This study compares the effectiveness of FES on exercise capacity, endothelial function, neurohormonal status, and emotional stress in New York Heart Association (NYHA) III-IV versus NYHA II patients. METHODS AND RESULTS Eighteen NYHA II and 13 age- and sex-matched NYHA III-IV patients with stable CHF (left ventricular ejection fraction <35%) underwent a 6-week FES training program. Questionnaires addressing quality of life (Kansas City Cardiomyopathy Questionnaire, functional and overall), and emotional stress (Zung self-rating depression scale, Beck Depression Inventory), as well as plasma B-type natriuretic peptide (BNP), 6-minute walking distance test (6MWT), and endothelial function (flow-mediated dilatation [FMD]) were assessed at baseline and after completion of training protocol. 6MWT and plasma BNP improved significantly in 2 patient groups (both P < .001) after training program. The improvement of BNP was statistically greater in NYHA III-IV patients posttreatment than in those with NYHA II class (F=315.342, P < .001). Similarly, the improvement of 6MWT was statistically greater in NYHA III-IV group than in NYHA II patients (F=79.818, P < .001). Finally, an FES-induced greater improvement of FMD (F=9.517, P=.004) and emotional stress scores was observed in NYHA III-IV patients in comparison to NYHA II patients. There was a higher proportion of NYHA III-IV patients adhering to the FES training program for additional 3 months compared with the NYHA II group of patients (76.9% vs. 55.6%, P < .001). CONCLUSION FES might exert a greater beneficial effect on clinical and neurohormonal status of NYHA III-IV patients in comparison to NYHA II patients. This effect may have important clinical relevance leading to increased adherence of severe CHF patients to exercise rehabilitation programs.

Effects of functional electrical stimulation on quality of life and emotional stress in patients with chronic heart failure secondary to ischaemic or idiopathic dilated cardiomyopathy: A randomised, placebo‐controlled trial

Functional electrical stimulation (FES) improves exercise capacity and endothelial function in chronic heart failure (CHF) patients. This study evaluates the impact of FES on quality of life and emotional stress in patients with moderate to severe CHF.

Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper

Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps.

Temporal trends in epidemiology, clinical presentation and management of acute heart failure: results from the Greek cohorts of the Acute Heart Failure Global Registry of Standard Treatment and the European Society of Cardiology-Heart Failure pilot survey

AIM Temporal trends of epidemiological data on acute heart failure (AHF) are limited. We sought to assess changes in epidemiology, clinical presentation and management of AHF in Greece using data from two international registries conducted three years apart. METHODS AND RESULTS The Acute Heart Failure Global Registry of Standard Treatment (ALARM-HF) and the European Society of Cardiology-Heart Failure (ESC-HF) pilot survey were conducted during 2006-2007 and 2009-2010, respectively. A total of 432 AHF patients were recruited by Greek sites in the two registries (255 in ALARM-HF and 177 in ESC-HF pilot survey). About 60% of patients in both registries presented with acutely decompensated chronic HF and 40% with de novo AHF. The use of life-prolonging, guideline-recommended medications increased over time (pre-admission use of angiotensin-converting enzyme (ACE) inhibitors/ angiotensin receptor blockers (ARBs) from 47% to 60%, beta-blockers from 31% to 65%, aldosterone antagonists from 18% to 45%). Those therapies also increased during hospitalisation in both registries. Patients were treated by cardiologists in >90% of cases during hospitalisation; the main intravenous therapies in both registries were diuretics (94% and 97%), followed by vasodilators (47% and 22%) and inotropes (31% and 20%). The length of hospitalisation remained similar (6-7 days in both registries), while in-hospital mortality dropped from 8.5% in the ALARM-HF to 4.5% in the ESC-HF pilot survey. CONCLUSIONS A temporal increase in the use of life-prolonging therapies along with an improvement of in-hospital mortality was observed. Clinical profiles, in-hospital management and outcome of AHF patients in Greece were similar to other European countries, despite regional differences in healthcare systems.

The Role of the Immunogenetic Background in the Development and Recurrence of Acute Idiopathic Pericarditis

Objectives: We assessed the role of the immunogenetic background in the development and recurrence of acute idiopathic pericarditis (AIP). Methods: Fifty-five patients with a first episode of AIP were followed for 23.8 ± 6.3 months and recurrences were recorded. The control group consisted of 246 healthy individuals. In all subjects, genomic human leukocyte antigen (HLA) typing was performed. Moreover, circulating lymphocyte subpopulations were studied in 44 randomly selected patients and in 20 controls. Results: An increased frequency of HLA-A*02, -Cw*07 and -DQB1*0202 alleles, and a decreased frequency of the -DQB1*0302 allele was detected in patients with AIP. The recurrence rate was 40% and time to recurrence was 202.8 ± 164.1 days. In patients with idiopathic recurrent pericarditis (RP), increased frequencies of HLA-A*02, -Cw*07 and -DQB1*0202 alleles were found. Notably, no patient with RP exhibited HLA-DRB1*04 and -DQB1*0302 alleles. Patients with RP exhibited lower CD4+/CD45RA+ naïve T cells (p = 0.03) than controls, and higher CD8+DR+ activated T cells (p = 0.01) than patients without recurrence and controls. Conclusions: HLA alleles may confer either susceptibility or resistance to AIP and RP. Circulating T-cell subpopulations may also predict RP. A combination of the above parameters might help to better define patients prone to recurrence.

Serum levels of the osteoprotegerin, receptor activator of nuclear factor κ-B ligand, metalloproteinase-1 (MMP-1) and tissue inhibitors of MMP-1 levels are increased in men 6 months after acute myocardial infarction

Abstract Background: Osteoprotegerin (OPG) and receptor activator of nuclear factor κ-B ligand (RANKL) are critical regulators of bone remodeling and RANKL/RANK signaling could also play an important role in the remodeling process of several tissues, such as myocardium. Therefore, we investigated whether the serum concentrations of OPG and RANKL correlate with the serum levels of metalloproteinase-1 (MMP-1), MMP-9 and tissue inhibitors of MMP-1 (TIMP-1), which are known regulators of myocardial healing in acute myocardial infarction (AMI) patients. Methods: We analyzed blood samples from 51 consecutively hospitalized men with AMI, 12 men with established ischemic heart failure (New York Heart Association category II, NYHA-II) and 12 healthy men age-matched to the NYHA-II patients. Serum levels of MMP-1, MMP-9, TIMP-1, OPG and RANKL were quantified using commercially available ELISA kits. AMI patients were sampled 4 days and 6 months after MI. Results: Our data revealed increased serum levels of OPG, RANKL, MMP-1 and TIMP-1 levels and significant correlations between increased RANKL levels and MMP-1 and TIMP-1 serum levels 6 months after MI. In addition, the ratio OPG/RANKL was very low 6 months after MI, suggesting that the nuclear factor κ-B signaling is possibly more active 6 months post-MI than it is on day 4 post-MI. Conclusions: Our data suggest that OPG, RANKL, MMP-1 and TIMP-1 serum levels can be potential mediators of myocardial healing after MI. However, further large studies are needed to confirm the utility of OPG and RANKL as markers of healing after ST elevation in MI. Clin Chem Lab Med 2008;46:510–6.