Acute Stress Disorder Symptoms Predict All-Cause Mortality Among Myocardial Infarction Patients: a 15-Year Longitudinal Study.

BACKGROUND: Studies have recognized myocardial infarction (MI) as a risk for acute stress disorder (ASD), manifested in dissociative, intrusive, avoidant, and hyperarousal symptoms during hospitalization. PURPOSE: This study examined the prognostic role of ASD symptoms in predicting all-cause mortality in MI patients over a period of 15 years. METHODS: One hundred and ninety-three MI patients filled out questionnaires assessing ASD symptoms during hospitalization. Risk factors and cardiac prognostic measures were collected from patients' hospital records. All-cause mortality was longitudinally assessed, with an endpoint of 15 years after the MI. RESULTS: Of the participants, 21.8 % died during the follow-up period. The decedents had reported higher levels of ASD symptoms during hospitalization than had the survivors, but this effect became nonsignificant when adjusting for age, sex, education, left ventricular ejection fraction, and depression. A series of analyses conducted on each of the ASD symptom clusters separately indicated that-after adjusting for age, sex, education, left ventricular ejection fraction, and depression-dissociative symptoms significantly predicted all-cause mortality, indicating that the higher the level of in-hospital dissociative symptoms, the shorter the MI patients' survival time. CONCLUSION: These findings suggest that in-hospital dissociative symptoms should be considered in the risk stratification of MI patients.

High sensitive C-reactive protein and the risk of acute kidney injury among ST elevation myocardial infarction patients undergoing primary percutaneous intervention.

BACKGROUND: Elevated periprocedural high sensitive C-reactive protein (hs-CRP) was shown to be associated with an increased risk for acute kidney injury (AKI) in non-myocardial infarction (MI) patients undergoing percutaneous coronary intervention (PCI), however, no information to date is present regarding its predicting role for AKI in MI patients. We evaluated whether admission serum hs-CRP levels may predict risk of AKI among ST elevation MI (STEMI) patients undergoing primary PCI. METHODS: Five hundred and sixty-two patients that were admitted with STEMI and treated with primary PCI were included in the study. Serum hs-CRP levels were determined from blood samples taken prior to PCI. Patients' medical records were reviewed for occurrence of AKI, in-hospital complications and 30 days mortality. RESULTS: Mean age was 62 ± 16 and 455 (80 %) were males. Patients were divided into two groups, according to their admission hs-CRP values: group 1: hs-CRP ≤9 mg/l (n = 394) and group 2: hs-CRP >9 mg/l (n = 168). Patients with hs-CRP >9 mg/l had significantly higher rate of AKI following PCI (17 vs. 6 %; p < 0.001), more in-hospital complications and higher30 -day mortality rate (11 vs. 1 %; p = 0.02). In a multivariable logistic regression model admission hs-CRP level >9 mg/l was an independent predictor for AKI (OR 2.7, 95 % CI: 1.39-5.29; p = 0.001) and a strong trend for 30 day mortality (OR 4.27, 95 % CI: 0.875-21.10; p = 0.07). CONCLUSION: Admission serum hs-CRP level >9 mg/l is an independent predictor for AKI following primary PCI in STEMI patients.

High Degree Atrioventricular Block Complicating Acute Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention: Incidence, Predictors and Outcomes.

BACKGROUND: In the era of primary percutaneous coronary intervention (PPCI), information on the incidence and prognostic significance of high degree atrioventricular block (AVB) in ST elevation myocardial infarction (STEMI) patients is limited. OBJECTIVES: To assess the incidence, time of onset, predictors and prognostic significance of high degree AVB in a large cohort of consecutive STEMI patients undergoing PPCI. METHODS: We retrospectively studied 1244 consecutive STEMI patients undergoing PPCI. Patient records were reviewed for the presence of high degree AVB, its time of occurrence and relation to in-hospital complications, as well as long-term mortality over a 5 year period. RESULTS: High degree AVB was present in 33 patients (3.0%), in 25 (76%) of whom the conduction disorder occurred prior to PPCI. Twelve patients (36%) required temporary pacing, all prior to or during coronary intervention, and all AVB resolved spontaneously before hospital discharge. AVB was associated with a significantly higher 30 day (15% vs. 2.0%, P = 0.001) and long-term mortality rate (30% vs. 6.0%, P < 0.001). Time of AVB had no effect on mortality. In a multivariate regression model, AVB emerged as an independent predictor for long-term mortality (hazard ratio 2.8, 95% confidence interval 1.20-6.44, P = 0.001). CONCLUSIONS: High degree AVB remains a significant prognostic marker in STEMI patients in the PPCI era, albeit transient.

Expediting Time from Symptoms to Medical Contact Utilizing a Telemedicine Call Center.

BACKGROUND: No definitive solution has been forthcoming for the often dangerously long interval between symptom onset and seeking medical care in the prehospital setting. We examined the implementation of telemedicine technology and characterization of its utilizers for its efficacy in reducing this possibly life-threatening time lag. MATERIALS AND METHODS: A retrospective observational study was performed on the working database of an operational telemedicine facility that included all subscribers. Time-to-contact measurements throughout 2012 were retrieved from its medical files, and data on age, gender, medical history, and main complaint were analyzed. RESULTS: Throughout 2012, 22,274 of a total of 46,556 calls (47.8%) were made ≤60 min from symptom onset. It is important that 26.9% of all calls (12,522/46,556) were made in <15 min. Significantly more males (10,794/22,229 [49%]) contacted in ≤60 min compared with females (11,480/24,327 [47%], p<0.03). Subjects <60 years of age (2,889/5,717 [51%]) called earlier than those >60 years (19,386/40,839 [47%], p<0.001). Patients with prior resuscitation and/or myocardial infarction contacted significantly more rapidly than those with other cardiac diseases. Over one-half of patients with cardiac complaints contacted the call center ≤60 min from symptom onset, as did those who suffered physical trauma, but not patients with gastrointestinal symptoms or pain elsewhere. CONCLUSIONS: A telemedicine system with rapid accessibility to a professional call center and prompt triage thereafter could be an additional promising strategy for shortening the interval between symptom onset and call for medical assistance. Implementation of a widespread telemedicine infrastructure may bridge the unmet gap between occurrence of symptoms to initiation of medical treatment.

Is telemedicine an answer to reducing 30-day readmission rates post-acute myocardial infarction?

BACKGROUND: Patients hospitalized for an acute myocardial infarction (AMI) are at risk for early readmission. Readmission rates in the community reportedly reach approximately 20%, and 30-day readmission rates have become a quality-of-care marker. Telemedicine is one strategy for improving clinical outcomes by offering real-time biometrics tracking and rapid intervention. We retrospectively assessed the 30-day readmission rate of post-AMI members of a telemedicine system. MATERIALS AND METHODS: All "SHL"-Telemedicine subscribers who sustained an AMI and those who became subscribers within 10 days from discharge post-AMI between 2009 and 2012 were assessed. Their files were reviewed for demographics, coronary risk factors, reasons for readmission, and discharge diagnoses. RESULTS: In total, 897 suitable patients (mean age, 62±14 years; 81% males) were included. They had made 3,318 calls to the monitor center for consultation. A mobile intensive care unit was dispatched for 158 patients, 64 were transported to the hospital, and 52 (5.8%) were readmitted (10 patients were readmitted twice). Thirty-five readmissions were for noncardiac reasons. Twelve patients had acute coronary syndrome (11 were revascularized). Readmission rates were higher in patients with repeat AMIs (11.9% versus 5.3% among those with no AMI history) and in females (9.6% versus 4.9% among males). Unlike published figures for the general population, there were no significant differences between readmitted and non-readmitted patients regarding diabetes, hypertension, or congestive heart failure. CONCLUSIONS: Telemedicine technology shows considerable promise for reducing 30-day readmission rates of post-AMI patients.

Is long-term beta-blocker therapy for myocardial infarction survivors still relevant in the era of primary percutaneous coronary intervention?

Studies on trials conducted before the use of thrombolysis demonstrated both short- and long-term benefits of beta-blockers, and one meta-analysis of those trials showed a 25% reduction in 1 year mortality. Treatment with beta-blockers was and continues to be recommended for patients after ST elevation myocardial infarction (STEMI), but many patients failed to receive these agents mostly because physicians were unconvinced of their benefit. A similar analysis of the studies in STEMI patients treated with thrombolysis also showed an overall 23% reduction in mortality associated with beta-blocker use in the era of primary percutaneous coronary intervention (PCI). In the present review, we examine the relationship between the pharmacology of beta-blockers and their potential utility in order to review early trials on their post-infarct efficacy and to place these findings in the context of this specific patient population in the era of primary PCI.

Left ventricular thrombus formation and bleeding complications during continuous in-hospital anticoagulation for acute anterior myocardial infarction.

BACKGROUND: The 20%-60% rate of acute anterior myocardial infarction (AAMI) patients with concomitant left ventricular thrombus (LVT) formation dropped to 10-20% when thrombolysis and primary percutaneous coronary intervention (PPCI) were introduced. OBJECTIVE: To test our hypothesis that prolonged anticoagulation post-PPCI will lower the LVT incidence even further. METHODS: Included in this study were all 296 inpatients with ST elevation AAMI who were treated with PPCI (from January 2006 to December 2009). Treatment included heparin anticoagulation (48 hours) followed by adjusted doses of low molecular weight heparin (3 more days). All patients underwent cardiac echocardiography on admission and at discharge. LVT and bleeding complications were reviewed and compared. RESULTS: LVT formation was present on the first echocardiogram in 6/296 patients. Another 8/289 patients displayed LVT only on their second echocardiogram (4.7%, 14/296). LVT patients had significantly lower LV ejection fractions than non-LVT patients at admission (P < 0.003) and at discharge (P < 0.001), and longer time to reperfusion (P = 0.168). All patients were epidemiologically and clinically similar. There were 6 bleeding episodes that required blood transfusion and 11 episodes of minor bleeding. CONCLUSIONS: Five days of continuous anticoagulation therapy post-PPCI in inpatients with AAMI is associated with low LVT occurrence without remarkably increasing bleeding events.

Diagnostic yield of extensive infectious panel testing in acute pericarditis.

OBJECTIVE: In an attempt to reconsider our local strategy, we evaluated patients with viral/idiopathic pericarditis in order to assess the diagnostic yield of our standard infectious panel, the characteristics of myocardial involvement, the utility of investigating myocardial involvement and the incidence of coronary evaluation tests. METHODS: Seventy-six consecutive cases of idiopathic/viral acute pericarditis treated between March 2005 and March 2008 were retrospectively enrolled. Telephonic questionnaires were answered by all. RESULTS: Myopericarditis was recorded in 45/71 (63.4%) consecutive patients. Sore throat on presentation (38 vs. 12%; p = 0.027) was the only symptom independently associated with myopericarditis. The following clinical features were significantly correlated with pericarditis rather than myopericarditis: age (42 ± 16 vs. 32 ± 12; p = 0.008), C-reactive protein (131 ± 75 vs. 78 ± 58; p = 0.009) and lower CPK and troponin levels (mean 96 vs. mean 489; p < 0.001 and mean 0 vs. mean 10; p < 0.001, respectively). The infectious panel revealed 6 positive results. After an average 3 years' fol- low-up, recurrence was documented in 5 patients (7%). No patient initially regarded idiopathic developed systemic disease during follow-up. CONCLUSIONS: Among patients presenting with presumed idiopathic/viral pericarditis, myopericarditis is relatively common and has a benign evolution. Extensive serological investigation with a broad infectious panel proved to be diagnostically and therapeutically futile in our area.

Telecardiology.

Telemedicine is the application of advanced telecommunication technology for diagnostic, monitoring and therapeutic purposes. It enables data transmission from the patient's whereabouts or his/her primary care provider to a specialized medical call center. Telecardiology is a highly developed medical discipline involving almost every aspect of cardiology, including acute coronary syndromes, arrhythmias, congestive heart failure, sudden cardiac arrest and others. Israel is one of the leading countries in the use of telecardiology, achieving extended survival, improvement of the patient's quality of life, and significant reduction in health costs.

Telemedicine for post-myocardial infarction patients: an observational study.

"SHL" Telemedicine (established 1987 in Israel) provides professional care to subscribers who use cardiobeepers and contact its medical call center via telecommunication networks. The extended 6-month Acute Coronary Syndrome Israel Survey (ACSIS) 2004 involved all 26 intensive cardiac care units in Israeli hospitals. We compared the 1-year survival rates of the "SHL" Telemedicine subscribers and ACSIS participants who survived hospitalization after sustaining an acute myocardial infarction. The myocardial infarction data for the ACSIS cohort (3,899 patients) and the SHL Telemedicine cohort (699 subscribers) were provided for this study by the ACSIS executive and SHL's files, respectively. One-year mortality was ascertained by telephone contacts with patients or their relatives. Mortality at 1 year was 4.4% for the "SHL" patients and 9.7% for the ACSIS patients (p < 0.0001). The "SHL" cohort was significantly older (p < 0.0001) than the ACSIS cohort (mean age [+/-SD] 69 +/- 11 versus 63 +/- 13 years), had significantly more past myocardial infarctions (p < 0.001), more past strokes (p < 0.0032), more heart failure (p < 0.0001), more hypertension (p = 0.002), and more hyperlipidemia (p < 0.0001). Gender distribution and diabetes status were similar for both groups. In spite of having more risk factors than the ACSIS subjects, the "SHL" Telemedicine subscribers had significantly higher survival rates at 1 year compared to the ACSIS patients, whose outcome is consistent with that of the Western world. Availability of medical call centers in the out-of-hospital setting for patients with suspected cardiac symptoms improves their motivation to seek timely and appropriate medical assistance.

Vigilance, awareness and a phone line: 20 years of expediting CPR for enhancing survival after out-of-hospital cardiac arrest. The 'SHL'-Telemedicine experience in Israel.

OBJECTIVES: The only large-scale report (1988) by the Israeli national ambulance service Magen David Adom (MDA) on the outcome of cardiac arrest victims who underwent cardiopulmonary resuscitation (CPR) by paramedics called for more frequent and more promptly initiated CPR and shorter time to arrival of paramedic care to improve survival. We report the 1987-2007 experience of resuscitation of out-of-hospital cardiac arrest victims who were 'SHL'-Telemedicine subscribers and who underwent CPR by SHL-Telemedicine mobile intensive care units (MICUs) personnel or under their instructions. METHODS: 'SHL's records of MICU reports and specifics of CPR maneuvers and outcome of resuscitated patients, as recorded by its MICU physicians, were analyzed to determine whether the system enhanced survival. RESULTS: A total of 1810 'SHL'-Telemedicine subscribers (mean age 76+/-12 years [16-104], 67% males) were resuscitated after cardiac arrest, 597 (33%) were hospitalized and 279 (15.4%) were discharged alive. Factors associated with successful resuscitation included witnessed collapse and documented ventricular fibrillation upon MICU arrival. A history of diabetes, hyperlipidemia, stroke or advanced age adversely affected the outcome. Time from collapse to CPR initiation and duration of CPR correlated significantly with survival. Laymen instructed telephonically by the 'SHL'-Telemedicine center performed CPR on 121 patients: 13 (10%) survived to hospital discharge. CONCLUSIONS: 'SHL'-Telemedicine's policy of bi-monthly contact with its subscribers led to heightened awareness of warning signs and need for rapid summoning of medical assistance in the setting of out-of-hospital sudden cardiac arrest.

Emotional events and anger at the workplace as triggers for a first event of the acute coronary syndrome: a case-crossover study.

BACKGROUND: Previous studies found that some factors such as physical exertion, anger and heavy meals were triggers for acute coronary syndrome. OBJECTIVES: To estimate the relative risk of an ACS episode associated with positive and negative emotional experiences and anger as potential work-related triggers. METHODS: A total of 209 consecutive patients were interviewed a median of 2 days after a cardiac event that occurred at work or up to 2 hours later. The case-crossover design was used. Positive and negative emotional experiences and anger episodes in the hours immediately before the onset of ACS were compared with episodes in the comparable hours during the previous workday. For anger the episodes were compared with the usual frequency at work during the previous year. Positive and negative emotional experiences were assessed by the PANAS questionnaire (Positive and Negative Affect Scale), and anger by the Onset Anger Scale. RESULTS: The relative risks of an acute coronary event during the first hour after exposure to negative and positive emotional experiences were RR = 14.0 (95% confidence interval 1.8-106.5) and RR = 3.50 (95% CI 0.7-16.8) respectively and RR = 9.0 (95% CI 1.1-71) for an episode of anger. Using conditional logistic regression analysis, the highest relative risk was associated with negative emotional experiences. CONCLUSIONS: Negative emotional experiences and anger at work can trigger the onset of an ACS episode. This could have implications for recognizing a cardiac event as a work accident. The implementation of stress-reduction programs in the workplace or use of preventive medications in workers at high risk for coronary heart disease should be investigated.

The involvement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in atherosclerosis.

OBJECTIVES: Herein, we determined the significance of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in atherosclerotic vascular disease. BACKGROUND: Inflammation is associated with the pathogenesis of atherosclerosis. The TNF-related apoptosis-inducing ligand/APO-2L, a member of the TNF superfamily, has a role in apoptosis induction and is recognized for its immunomodulatory properties. METHODS: Stable and vulnerable atherosclerotic human plaques and aortas from atherosclerotic mice were assayed for the presence of TRAIL, and its inducibility was assayed by immunoblot and real-time polymerase chain reaction on peripheral mononuclear cells incubated with oxidized low-density lipoprotein (oxLDL). Enzyme-linked immunosorbent assay was used for the determination of soluble TRAIL levels in atherosclerotic patients. RESULTS: Tumor necrosis factor-related apoptosis-inducing ligand is present in stable atherosclerotic lesions, is increased in vulnerable plaques, and is found to colocalize with CD3 cells and oxLDL. The TNF-related apoptosis-inducing ligand messenger ribonucleic acid (mRNA) and protein expression was up-regulated in peripheral blood mononuclear cells after incubation with oxLDL. Serum levels of soluble TRAIL but not TNF-alpha or Fas-ligand were reduced significantly in patients with unstable angina as compared with patients with stable atherosclerotic disease and healthy subjects. A negative correlation was demonstrated between soluble TRAIL and C-reactive protein levels but not with levels of mRNA of TRAIL in peripheral blood mononuclear cells. CONCLUSIONS: Tumor necrosis factor-related apoptosis-inducing ligand is expressed in plaque-infiltrating CD3 cells and induced by oxLDL, whereas levels of soluble TRAIL are reduced in patients with acute coronary syndromes and negatively correlate with C-reactive protein levels. These results support a possible role for TRAIL in atherosclerosis.

Usefulness of anti-oxidized LDL antibody determination for assessment of clinical control in patients with heart failure.

BACKGROUND: It has been suggested that oxidative stress may play a role in the pathogenesis of heart failure, this may have potential implications for therapeutic strategies. However, measures of oxidative stress are subject to confounding inaccuracies. IgG antibodies to oxidized LDL reflect exposure to the lipoprotein over an extended period and may thus mirror oxidative stress over a prolonged time frame. Therefore, we tested the hypothesis that anti-oxLDL antibodies correlate with the control of heart failure (HF), as manifested by hospital admissions for cardiac dysfunction. METHODS: One hundred and two consecutive patients attending the HF clinic with either systolic or diastolic HF were enrolled and the quality of clinical control was evaluated by assessing hospital admissions over the year prior to index determination of the oxidative stress marker. Antibodies to oxLDL were determined by ELISA and pro-BNP levels were also measured. RESULTS: Most patients (mean age 71.5 years) had systolic HF; mean NYHA functional class was 2.7 and mean left ventricular ejection fraction was 39.7%. Anti-oxLDL antibodies, but not pro-BNP, correlated significantly with mean NYHA score (averaged from all clinic visits in the year prior to blood testing), and with hospital admissions over the year prior to blood testing. Mean IgG anti-oxLDL antibody levels in patients with hospital admissions were 3.4 times higher than those in subjects not hospitalized over the previous year. CONCLUSION: IgG anti-oxLDL antibody levels correlate with the severity of HF.

Comparative analysis of methods for assessment of circulating endothelial progenitor cells.

The number and properties of endothelial progenitor cells (EPC) in disease states is of considerable interest due to the importance attributed to this distinct cell population. However, there has been no study comparing each of the methods employed in the same sampled individuals. Herein, we performed an analysis of several methods used for circulating EPC assessment and correlated them with humoral factors known to influence their numbers. Thirty-eight individuals (mean age of 34 +/- 9 years) were tested. Peripheral blood mononuclear cells were obtained and stained for FACS analysis with antibodies to CD34, CD45, CD133, and KDR and the remaining cells grown under endothelial cell conditions for assessment of colony-forming unit (CFU) numbers and adhesive properties. Levels of circulating vascular endothelial growth factor (VEGF), erythropoietin (EPO), and C-reactive protein (CRP) were determined and correlated with each of the EPC markers. CFU numbers did not correlate with CD34/KDR or CD34/CD133/KDR and negatively correlated with CD34/ CD133 numbers. CD34/KDR numbers correlated with CD34/CD133/KDR, but not with CD34/ CD133. Only CD34/KDR and CD34/CD133/KDR correlated with VEGF serum levels. The number of EPC adhering to fibronectin and endothelial cells correlated with CFU numbers and not with either of the EPC membrane markers. Current methods for quantitatively assessing numbers of circulating EPC are not correlated. VEGF serum levels are associated only with CD34/KDR and CD34/ CD133/KDR, whereas CFU numbers correlate with EPC functional properties. These findings may suggest that CD34/KDR is more appropriate for the definition of circulating EPC, whereas CFU numbers are more likely to reflect their ability to proliferate.

Cellular autoimmunity to cardiac myosin in patients with a recent myocardial infarction.

After a large myocardial infarction (MI) a progressive remodeling process can occur that results in a severe mechanical dysfunction of the heart. Among the determinants of remodeling, immune mediated inflammation has been suggested as an important contributor. However, the role of autoimmunity to cardiac antigens that are released to the circulation has not been sufficiently addressed. Cardiac myosin is a contractile protein that is unique to the myocardium and has been shown to induce a humoral immune response in patients after MI, and to trigger an autoimmune myocarditis in experimental rats and mice. In the current study, we evaluated humoral and cellular immune responses to myosin in patients with and without a history of recent MI. Eighteen patients with MI, 2 weeks to 4 months prior to initiation of the study, and eighteen control subjects were enrolled. Peripheral blood mononuclear cells (PMBC) were obtained and subjected to priming with different concentrations of cardiac myosin. Interferon-gamma and TNF-alpha were measured in conditioned medium obtained from the cultured PMBC upon priming with cardiac myosin. Humoral immune responses were also assessed by evaluating IgG anti-myosin antibodies. We have found that a third of the patients with the recent history of MI and none of the control subjects had a proliferative response to cardiac myosin evident by stimulation indices greater than 1.5. No differences were detected between the patients and controls with regard to IFN-gamma and TNF-alpha secreted by their PMBC, nor were there differences in the serum levels of IgG anti-myosin antibodies. Thus, in patients with a recent history of MI, cellular autoimmunity to cardiac myosin is present as compared with controls. It remains to be determined whether this autoimmune response is associated with an adverse outcome.

Telecardiology for patients with acute or chronic cardiac complaints: the 'SHL' experience in Israel and Germany.

OBJECTIVE: To assess the impact of a telemedicine program in which electrocardiogram (EKG), body weight and/or blood pressure are measured at home and medically trained personnel judge the transmitted data and council the patients by telephone. METHOD: We systematically studied the outcome and cost-effectiveness of the cardiac programs carried out by Shahal (SHL) during the past 19 years. RESULT: Most patients (85%) with acute complaints resembling coronary artery disease, could be reassured, representing a savings of about 677.000 euro per 10,000 members/yr in Israël in 1989, and a marked reduction in patient delay to 44 min (median). In chronic heart failure a 66% reduction in hospitalisation days was observed, together with an improvement in quality of life. A large Healthcare Insurance Company in Germany (Taunus BKK) has calculated that it can save at least 5 million euro per year with the use of such services. CONCLUSION: Disease management with concomitant telemedicine for coronary artery disease and chronic heart failure is safe and effective and has a huge potential for cost savings, improvements in quality of life and in prognosis of heart disease.

Erythropoietin promotes endothelial progenitor cell proliferative and adhesive properties in a PI 3-kinase-dependent manner.

OBJECTIVES: Patients with congestive heart failure (CHF) suffer considerable morbidity and mortality despite advances in therapy. Treatment with erythropoietin (Epo) has shown promise in CHF patients, yet its mechanisms of action remain elusive. Endothelial progenitor cells (EPC) contribute to postnatal angiogenesis and vasculogenesis, and Epo was shown to promote EPC mobilization. We explored the effect of chronic treatment with Epo on the numbers and functional properties of EPC in CHF patients. METHODS AND RESULTS: Twenty-eight patients with CHF treated with Epo for a mean period of 28 months were compared to a matched group (n = 28) with regard to the number of circulating hematopoietic and endothelial stem cells (either CD34+, CD34+/CD45+, CD34+/CD133+, CD34+/VEGF-R2+ or CD34+/CD133+/VEGF-R2+) as well as their proliferative and adhesive capacity. In vitro, Epo was added to cultured EPC from healthy subjects to test proliferation and adhesion. No differences were observed in circulating numbers of hematopoietic and endothelial stem cells between CHF patients chronically treated with Epo or untreated. EPC from Epo-treated patients exhibited enhanced proliferation as well as a trend towards adhesion to cultured endothelial cells prior to and following stimulation with TNF-alpha. Addition of Epo to EPC from healthy subjects dose-dependently increased their proliferation and adhesion to fibronectin, cultured endothelial cells, and cardiomyocytes. These effects were significantly reduced in the presence of phosphatidylinositol (PI) 3-kinase inhibitors. CONCLUSIONS: Chronic Epo treatment is associated with an increase in the adhesive and proliferative properties of circulating EPC in patients with CHF.