CD34+ enriched cell products intended for autologous transendocardial CD34+ cell transplantation release significant amounts of angiopoietin-1.

OBJECTIVES: Cell-based therapy has emerged as a promising strategy for the treatment of patients with heart failure. Increasing evidence supports the hypothesis that paracrine mechanisms mediated by soluble factors released by the cells play a predominate role in reparative processes. The aim of our study was to analyze which cytokines are released by CD34+ enriched cell products intended for autologous transendocardial CD34+ cell transplantation in patients with cardiomyopathy. MATERIAL AND METHODS: The peripheral blood CD34+ cells from 12 patients were mobilized with granulocyte colony-stimulating factor, collected via apheresis and enriched by immunoselection. RESULTS: In CD34+ enriched cell population, hematopoietic, but not mesenchymal or endothelial, progenitors were detected. Except for angiopoietin-1, other measured cytokines (FGF1, FGF2, VEGF, PDGF, IL-6, HGH, SDF-1α/CXCL12, NRG1) were not released by CD34+ cells. The average concentration of angiopoietin-1 released by 5×106 CD34+ cells grown in neutral DMEM medium was 213.6±130.0pg/mL (range: 74-448pg/mL). Angiopoietin-1 secretion correlated well with CD34+ cell's capacity for generating colonies derived from hematopoietic progenitors (Pearson's correlation=0.964; P<0.001). CONCLUSION: Our study presents angiopoietin-1 as an interesting candidate and suggests future studies to explore how its release by CD34+ cells might impact the success of autologous CD34+ cell transplantation.

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.

CD34+ stem cell therapy in nonischemic dilated cardiomyopathy patients.

Recent trends indicate that patients with nonischemic dilated cardiomyopathy represent the largest subpopulation of heart failure patients with a significant need for alternative treatment modalities. Similar to patients with ischemic cardiomyopathy, patients with nonischemic dilated cardiomyopathy have been found to have myocardial regions with flow abnormalities, which may represent targets for neoangiogenic therapies. CD34(+) stem cells might contribute to the formation of new blood vessels from existing vascular structures in ischemic tissues by the direct incorporation of injected cells into the newly developing vasculature or by the production and secretion of angiogenic cytokines. This review summarizes the long-term clinical effects and potential underlying mechanisms of CD34(+) cell therapy in patients with nonischemic dilated cardiomyopathy.

Granulocyte colony-stimulating factor therapy is associated with a reduced incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients.

BACKGROUND: We evaluated the potential effects of granulocyte colony-simulating factor (G- CSF) on the incidence of rejection and allograft vasculopathy in heart transplant recipients. METHODS: Of 247 patients undergoing heart transplantation from 2000 to 2007, 52 (21%) developed leukopenia (white blood cell [WBC] <2.5 × 10(9) cells/L) in the absence of active infection, rejection, or malignancy. In 24 (46%) patients a clinical decision was made to treat the leukopenia with G-CSF (G-CSF group), and 28 (54%) Patients received no G-CSF (non-GCSF group). Patients followed up for 1 year after the period of leukopenia were assessed for allograft vasculopathy and acute rejection incidence. RESULTS: At baseline, the G-CSF group and the non-GCSF group did not differ in age, gender, race, heart failure etiology, creatinine, left ventricular ejection fraction (LVEF) or immunosupressive regimen. During 1-year follow-up there were no deaths in the G-CSF group, and 1 death in the non-GCSF group (P = .34). The incidence of rejection or progressive allograft vasculopathy was lower in the G-CSF group when compared with the non-GCSF group (2 [8%] vs 15 [53%]; P < .01). Multivariate analysis identified both prior rejection episodes and G-CSF therapy as factors associated with the combined end-point of rejection or progressive allograft vasculopathy (odds ratio [OR] = 7.89 [1.67-37.2] and OR = 0.09 [0.02-0.52], respectively). CONCLUSIONS: G-CSF therapy appears to be associated with a decreased incidence of acute rejection episodes or allograft vasculopathy in heart transplant recipients, suggesting a potential immunomodulatory effect of G-CSF.

ST-elevation myocardial infarction following heart transplantation as an unusual presentation of coronary allograft vasculopathy: a case report.

BACKGROUND: The presentation, mechanisms, and incidence of ST elevation myocardial infarction (STEMI) in heart transplant recipients have been characterized only to a limited degree in the current literature. Herein, we present a unique case of STEMI years after heart transplantation with a focus on the salient features of its diagnosis and interventions. We also provide a review of the epidemiology of this phenomenon. CASE REPORT: A 33-year-old woman who was status post cardiac transplantation for dilated cardiomyopathy presented to the clinic with mild nonspecific fatigue and concern after having noticed relative bradycardia compared with her posttransplantation baseline heart rate. Electrocardiogram (ECG) showed junctional rhythm and inferior ST elevations, likely reflecting nodal ischemia. Troponins were grossly positive and echocardiogram showed marked right ventricular dysfunction. RESULTS: Successful percutaneous coronary intervention (PCI) with aspiration thrombectomy and drug-eluting stent placement was emergently performed. The heart's rhythm soon returned to sinus tachycardia. Right ventricular wall-motion abnormalities resolved. The patient suffered no clinical sequelae of her STEMI. CONCLUSION: This case illustrated that "classic" symptoms of STEMI may not occur at all in the setting of heart transplantation. To our knowledge, this is the first case of posttransplantation STEMI presenting as asymptomatic bradycardia, and highlights the importance of maintaining high clinical suspicion for ischemia in transplant recipients with subtle changes. In reviewing the epidemiology of this case, we locate and bundle different types of studies that have directly or indirectly looked at STEMI in heart transplantation. For a variety of putative pathophysiological reasons, STEMI is indeed a rare manifestation of the common transplant phenomenon of coronary artery vasculopathy (CAV).

Testosterone-related shortening of QTc interval in women with polycystic ovary syndrome.

CONTEXT: The presence of several cardiovascular risk factors is observed in women with polycystic ovary syndrome (PCOS). On the other hand, the QTc interval duration, which is related to cardiac arrhythmia and sudden death, has not been investigated thoroughly in PCOS population. OBJECTIVE: To investigate QTc interval duration and its relation to testosterone in women with PCOS. DESIGN: Cross sectional case-control study. SETTING: Outpatient setting, tertiary university medical centre. PATIENTS: We enrolled 119 consecutive patients in whom PCOS was diagnosed based on oligomenorrhea, infertility (>2 yr), ineffective ovarian stimulation, and ultrasonographic criteria. The control group (controls) included 64 age-matched healthy women without clinical or laboratory evidence of PCOS. INTERVENTIONS: In all participants we measured QTc interval duration on a standard electrocardiogram and determined plasma levels of high sensitivity C-reactive protein (hsCRP), endothelin-1 (ET-1), insulin, and testosterone. MAIN OUTCOME MEASURE: Shorter QTc interval duration in PCOS patients. RESULTS: When compared to controls, PCOS patients displayed higher values of hsCRP (2.35+/-2.14 mg/l vs 1.18+/-1.24 mg/l; p=0.01), ET-1 (23.6+/-10.3 ng/l vs 12.9+/-20.7 ng/l; p=0.03), insulin (18.5+/-7.8 mIU/l vs 10.7+/-9.1 mIU/l; p=0.02), and testosterone (2.7+/-2.1 nmol/l vs 1.4+/-1.7 nmol/l; p=0.01). QTc interval in PCOS patients was significantly shorter than in controls (401+/-61 msec vs 467+/-61 msec; p=0.007), and inversely related to the plasma levels of testosterone (Spearman -0.45, p=0.005). CONCLUSIONS: QTc interval in PCOS patients is short, and inversely associated with increased levels of testosterone. QTc interval duration is not part of an adverse cardiac risk profile in PCOS.

Metabolic and cardiovascular changes in women with polycystic ovary syndrome.

OBJECTIVE: To analyze the relationship between QTc interval and cardiovascular risk factors in women with polycystic ovary syndrome (PCOS). METHODS: Study group included 119 PCOS women (age: 32.2+/-5.2 years) and the control group 64 age-matched healthy women; they all underwent QT interval measurement, and plasma levels of high-sensitivity CRP (hsCRP), endothelin-1 (ET1), insulin, and testosterone determinations. RESULTS: In PCOS women hsCRP (2.35+/-2.14 mg/L vs. 1.01+/-1.28 mg/L; P=0.04), ET1 (23.6+/-10.3 ng/L vs. 7.7+/-15.9 ng/L; P=0.01), and insulin (16.5+/-7.8 mIU/L vs. 11.8+/-10.7 mIU/L; P=0.03) levels were significantly higher, and QTc interval significantly shorter than in controls (401+/-61 ms vs. 467+/-61 ms; P=0.007). In 67 (56%) PCOS patients with a short QTc interval (<400 ms), plasma testosterone levels were significantly higher than in PCOS women with normal QTc interval (2.3+/-2.1 nmol/L vs. 1.4+/-1.7 nmol/L; P=0.02). CONCLUSIONS: In patients with polycystic ovary syndrome increased testosterone levels may attenuate the effects of coronary risk factors.

Noninvasive monitoring of rejection therapy based on intramyocardial electrograms after orthotopic heart transplantation. Initial experience with 14 cases.

Despite the use of increasingly specific immunosuppressive therapy, rejection remains the leading cause of death in cardiac transplant patients. Endomyocardial biopsy (EMB) is the gold standard for early detection and monitoring of cardiac transplant rejection. However, this approach is invasive and not suitable for routine use. A noninvasive alternative for monitoring cardiac transplant patients uses the analysis of the ventricular evoked response (VER) obtained by programmed electrical stimulation. Rejection-sensitive parameters (RSP) and infection-specific parameters (ISP) are extracted from changes in the slope of the T-wave and from the duration of repolarization, respectively. For the analysis of intramyocardial electrograms, separate left and right ventricular pacing at a rate of 100 beats/min and lasting 60 s is required, following the same protocol. From year 2000, telemetric pacemakers were implanted in 14 patients undergoing heart transplantation at this institution. A total of 95 endomyocardial biopsies and 275 ventricular evoked response measurements were carried out. Five out of 6 cases with significant rejection were correctly identified by RSP values below a threshold of 98% (sensitivity=80%, specificity=50%, negative predictive value=97%, positive predictive value=11%; P<0.002). Of the EMBs, 45% could have been saved if the diagnosis model had been used to indicate need for EMB. Noninvasive cardiac graft monitoring can reduce the need for surveillance biopsies and may offer a tool to optimize immunosupressive therapy after heart transplantation. Rejection grade 2 or higher can safely be detected.

Comparison of intravenous ganciclovir and cytomegalovirus hyperimmune globulin pre-emptive treatment in cytomegalovirus-positive heart transplant recipients.

BACKGROUND: We compared the use of intravenous ganciclovir and cytomegalovirus hyperimmune globulin (CMVIG) as a pre-emptive treatment for cytomegalovirus (CMV)-positive heart transplant recipients. METHODS: Of 59 CMV-seropositive adult heart transplant recipients enrolled in Group 1, 37 tested positive for pp65 antigen within 12 weeks post-transplantation. These patients were randomized to receive either intravenous ganciclovir (n = 23) or CMVIG (n = 14). Group 2 included 133 CMV-seropositive heart transplant recipients who were not tested for CMV antigenemia and who received no anti-CMV therapy. RESULTS: CMV disease developed in 0 of 59 patients from Group 1, and in 27 of 133 patients (20%) in Group 2 (p = 0.0001). The incidence of superinfections was lower in Group 1 (0.28 +/- 0.46) than in Group 2 (1.10 +/- 1.33) (p = 0.01). The 2 groups did not differ with regard to incidence of rejection (0.7 +/- 0.9 in Group 1 vs 1.0 +/- 1.2 in Group 2; p = NS), transplant coronary artery disease at 1 year (14% in Group 1 vs 16% in Group 2; p = NS) or post-transplant lymphoproliferative disease (0% in Group 1 vs 2% in Group 2; p = NS). Ganciclovir and CMVIG therapies were associated with similar rates of rejection (0.52 +/- 0.6 with ganciclovir vs 0.50 +/- 0.60 with CMVIG; p = NS), superinfection (0.30 +/- 0.48 with ganciclovir vs 0.25 +/- 0.46 with CMVIG; p = NS), and transplant coronary artery disease at 1 year (13% with ganciclovir vs 14% with CMVIG, p = NS). CONCLUSIONS: The pre-emptive anti-CMV approach is superior to prophylaxis in CMV-seropositive heart transplant recipients. Both ganciclovir and CMVIG are equally effective.

Sirolimus therapy in cardiac transplantation.

Rapamycin powerfully inhibits the progression of antigen-activated T cells through the cell cycle. In animal heart transplantation models, rapamycin therapy has been associated with profound immunosuppressive effects on host humoral and cellular responses. In consequence, further studies have been conducted to evaluate the efficiency of rapamycin in preventing acute heart allograft rejection, treating refractory acute heart allograft rejection, inducing transplantation tolerance, and preventing and treating transplant coronary artery disease. The results of these studies indicated that rapamycin can effectively prevent acute graft rejection and inhibit refractory acute graft rejection in heart transplant recipients by exerting potent immunosuppressive and antiproliferative effects without adversely affecting renal function. This supports the use of rapamycin therapy in heart transplant recipients, especially in those with renal dysfunction, for whom treatment with calcineurin inhibitors is contraindicated. Rapamycin may also halt and even reverse the progression of cardiac allograft vasculopathy, which warrants further clinical trials in humans. Finally, rapamycin may be able to induce transplantation tolerance, thus making it one of the most promising modalities for improving the long-term survival of heart transplant recipients.

The effect of estrogen replacement therapy on ventricular repolarization dynamics in healthy postmenopausal women.

Even though gender-specific differences in ventricular repolarization have gained wide recognition, the underlying mechanisms remain unknown. Because estrogen hormones may represent a causative factor for the changes in ventricular repolarization in women, this study evaluates a potential impact of estrogen replacement therapy on ventricular repolarization dynamics. Beat-to-beat QT and RR interval variability and QT/RR relationship during 5 minute resting high-resolution electrocardiogram recordings were measured in 30 healthy postmenopausal women (mean age 54.5 years) before and after 10 weeks of estrogen replacement therapy (ERT) with estradiol 2 mg/day. The 2 control groups included 12 healthy postmenopausal women of the similar age, who did not receive ERT, and 11 comparably healthy age-matched men. To evaluate ventricular repolarization dynamics, QT/RR linear regression slopes were calculated. After the 10-week period, the QT/RR regression slope increased by 93% in the ERT group (P <.001), but no alterations were noted in either the male or female controls. The overall variability of RR and QT intervals did not change in any of the groups studied. Our results suggest that ERT causes alterations in ventricular repolarization dynamics without significantly affecting the autonomic nervous tone.

Beat-to-beat QT interval variability in coronary patients.

Changes in ventricular repolarization have been described in patients after myocardial infarction, whereas data for coronary patients without prior myocardial infarction are lacking. This study was designed to evaluate ventricular repolarization in coronary patients with effort angina pectoris. Beat-to-beat QT interval variability (QTV) using 5-minute resting high-resolution ECG recordings was measured in 26 men (mean age 62.1 years) with effort angina pectoris and without prior myocardial infarction, and in 30 age-matched men without clinically evident coronary heart disease (controls). To evaluate the degree of coronary artery disease in coronary patients, coronary angiography was performed. Coronary patients displayed significantly higher values of QTV compared with the control patients (P < .001). Rate adaptation of QT interval correlated significantly with the degree of coronary artery disease in the study group patients (P < .05). The significant association between QTV and coronary heart disease suggests altered ventricular repolarization in coronary patients without prior myocardial infarction.

Carotid intima-media thickness of young coronary patients.

BACKGROUND: Although a greater than normal intima-media thickness (IMT) has been found in older coronary patients, the data for younger patients are lacking. OBJECTIVE: To determine the carotid IMT in patients with premature myocardial infarction. METHODS: We measured IMT (common and internal carotid, carotid bifurcation) in 30 coronary patients, aged 30-50 years (mean 46 years), who had survived myocardial infarctions 1-9 years (mean 6 years) earlier, and in 30 age-matched men without clinically evident coronary heart disease (controls) by B-mode ultrasonography. Blood levels of lipoproteins, glucose, iron and transferrin, fibrinogen, tissue plasminogen activator (t-PA) antigen level and activity and plasminogen activator inhibitor (PAI-1) antigen level and activity were also determined. RESULTS: IMT in all segments of carotid arteries in the patients was significantly greater than that in the controls (P < 0.0001). The presence of atherosclerotic plaques was correlated to greater than normal carotid IMT. Other risk factors displaying statistically significant correlations to mean carotid IMT were t-PA antigen level and activity, PAI-1 antigen level and level of high-density lipoprotein cholesterol. CONCLUSIONS: The significant association between carotid IMT and coronary heart disease suggests that carotid and coronary atherosclerosis evolve simultaneously. Hence carotid IMT can be used as a predictor of coronary atherosclerosis.

[Ionization of the cervix uteri]. / Ionisatio cervixis uteri.

A procedure of copper ionization of the cervix uteri performed in 1054 cases of chronic cervicitis is described. This way of treatment resulted in the reduction of exaggerated cervical discharge, the volume of the cervix was diminished, and erosions became smaller. Slight bleeding after this therapy was recorded as complication in two cases. In 85% of cases only one ionization is needed to reach the optimal therapeutic effect.