Cell therapy for human ischemic heart diseases: critical review and summary of the clinical experiences.

A decade ago, stem or progenitor cells held the promise of tissue regeneration in human myocardium, with the expectation that these therapies could rescue ischemic myocyte damage, enhance vascular density and rebuild injured myocardium. The accumulated evidence in 2014 indicates, however, that the therapeutic success of these cells is modest and the tissue regeneration involves much more complex processes than cell-related biologics. As the quest for the ideal cell or combination of cells continues, alternative cell types, such as resident cardiac cells, adipose-derived or phenotypic modified stem or progenitor cells have also been applied, with the objective of increasing both the number and the retention of the reparative cells in the myocardium. Two main delivery routes (intracoronary and percutaneous intramyocardial) of stem cells are currently used preferably for patients with recent acute myocardial infarction or ischemic cardiomyopathy. Other delivery modes, such as surgical or intravenous via peripheral veins or coronary sinus have also been utilized with less success. Due to the difficult recruitment of patients within conceivable timeframe into cardiac regenerative trials, meta-analyses of human cardiac cell-based studies have tried to gather sufficient number of subjects to present a statistical compelling statement, reporting modest success with a mean increase of 0.9-6.1% in left ventricular global ejection fraction. Additionally, nearly half of the long-term studies reported the disappearance of the initial benefit of this treatment. Beside further extensive efforts to increase the efficacy of currently available methods, pre-clinical experiments using new techniques such as tissue engineering or exploiting paracrine effect hold promise to regenerate injured human cardiac tissue.

Cost-effectiveness of percutaneous coronary intervention with drug-eluting stents in patients with multivessel coronary artery disease compared to coronary artery bypass surgery five-years after intervention.

OBJECTIVES: Cost-effectiveness of percutaneous coronary intervention (PCI) using drug-eluting stents (DES), and coronary artery bypass surgery (CABG) was analyzed in patients with multivessel coronary artery disease over a 5-year follow-up. BACKGROUND: DES implantation reducing revascularization rate and associated costs might be attractive for health economics as compared to CABG. METHODS: Consecutive patients with multivessel DES-PCI (n = 114, 3.3 ± 1.2 DES/patient) or CABG (n = 85, 2.7 ± 0.9 grafts/patient) were included prospectively. Primary endpoint was cost-benefit of multivessel DES-PCI over CABG, and the incremental cost-effectiveness ratio (ICER) was calculated. Secondary endpoint was the incidence of major adverse cardiac and cerebrovascular events (MACCE), including acute myocardial infarction (AMI), all-cause death, revascularization, and stroke. RESULTS: Despite multiple uses for DES, in-hospital costs were significantly less for PCI than CABG, with 4551 €/patient difference between the groups. At 5-years, the overall costs remained higher for CABG patients (mean difference 5400 € between groups). Cost-effectiveness planes including all patients or subgroups of elderly patients, diabetic patients, or Syntax score >32 indicated that CABG is a more effective, more costly treatment mode for multivessel disease. At the 5-year follow-up, a higher incidence of MACCE (37.7% vs. 25.8%; log rank P = 0.048) and a trend towards more AMI/death/stroke (25.4% vs. 21.2%, log rank P = 0.359) was observed in PCI as compared to CABG. ICER indicated 45615 € or 126683 € to prevent one MACCE or AMI/death/stroke if CABG is performed. CONCLUSIONS: Cost-effectiveness analysis of DES-PCI vs. CABG demonstrated that CABG is the most effective, but most costly, treatment for preventing MACCE in patients with multivessel disease.

Inhaled iloprost for patients with precapillary pulmonary hypertension and right-side heart failure.

BACKGROUND: Pulmonary hypertension (PH) can lead to right-side heart failure (RHF) and death. There are no therapeutic recommendations for patients experiencing acute RHF in the course of PH. This study aimed to examine the safety and efficacy of inhaled iloprost in patients with precapillary PH and RHF. METHODS AND RESULTS: Between October 2007 and December 2008, 7 patients with precapillary PH and RHF were enrolled. Per protocol, iloprost was inhaled hourly for a minimum of 12 hours during a 24-hour period. The starting dose of 2.5 µg was increased hourly by 2.5 µg as long as the increases were tolerated. Safety and efficacy were determined by continuous invasive monitoring of systemic and pulmonary hemodynamic parameters. Systemic pressures remained stable during inhalation (66.1 ± 6.9 mm Hg at baseline and 69.1 ± 6.4 mm Hg immediately after inhalation therapy, P = 0.48). Cardiac index increased from 2.4 ± 0.7 L/min/m(2) to 2.9 ± 0.9 L/min/m(2) (P = .008). Pulmonary vascular resistance decreased from 634.6 ± 218.3 dyn·s·cm(-5) to 489.6 ± 173.8 dyn·s·cm(-5) (P = .044), and N-terminal B-type natriuretic peptide levels decreased from 13,591 ± 10,939 pg/mL to 9,944 ± 8,569 pg/mL (P = .051). CONCLUSION: Blood pressure-guided hourly inhalation of iloprost may offer a safe and effective strategy for the treatment of PH patients with RHF.

Plasma MMP-9 and TIMP-1 levels on ICU admission are associated with 30-day survival.

BACKGROUND: Matrix metalloproteinases (MMPs) are involved in systemic inflammatory responses and organ failure. The aim of this study was to evaluate early circulating plasma levels of MMP­2, MMP­9 and their inhibitors TIMP­1 and TIMP­2 and their prognostic significance in critically ill patients on admission to the intensive care unit (ICU). METHODS: In a single center prospective study 120 consecutive patients (72.5% male, mean age 66.8 ± 13.3 years, mean simplified acute physiology score [SAPS II] score 52.9 ± 21.9) were enrolled on transfer to the ICU of a cardiology department. The most common underlying conditions were cardiac diseases (n = 42.5%), respiratory failure (n = 10.8%) and sepsis (n = 6.7%). Blood samples were taken within 12 h of ICU admission. The MMP­2, MMP­9, TIMP­1 and TIMP­2 levels in plasma were evaluated in terms of 30-day survival, underlying condition and clinical score. RESULTS: On ICU admission 30-day survivors had significantly lower plasma MMP­9 (odds ratio, OR 1.67 per 1 SD; 95% confidence interval, CI 1.10-2.53; p = 0.016) and TIMP­1 (OR 2.15 per 1 SD; 95% CI 1.27-3.64; p = 0.004) levels than non-survivors; furthermore, MMP­9 and TIMP­1 correlated well with SAPS II (both p < 0.01). In patients with underlying cardiac diseases, MMP­9 (p = 0.002) and TIMP­1 (p = 0.01) were independent predictors of survival (Cox regression). No significant correlation was found between MMP­2 and TIMP­2 levels, MMP/TIMP ratios and 30-day mortality. CONCLUSION: The MMP­9 and TIMP­1 levels are significantly elevated in acute critical care settings with increased short-term mortality risk, especially in patients with underlying heart disease. These findings support the value of MMPs and TIMPs as prognostic markers and potential therapeutic targets in conditions leading to systemic inflammation and acute organ failure.

Mild hyperhomocysteinemia is associated with a decreased fibrinolytic activity in patients after ST-elevation myocardial infarction.

BACKGROUND: Elevated homocysteine (Hcy) levels have been associated with increased risk for cardiovascular disease and it has been shown that hyperhomocysteinemia is associated with increased levels of t-PA antigen in individuals without evidence for coronary artery disease (CAD). The aim of this study was to examine if Hcy plasma levels are associated with plasma levels of fibrinolytic factors in patients with CAD and a history of acute myocardial infarction. METHODS: We measured in 56 patients with CAD, 1 month after their first ST-elevation myocardial infarction, plasma levels of Hcy, the fibrinolytic parameters tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-type-1 (PAI-1), and t-PA-PAI-1 complexes. RESULTS: Hcy plasma levels inversely correlated with t-PA activity (r=-0.303, p<0.05). Patients with mild hyperhomocysteinemia (Hcy>15 micromol/L, n=8) showed significantly lower plasma levels of t-PA activity (p<0.05). Regression analysis revealed that out of cardiovascular risk factors and medical treatment only Hcy was significantly associated with t-PA activity. CONCLUSIONS: Patients with CAD after a first myocardial infarction and hyperhomocysteinemia show a reduced t-PA activity independently from cardiovascular risk factors and medical treatment. Homocysteine lowering therapies may increase fibrinolytic activity and thereby may help to avoid atherothrombotic events in patients with CAD after a first myocardial infarction.

Premature compared with late onset of coronary artery disease: young patients show a severe defect in fibrinolytic response to venous occlusion.

Inflammatory processes play a role in the onset of acute cardiovascular events associated with activation of the coagulation system whereas the fibrinolytic system may prevent local thrombus formation. We compared 25 patients with premature coronary artery disease (CAD) (first ST-elevation myocardial infarction, < 55 years old) with 25 sex-matched patients older than 55 years at their first myocardial infarction. Six months after the acute event, patients with late onset of CAD showed a significantly higher increase of tissue-type plasminogen activator activity during venous occlusion compared with patients with premature CAD (P < 0.005). Prothrombin fragment 1+2 was higher in patients with late-onset CAD (P < 0.05), whereas the inflammatory markers C-reactive protein and soluble intercellular cell adhesion molecule-1 were not different in both groups. A multivariate analysis including cardiovascular risk factors showed that the tissue-type plasminogen activator response to venous occlusion was independently associated with patient age at onset of first ST-elevation myocardial infarction. Although in our series high age was associated with a prothrombotic state, a high fibrinolytic capacity might have some beneficial effect and contribute to a delayed onset of adverse cardiovascular events in these patients.

An increase of C-reactive protein is associated with enhanced activation of endogenous fibrinolysis at baseline but an impaired endothelial fibrinolytic response after venous occlusion.

OBJECTIVES: The goal of this study was to determine whether chronic inflammation of the vascular wall may be associated with an impaired activation of the fibrinolytic system. BACKGROUND: Inflammation plays an important role in the initiation and progression of atherosclerosis, and the fibrinolytic system may prevent local thrombus formation. METHODS: We included 50 patients six months after their first myocardial infarction. Plasma levels of the inflammatory marker C-reactive protein (CRP) were determined at basal conditions, and the fibrinolytic parameters tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) were measured at basal conditions and after a standardized venous occlusion (VO) of the forearm. RESULTS: Patients with high CRP levels (> or =3 mg/l) showed a significantly higher t-PA activity at baseline compared with patients with medium (1 to 2.9 mg/l) and low (<1 mg/l) CRP levels (p <0.005). In contrast, patients with low CRP levels showed a higher increase of t-PA activity (p <0.05) and a higher reduction of PAI-1 activity during VO (p <0.05) compared with patients with medium and high CRP levels. A multivariate analysis that included cardiovascular risk factors and medical treatment showed that CRP is an independent predictor of the t-PA response after a standardized VO. CONCLUSIONS: Chronic low-grade inflammation is associated with enhanced activation of endogenous fibrinolysis at baseline but a reduced fibrinolytic response to VO. This impaired endogenous fibrinolytic capacity might be an important contributor to the increased coronary event rate associated with elevated CRP levels.

Outcome and functional capacity after prolonged intensive care unit stay.

BACKGROUND: An important proportion of critically ill patients who survives their acute illness remains in a critical state requiring intensive care management for weeks to months. Nevertheless, data on risk factors for in-hospital mortality and especially for long-term mortality and functional capacity are scarce. This study investigated outcome and prognostic factors in long-term critically ill patients. METHODS: This retrospective observational cohort study was performed at our mixed adult 8-bed cardiologic ICU at a 2200-bed University Hospital. Patient data from our local database connected to an Austrian multicenter program for quality assurance in intensive care were analyzed. Data were collected between March 1(st), 1998 and December 31(st), 2003. Patients with an ICU stay > or =30 days formed the long-term study group. Morbidity and functional capacity were assessed using the Barthel mobility index in telephone interviews. RESULTS: Patients spending > or =30 days in the ICU numbered 135 (10%) and occupied 5962 bed-days, representing 40.9% of the total bed-days. Compared with patients with an ICU stay <30 days, patients in the long-term group had a significantly higher SAPS II score during the first 24 hours after ICU admission (54 [IQR 41-65] vs. 38 [IQR 27-56], p < 0.001). There was a trend towards male preponderance in the long-term group (98/135 [82.6%] vs. 782/1215 [64.4%], p = 0.05). Differences in ICU and in-hospital mortality were not significant (28/135 (20.7%) vs. 295/1215 (24.3%), p = 0.620 and 46/135 [34.1%] vs. 360/1215 [29.6%], p = 0.285, respectively). After 12 and 48 months, the overall cumulative rates of death in hospital survivors were 14% and 26%, respectively in the short-term ICU group and 31% and 61% in the long-term group. A log-rank test revealed a significantly higher probability of survival in the short-term group after hospital discharge (log rank = 34.3, p < 0.001). Multivariate analysis of hospital survivors and non-survivors in the long-term group showed that the need for renal replacement therapy during the ICU stay was the sole independent predictor for in-hospital death and death within 1 year after ICU discharge (OR = 2.88; 95%CI 1.12-7.41, p = 0.028 and OR = 3.66, 95%CI 1.36-9.83, p = 0.01, respectively). In 28/31 long-term survivors (90%) in the long-term ICU group, the Barthel index indicated no or only moderate disability during daily activities. CONCLUSION: Hospital mortality rates in critically ill patients with a stay <30 or > or =30 days were comparable. The necessity for renal replacement therapy was the sole independent predictor for in-hospital and 1-year mortality in long-term ICU patients. Critically ill patients with a stay > or =30 days have a high and ongoing risk of death after hospital discharge; however, a substantial number of these patients are long-term survivors with no or only moderate disability during daily activities.

The adaptive immune system and long-term outcome in patients with stable coronary disease. Predictive value of routine laboratory measurements.

Components of the adaptive immune system, in particular lymphocytes and immunoglobulin, play a major role in advanced atherosclerotic lesions. We sought to determine whether routine, measurements of the relative number of circulating lymphocytes (%L) and gamma-globulin (%G) reflecting immunoglobulin are related to event-free survival in patients with stable coronary artery disease (CAD). We prospectively studied the combined endpoint all-cause mortality, myocardial infarction and coronary revascularization procedures in 141 patients after successful percutaneous coronary intervention during a median follow-up time of 13.2 years. Using Cox regression, we found a significant influence of %L on event-free survival (P=0.007) with a relative risk of 2.21 comparing third to first tertile. Subjects with higher %G values likewise had a shorter event-free survival (P=0.008) with a relative risk of 1.67 comparing third to first tertile. The predictive value of %L and %G remained significant after adjustment for demographic data, cardiovascular risk factors, extent of CAD and other inflammatory markers. We conclude that the fraction of gamma-globulin and in particular the relative lymphocyte cell count may serve as readily available and reliable prognostic tools for the long-term outcome in patients with stable CAD.