Ultra-low-dose CT versus chest X-ray for patients suspected of pulmonary disease at the emergency department: a multicentre randomised clinical trial.

BACKGROUND: Chest CT displays chest pathology better than chest X-ray (CXR). We evaluated the effects on health outcomes of replacing CXR by ultra-low-dose chest-CT (ULDCT) in the diagnostic work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. METHODS: Pragmatic, multicentre, non-inferiority randomised clinical trial in patients suspected of non-traumatic pulmonary disease at the emergency department. Between 31 January 2017 and 31 May 2018, every month, participating centres were randomly allocated to using ULDCT or CXR. Primary outcome was functional health at 28 days, measured by the Short Form (SF)-12 physical component summary scale score (PCS score), non-inferiority margin was set at 1 point. Secondary outcomes included hospital admission, hospital length of stay (LOS) and patients in follow-up because of incidental findings. RESULTS: 2418 consecutive patients (ULDCT: 1208 and CXR: 1210) were included. Mean SF-12 PCS score at 28 days was 37.0 for ULDCT and 35.9 for CXR (difference 1.1; 95% lower CI: 0.003). After ULDCT, 638/1208 (52.7%) patients were admitted (median LOS of 4.8 days; IQR 2.1-8.8) compared with 659/1210 (54.5%) patients after CXR (median LOS 4.6 days; IQR 2.1-8.8). More ULDCT patients were in follow-up because of incidental findings: 26 (2.2%) versus 4 (0.3%). CONCLUSIONS: Short-term functional health was comparable between ULDCT and CXR, as were hospital admissions and LOS, but more incidental findings were found in the ULDCT group. Our trial does not support routine use of ULDCT in the work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. TRIAL REGISTRATION NUMBER: NTR6163.

Percutaneous coronary intervention of native coronary artery versus saphenous vein graft in patients with prior coronary artery bypass graft surgery: Rationale and design of the multicenter, randomized PROCTOR trial.

BACKGROUND: Patients with prior coronary artery bypass grafting (CABG) frequently require repeat percutaneous revascularization due to advanced age, progressive coronary artery disease and bypass graft failure. Percutaneous coronary intervention (PCI) of either the bypass graft or the native coronary artery may be performed. Randomized trials comparing native vessel PCI with bypass graft PCI are lacking and long-term outcomes have not been reported. METHODS: PROCTOR (NCT03805048) is a prospective, multicenter, randomized controlled trial, that will include 584 patients presenting with saphenous vein graft (SVG) failure and a clinical indication for revascularization, as determined by the local Heart Team. The trial is designed to compare the clinical and angiographic outcomes in patients randomly allocated in a 1:1 fashion to either a strategy of native vessel PCI or SVG PCI. The primary study endpoint is a 3-year composite of major adverse cardiac events (MACE: all-cause mortality, non-fatal target coronary territory myocardial infarction [MI], or clinically driven target coronary territory revascularization). At 3-years, after evaluation of the primary endpoint, follow-up invasive coronary angiography will be performed. Secondary endpoints comprise individual components of MACE at 1, 3 and 5 years follow-up, PCI-related MI, MI >48 hours after index PCI, target vessel failure, target lesion revascularization, renal failure requiring renal-replacement therapy, angiographic outcomes at 3-years and quality of life (delta Seattle Angina Questionnaire, Canadian Cardiovascular Society Grading Scale and Rose Dyspnea Scale). CONCLUSION: PROCTOR is the first randomized trial comparing an invasive strategy of native coronary artery PCI with SVG PCI in post-CABG patients presenting with SVG failure.

Non-invasive procedural planning using computed tomography-derived fractional flow reserve.

OBJECTIVES: This study aimed to investigate the performance of computed tomography derived fractional flow reserve based interactive planner (FFRCT planner) to predict the physiological benefits of percutaneous coronary intervention (PCI) as defined by invasive post-PCI FFR. BACKGROUND: Advances in FFRCT technology have enabled the simulation of hyperemic pressure changes after virtual removal of stenoses. METHODS: In 56 patients (63 vessels) invasive FFR measurements before and after PCI were obtained and FFRCT was calculated using pre-PCI coronary CT angiography. Subsequently, FFRCT and invasive coronary angiography models were aligned allowing virtual removal of coronary stenoses on pre-PCI FFRCT models in the same locations as PCI was performed. Relationships between invasive FFR and FFRCT , between post-PCI FFR and FFRCT planner, and between delta FFR and delta FFRCT were evaluated. RESULTS: Pre PCI, invasive FFR was 0.65 ± 0.12 and FFRCT was 0.64 ± 0.13 (p = .34) with a mean difference of 0.015 (95% CI: -0.23-0.26). Post-PCI invasive FFR was 0.89 ± 0.07 and FFRCT planner was 0.85 ± 0.07 (p < .001) with a mean difference of 0.040 (95% CI: -0.10-0.18). Delta invasive FFR and delta FFRCT were 0.23 ± 0.12 and 0.21 ± 0.12 (p = .09) with a mean difference of 0.025 (95% CI: -0.20-0.25). Significant correlations were found between pre-PCI FFR and FFRCT (r = 0.53, p < .001), between post-PCI FFR and FFRCT planner (r = 0.41, p = .001), and between delta FFR and delta FFRCT (r = 0.57, p < .001). CONCLUSIONS: The non-invasive FFRCT planner tool demonstrated significant albeit modest agreement with post-PCI FFR and change in FFR values after PCI. The FFRCT planner tool may hold promise for PCI procedural planning; however, improvement in technology is warranted before clinical application.

High and immeasurable ankle-brachial index as predictor of poor amputation-free survival in critical limb ischemia.

OBJECTIVE: The objective of this study was to assess the prognostic value of a high or immeasurable ankle-brachial index (ABI) at baseline for major amputation and amputation-free survival (AFS) in patients with critical limb ischemia (CLI). METHODS: Data from two recent trials in patients with CLI and proven infrapopliteal arterial obstructive disease were pooled. Patients were allocated to the low (<0.7), intermediate (0.7-1.4), or high (>1.4)/immeasurable ABI subgroup. Major amputation and AFS rates were compared. Hazard ratios for major amputation and death were calculated. The net reclassification improvement of incorporating high/immeasurable ABI in the Project of Ex-Vivo vein graft Engineering via Transfection III (PREVENT III) prediction model was derived. RESULTS: There were 146 patients (56.2%) who had a low ABI, 81 patients (31.2%) who had an intermediate ABI, and 33 patients (12.7%) who had a high/immeasurable ABI at baseline. Patients with high/immeasurable ABI showed higher 5-year major amputation (52.1%) and lower 5-year AFS (5.0%) rates than the intermediate (25.5% and 41.6%, respectively) and low ABI patients (23.5% and 46.9%, respectively; both P < .001). This same trend was observed in subgroup analysis of diabetics and nondiabetics. Adjusted hazard ratio of high/immeasurable ABI for major amputation/death risk was 2.93 (P < .001). Adding a high/immeasurable ABI as model factor to the PREVENT III model yielded a net reclassification index of 0.38 (P < .0001). CONCLUSIONS: A high/immeasurable ABI in patients with CLI and infrapopliteal arterial obstructive disease is an independent risk factor of major amputation and of poor AFS, in both diabetics and nondiabetics. Incorporating high/immeasurable ABI in the PREVENT III prediction model improves its performance.

Heart Function Analysis in Cardiac Patients with Focus on Sex-Specific Aspects.

Cardiac function is best described by investigating the pressure-volume relationships. This information permits description in terms of the ventricular volume regulation graph (VRG), estimation of systolic elastance, evaluation of lusitropic properties, and assessment of ventriculo-arterial coupling. Current techniques yield noninvasive determination of cardiac compartmental volumes, along with systolic/diastolic arterial pressure, while ventricular end-diastolic pressure can be inferred from an echocardiography-based surrogate measure. Ventricular volume is known to vary with age, as well as to be affected by intrinsic cardiac disease and abnormalities of the vascular system. Moreover, 35 years ago it has been shown in healthy adults that left ventricular volume is significantly smaller in women compared to men. This important observation has serious implications for several metrics which are routinely used in clinical practice, e.g., ejection fraction. The remarkable difference between ventricular size in men and women is also a powerful starting point for the study of aging and the investigation of interventions such as exercise. In this review we evaluate sex-specific characteristics of the VRG and the implications for various cardiac patient populations, during basal conditions and intervention such as exercise.

Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial.

BACKGROUND: Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow-derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of bone marrow mononuclear cells (BMMNCs) in patients with severe, nonrevascularizable limb ischemia can prevent major amputation. METHODS AND RESULTS: The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, nonrevascularizable limb ischemia. Patients were randomly assigned to repetitive (3 times; 3-week interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, ie, major amputation at 6 months, with major amputation rates of 19% in the BMMNC versus 13% in the placebo group (relative risk, 1.46; 95% confidence interval, 0.62-3.42). The safety outcome (all-cause mortality, occurrence of malignancy, or hospitalization due to infection) was not significantly different between the groups (relative risk, 1.46; 95% confidence interval, 0.63-3.38), neither was all-cause mortality at 6 months with 5% versus 6% (relative risk, 0.78; 95% confidence interval, 0.22-2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups. CONCLUSIONS: Repetitive intra-arterial infusion of autologous BMMNCs into the common femoral artery did not reduce major amputation rates in patients with severe, nonrevascularizable limb ischemia in comparison with placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC and the placebo group, as well, underlines the essential role for placebo-controlled design of future trials. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00371371.

Core diameter of bone marrow aspiration devices influences cell density of bone marrow aspirate in patients with severe peripheral artery disease.

BACKGROUND AIMS: Bone marrow (BM) transplantations are an accepted therapeutic strategy for hematologic conditions. In the past decades, interest for BM-derived cell therapy has extended toward the field of regenerative medicine. Irrespective of the treatment strategy, its success depends on the amount of cells available for transplantation. Both patient and procedural factors have been shown to influence the cell density of the BM aspirate. In the present study, the influence of core diameter of the BM aspiration device on cell density of the BM aspirate is studied. METHODS: BM harvesting procedures performed in a clinical trial investigating the effect of BM cell therapy in patients with severe peripheral artery disease were retrospectively studied (clinicaltrials.gov NCT00371371). Patients underwent BM harvesting through the use of either a 15-gauge (n = 85) or an 8-gauge (n = 75) needle. The numbers of harvested white blood cells (WBC) and CD34(+) hematopoietic cells (HPC) were quantified. RESULTS: The amount of WBC per milliliter of BM aspirate was significantly higher when the 8-gauge needle (27.8 × 10(6) WBC/mL [95%CI 25.4-30.5 × 10(6)]) was used compared with the smaller 15-gauge core needle (20.1 × 10(6) WBC/mL [95% confidence interval (CI), 18.7-21.7 × 10(6)], P < 0.001). For the amount of CD34(+) HPC, a similar pattern was observed (185 × 10(3) HPC/mL [95% CI, 161-213 × 10(3)]; 114 × 10(3) HPC/mL [95% CI, 96-134 × 10(3)]; P < 0.001). CONCLUSIONS: The application of a BM aspiration device with a larger core diameter is associated with an increased cell density of the BM aspiration product in patients with severe peripheral artery disease.

AI-Guided Quantitative Plaque Staging Predicts Long-Term Cardiovascular Outcomes in Patients at Risk for Atherosclerotic CVD.

BACKGROUND: The recent development of artificial intelligence-guided quantitative coronary computed tomography angiography analysis (AI-QCT) has enabled rapid analysis of atherosclerotic plaque burden and characteristics. OBJECTIVES: This study set out to investigate the 10-year prognostic value of atherosclerotic burden derived from AI-QCT and to compare the spectrum of plaque to manually assessed coronary computed tomography angiography (CCTA), coronary artery calcium scoring (CACS), and clinical risk characteristics. METHODS: This was a long-term follow-up study of 536 patients referred for suspected coronary artery disease. CCTA scans were analyzed with AI-QCT and plaque burden was classified with a plaque staging system (stage 0: 0% percentage atheroma volume [PAV]; stage 1: >0%-5% PAV; stage 2: >5%-15% PAV; stage 3: >15% PAV). The primary major adverse cardiac event (MACE) outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, and all-cause mortality. RESULTS: The mean age at baseline was 58.6 years and 297 patients (55%) were male. During a median follow-up of 10.3 years (IQR: 8.6-11.5 years), 114 patients (21%) experienced the primary outcome. Compared to stages 0 and 1, patients with stage 3 PAV and percentage of noncalcified plaque volume of >7.5% had a more than 3-fold (adjusted HR: 3.57; 95% CI 2.12-6.00; P < 0.001) and 4-fold (adjusted HR: 4.37; 95% CI: 2.51-7.62; P < 0.001) increased risk of MACE, respectively. Addition of AI-QCT improved a model with clinical risk factors and CACS at different time points during follow-up (10-year AUC: 0.82 [95% CI: 0.78-0.87] vs 0.73 [95% CI: 0.68-0.79]; P < 0.001; net reclassification improvement: 0.21 [95% CI: 0.09-0.38]). Furthermore, AI-QCT achieved an improved area under the curve compared to Coronary Artery Disease Reporting and Data System 2.0 (10-year AUC: 0.78; 95% CI: 0.73-0.83; P = 0.023) and manual QCT (10-year AUC: 0.78; 95% CI: 0.73-0.83; P = 0.040), although net reclassification improvement was modest (0.09 [95% CI: -0.02 to 0.29] and 0.04 [95% CI: -0.05 to 0.27], respectively). CONCLUSIONS: Through 10-year follow-up, AI-QCT plaque staging showed important prognostic value for MACE and showed additional discriminatory value over clinical risk factors, CACS, and manual guideline-recommended CCTA assessment.

Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials.

BACKGROUND: Critical Limb Ischemia (CLI) is the most advanced stage of peripheral arterial disease and is usually treated with bypass surgery or endovascular revascularization. However, a considerable proportion of CLI patients are not eligible to these treatment strategies and amputation is often the only option left. In the past decade, research has focused on bone marrow (BM)-derived cell-based strategies that aim at neovascularization to improve limb perfusion. Individual studies did not convincingly prove efficacy of BM-derived cell therapy in CLI patients thus far. OBJECTIVES: Perform a meta-analysis of all randomized controlled trials (RCTs) available that studied BM-derived cell therapy compared to standard care with or without placebo in CLI patients and provide summary efficacy data on this approach. METHODS: A systematic search in the electronic databases of Medline, Embase, and the Cochrane Controlled Trials Register was performed. All studies were critically appraised and data were extracted and meta-analyzed using a random-effects model. Major amputation and amputation-free survival were considered as the primary endpoints. RESULTS: A total of 12 RCTs jointly including 510 CLI patients were identified and analyzed. The meta-analysis showed beneficial effects of BM-derived cell therapy on both subjective and surrogate objective endpoints, that is, pain score, pain-free walking distance, ankle-brachial index, and transcutaneous oxygen measurements (all P < 0.00001). Overall, the RCTs showed reduced amputation rates in the therapeutic arms of the included trials with a relative risk (RR) on major amputation of 0.58 [95% confidence interval (CI), 0.40-0.84; P = 0.004]. However, when only the placebo-controlled RCTs were considered, the beneficial effect on major amputation rates was considerably reduced and nonsignificant (RR = 0.78; 95% CI, 0.40-1.51; P = 0.46). Amputation-free survival did not significantly differ between the BM treated and the control group (RR = 1.16; 95% CI, 0.92-1.48; P = 0.22). CONCLUSIONS: This meta-analysis underlines the promising potential of BM-derived cell therapy in CLI patients. Importantly, the results of placebo-controlled and non-placebo-controlled RCTs seem to diverge, which stresses the necessity to use placebo in the control arms of these trials. Future well-designed larger placebo-controlled RCTs are needed and should include long-term follow-up data to assess durability of treatment effects.

Rationale and design of the JUVENTAS trial for repeated intra-arterial infusion of autologous bone marrow-derived mononuclear cells in patients with critical limb ischemia.

Critical limb ischemia (CLI) continues to form a substantial burden on Western healthcare. Many patients still face amputation as a last treatment option. Autologous bone marrow (BM)-derived cell administration has emerged as a potential new treatment, but proof for sustainable clinical effects of BM-derived cell therapy in CLI is still lacking. The JUVENTAS (reJUVenating ENdothelial progenitor cells via Transcutaneous intra-Arterial Supplementation) trial is the first randomized, placebo-controlled, double-blinded clinical trial on repeated intra-arterial BM mononuclear cell (MNC) infusion in 110 to 160 CLI patients, designed to provide definite proof for the efficacy of stem cell therapy. Primary outcome is the incidence of major amputation at 6 months. Inclusion of patients is well underway. If BM-MNC cells therapy is beneficial, it could become a novel treatment to prevent amputation in patients with CLI.

Quality of life in patients with no-option critical limb ischemia underlines the need for new effective treatment.

OBJECTIVE: To provide a solid baseline reference for quality of life (QoL) in patients with no-option critical limb ischemia (CLI). CLI is associated with surgery, endovascular interventions, hospitalization, and a poor prognosis. An increasing number of clinical trials are, therefore, investigating new treatment strategies (eg, therapeutic neovascularization) in patients with CLI. QoL serves as an important secondary endpoint in many of these trials, but solid reference QoL data for patients with no-option CLI are lacking. METHODS: The Medical Outcomes Study Short Form 36 (SF-36) and the EuroQol-5D (EQ-5D) questionnaires were used to obtain baseline QoL scores from 47 patients with no-option CLI participating in a therapeutic neovascularization trial. To allow for easy comparability, a norm-based scoring (NBS) method was used to report the results of the SF-36. Scores of patients with CLI were furthermore compared with scores of patients with milder forms of peripheral arterial disease (PAD) and with patients with cardiovascular risk factors only. Determinants of QoL in patients with PAD were identified using multiple linear regression methods. RESULTS: Patients with no-option CLI reported QoL scores below the general population mean on every health dimension of the SF-36. Physical functioning, role physical functioning, and bodily pain were affected most intensively. These poor physical QoL scores were further underlined when compared with other patients with milder forms of PAD or patients with cardiovascular risk factors only. Patients with CLI scored poorly on the pain/discomfort and the usual activities domain of the EQ-5D. Diabetes, female gender, body mass index, and the ankle-brachial index at rest were significant determinants of the QoL in PAD on multivariate analysis. CONCLUSION: The QoL data of patients with no-option CLI using NBS methods for the SF-36 provide a baseline reference for ongoing clinical trials on new treatment strategies. Our data stress the need for new revascularization therapies in patients with no-option CLI.

Prediction rule for cardiovascular events and mortality in peripheral arterial disease patients: data from the prospective Second Manifestations of ARTerial disease (SMART) cohort study.

BACKGROUND: Patients with peripheral arterial disease (PAD) are at high risk of secondary cardiovascular death and events such as myocardial infarction or stroke. To minimize this elevated risk, cardiovascular risk factors should be treated in all PAD patients. Secondary risk management may benefit from a prediction tool to identify PAD patients at the highest risk who could be referred for an additional extensive workup. Stratifying PAD patients according to their risk of secondary events could aid in achieving optimal therapy compliance. To this end we developed a prediction model for secondary cardiovascular events in PAD patients. METHODS: The model was developed using data from 800 PAD patients who participated in the Second Manifestations of ARTerial disease (SMART) cohort study. From the baseline characteristics, 13 candidate predictors were selected for the model development. Missing values were imputed by means of single regression imputation. Continuous predictors were truncated and transformed where necessary, followed by model reduction by means of backward stepwise selection. To correct for over-fitting, a bootstrapping technique was applied. Finally, a score chart was created that divides patients in four risk categories that have been linked to the risk of a cardiovascular event during 1- and 5-year follow-up. RESULTS: During a mean follow-up of 4.7 years, 120 events occurred (27% nonfatal myocardial infarction, 21% nonfatal stroke, and 52% mortality from vascular causes), corresponding to a 1- and 5-year cumulative incidence of 3.1% and 13.2%, respectively. Important predictors for the secondary risk of a cardiovascular event are age, history of symptomatic cardiovascular disease, systolic blood pressure, high-density lipoprotein cholesterol, smoking behavior, ankle-brachial pressure index, and creatinine level. The risk of a cardiovascular event in a patient as predicted by the model was 0% to 10% and 1% to 28% for the four risk categories at 1- and 5-year follow-up, respectively. The discriminating capacity of the prediction model, indicated by the c statistic, was 0.76 (95% confidence interval, 0.71-0.80). CONCLUSION: A prediction model can be used to predict secondary cardiovascular risk in PAD patients. We propose such a prediction model to allow for the identification of PAD patients at the highest risk of a cardiovascular event or cardiovascular death, which may be a viable tool in vascular secondary health care practice.

The Pythagorean theorem reveals the inherent companion of cardiac ejection fraction.

BACKGROUND: Quantification of ventricular performance requires a comprehensive metric which is manageable for patient care and clinical trials. Ejection fraction (EF) has been embraced as an attractive candidate. However, being a dimensionless ratio, EF has serious limitations. METHODS: We aim to identify what information is not recognized when limiting the volume-related analysis by exclusively relying on EF. This investigation applies the volume domain concept, relating end-systolic volume (ESV) to end-diastolic volume (EDV). This approach allows graphical identification of the information not covered by EF. Implications for atria, left ventricle (LV) and right ventricle (RV) are investigated in healthy individuals, and cardiac patient groups using various imaging modalities. RESULTS: The Pythagorean theorem indicates that the hypotenuse which relates any {EDV, ESV} combination to EF corresponds with the information not covered by the single metric EF. The impact of the recovered EF companion (EFC) is illustrated in healthy adults (N = 410, LV 2D echocardiography), heart transplant patients (N = 101, LV CT), individuals with heart failure (N = 197, biplane angiocardiography), for the RV with corrected Fallot (N = 124, MRI), diameters for left atrium (N = 49, MRI) and area for right atrium (N = 51, MRI). For any limited EF range we find a spectrum of EFC values, showing that the two metrics contain (partly) independent information, and emphasizing that the sole use of EF only partially conveys the full information available. CONCLUSIONS: The EFC is a neglected companion, containing information which is additive to EF. Analysis based on ESV and EDV is preferred over the use of EF.

Diabetes Is Associated With Decreased Limb Survival in Patients With Critical Limb Ischemia: Pooled Data From Two Randomized Controlled Trials.

OBJECTIVE: Although never assessed prospectively, diabetes mellitus (DM) is assumed to negatively affect the outcomes of critical limb ischemia (CLI). DM was highly prevalent in two recently conducted randomized controlled trials in CLI patients, the PADI (Percutaneous Transluminal Balloon Angioplasty [PTA] and Drug Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia) and JUVENTAS (Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-Arterial Supplementation) trials. To determine the implications of DM in a population of patients with infrapopliteal CLI, clinical outcomes were compared in patients with and without DM. RESEARCH DESIGN AND METHODS: Individual data from patients with CLI (Rutherford category ≥4) were pooled. Patients were considered to have DM when this diagnosis was reported in the hospital electronic medical records. Rates of major amputation (above ankle level) and major events (major amputation or death) were compared between CLI patients with and without DM. Hazard ratios (HRs) were calculated. RESULTS: Of a total of 281 patients, DM was present in 49.1%. The major amputation rate at 5 years of follow-up was higher in patients with DM than in patients without DM (34.1% vs. 20.4%, P = 0.015). The major event and death rate did not differ. The unadjusted HR of DM for the major amputation risk was 1.87 (95% CI 1.12-3.12). Model factors with significant HRs in the multivariate analysis were baseline Rutherford category (HR 1.95; 95% CI 1.24-3.06) and ankle-brachial index (ABI) >1.4 (HR 2.78; 95% CI 1.37-5.64). CONCLUSIONS: CLI patients with DM are at a significantly higher risk of major amputation than CLI patients without DM. This increased risk is associated with a higher prevalence of baseline ABI >1.4 and more severe ischemia at initial presentation in patients with DM.

Bone marrow alterations and lower endothelial progenitor cell numbers in critical limb ischemia patients.

BACKGROUND: Critical limb ischemia (CLI) is characterized by lower extremity artery obstruction and a largely unexplained impaired ischemic neovascularization response. Bone marrow (BM) derived endothelial progenitor cells (EPC) contribute to neovascularization. We hypothesize that reduced levels and function of circulating progenitor cells and alterations in the BM contribute to impaired neovascularization in CLI. METHODS: Levels of primitive (CD34(+) and CD133(+)) progenitors and CD34(+)KDR(+) EPC were analyzed using flow cytometry in blood and BM from 101 CLI patients in the JUVENTAS-trial (NCT00371371) and healthy controls. Blood levels of markers for endothelial injury (sE-selectin, sICAM-1, sVCAM-1, and thrombomodulin), and progenitor cell mobilizing and inflammatory factors were assessed by conventional and multiplex ELISA. BM levels and activity of the EPC mobilizing protease MMP-9 were assessed by ELISA and zymography. Circulating angiogenic cells (CAC) were cultured and their paracrine function was assessed. RESULTS: Endothelial injury markers were higher in CLI (P<0.01). CLI patients had higher levels of VEGF, SDF-1α, SCF, G-CSF (P<0.05) and of IL-6, IL-8 and IP-10 (P<0.05). Circulating EPC and BM CD34(+) cells (P<0.05), lymphocytic expression of CXCR4 and CD26 in BM (P<0.05), and BM levels and activity of MMP-9 (P<0.01) were lower in CLI. Multivariate regression analysis showed an inverse association between IL-6 and BM CD34(+) cell levels (P = 0.007). CAC from CLI patients had reduced paracrine function (P<0.0001). CONCLUSION: CLI patients have reduced levels of circulating EPC, despite profound endothelial injury and an EPC mobilizing response. Moreover, CLI patients have lower BM CD34(+)-cell levels, which were inversely associated with the inflammatory marker IL-6, and lower BM MMP-9 levels and activity. The results of this study suggest that inflammation-induced BM exhaustion and a disturbed progenitor cell mobilization response due to reduced levels and activity of MMP-9 in the BM and alterations in the SDF-1α/CXCR4 interaction contribute to the attenuated neovascularization in CLI patients.

Progenitor cell therapy in patients with critical limb ischemia without surgical options.

OBJECTIVE: To provide a review on progenitor cell therapy for critical limb ischemia. SUMMARY BACKGROUND DATA: Critical limb ischemia is estimated to develop in 500 to 1000 individuals per million persons per year and has a major impact on the quality of life. Despite recent advances in surgical and radiologic vascular procedures, a large number of patients ( approximately 40%) are not eligible for these revascularization procedures. New strategies for revascularization need to be explored. Recent evidence indicates that bone marrow-derived mononuclear cells are a potential new therapeutic target. METHODS: A comprehensive review of all published literature on progenitor cell therapy in patients with critical limb ischemia was performed. RESULTS: Twenty-five clinical studies that reported on the use of mononuclear cells or progenitor cells for the treatment of patients with critical limb ischemia have been published, of which 18 were included in this review. Seven studies were published in Chinese, Japanese, or Polish and, therefore, not included. CONCLUSIONS: Pioneering clinical studies report promising results for progenitor cell-based therapies for chronic limb ischemia, but no definite proof is available because the clinical studies thus far have been small and lacked double-blinded controls. Larger, randomized, blinded, placebo-controlled trials to investigate the potential clinical effects of bone marrow progenitor cell administration in patients with critical limb ischemia are needed.