Health related quality of life in patients with critical limb ischemia.

Critical limb ischemia (CLI) is the terminal stage of peripheral artery disease. Research in recent years has been largely focussed on treatment options such as bypass surgery / endovascular treatment, surgery / primary amputation and additional benefits of supportive pharmacotherapy. Despite this plethora of treatment options, however, patients continue to have a reduced health related quality of life (HRQoL). Aim of the present work was to review the available evidence of improvement of HRQoL with regard to different treatment options. We found that a number of clinical studies have been conducted using HRQoL measures mostly as secondary outcomes in patients with CLI and other less severe forms of peripheral arterial disease. The studies demonstrate a consistent improvement of HRQoL over baseline within the first few months after the intervention. Prostaglandins, but no other pharmacotherapies, appear to be effective in patients without an option for revascularization. Due to a largely differing patient population under investigation and the different degrees of disease progression it appears difficult however to compare different treatment options with respect to their impact on HRQoL. HRQoL improvement as a predefined endpoint of novel therapeutic approach studies should be considered more consequently.

Treatment of peripheral arterial disease using stem and progenitor cell therapy.

Peripheral arterial disease (PAD) is a highly prevalent atherosclerotic syndrome associated with significant morbidity and mortality. PAD is most commonly caused by atherosclerosis obliterans (ASO) and thromboangiitis obliterans (TAO), and can lead to claudication and critical limb ischemia (CLI), often resulting in a need for major amputation and subsequent death. Standard treatment for such severe cases of PAD is surgical or endovascular revascularization. However, up to 30% of patients are not candidates for such interventions, due to high operative risk or unfavorable vascular involvement. Therefore, new strategies are needed to offer these patients a viable therapeutic option. Bone-marrow derived stem and progenitor cells have been identified as a potential new therapeutic option to induce angiogenesis. These findings prompted clinical researchers to explore the feasibility of cell therapies in patients with peripheral and coronary artery disease in several small trials. Clinical benefits were reported from these trials including improvement of ankle-brachial index (ABI), transcutaneous partial pressure of oxygen (TcO(2)), reduction of pain, and decreased need for amputation. Nonetheless, large randomized, placebo-controlled, double-blind studies are necessary and currently ongoing to provide stronger safety and efficacy data on cell therapy. Current literature is supportive of intramuscular bone marrow cell administration as a relatively safe, feasible, and possibly effective therapy for patients with PAD who are not subjects for conventional revascularization.

Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease.

Bone marrow cell transplantation has been shown to induce angiogenesis and thus improve ischemic artery disease. This study evaluates the effects of intramuscular bone marrow cell transplantation in patients with limb-threatening critical limb ischemia with a very high risk for major amputation. After failed or impossible operative and/or interventional revascularization and after unsuccessful maximum conservative therapy, 51 patients with impending major amputation due to severe critical limb ischemia had autologous bone marrow cells (BMC) transplanted into the ischemic leg. Patients 1-12 received Ficoll-isolated bone marrow mononuclear cells (total cell number 1.1 +/- 1.1 x 10(9)), patients 13-51 received point of care isolated bone marrow total nucleated cells (3.0 +/- 1.7 x 10(9)). Limb salvage was 59% at 6 months and 53% at last follow-up (mean 411 +/- 261 days, range 175-1186). Perfusion measured with ankle-brachial index (ABI) and transcutaneous oxygen tension (tcpO(2)) at baseline and after 6 months increased in patients with consecutive limb salvage (ABI 0.33 +/- 0.18 to 0.46 +/- 0.15, tcpO(2) 12 +/- 12 to 25 +/- 15 mmHg) and did not change in patients eventually undergoing major amputation. No difference in clinical outcome between the isolation methods were seen. Clinically most important, patients with limb salvage improved from a mean Rutherford category of 4.9 at baseline to 3.3 at 6 months (p = 0.0001). Analgesics consumption was reduced by 62%. Total walking distance improved in nonamputees from zero to 40 m. Three severe periprocedural adverse events resolved without sequelae, and no unexpected long-term adverse events occurred. In no-option patients with end-stage critical limb ischemia due to peripheral artery disease, bone marrow cell transplantation is a safe procedure that can improve leg perfusion sufficiently to reduce major amputations and permit durable limb salvage.

Prevalence and risks of undiagnosed diabetes mellitus in patients undergoing coronary artery bypass grafting.

BACKGROUND: Numerous studies have shown that diabetes mellitus (DM) is not identified and, consequently, inadequately treated in a substantial proportion of the patients in the general population. We know very little about the extent and the consequences of undiagnosed diabetes in the risk group of patients with coronary heart diseases. The objective of this study was therefore to determine the prevalence and the risks of undiagnosed DM among patients with coronary artery bypass. METHODS AND RESULTS: The data of 7310 patients who have undergone coronary bypass operations between 1996 and 2003 were analyzed. Depending on their diagnosis on admission and their fasting plasma glucose (FPG) level, these patients were classified as known diabetics, undiagnosed diabetics (FPG > or =126 mg/dL), or as nondiabetics (FPG <126 mg/dL) and were compared in terms of their preoperative, intraoperative, and postoperative characteristics. Among the patients with coronary bypass that we examined, we found a prevalence of diagnosed diabetics of 29.6%. The prevalence of patients with undiagnosed DM (FPG > or =126 mg/dL) was 5.2%. In comparison with the other groups (non-DM versus undiagnosed DM versus known DM), the undiagnosed diabetics more frequently required resuscitation (1.7% versus 4.2% versus 1.5%; P<0.01) and reintubation (2.1% versus 5.0% versus 3.5%; P<0.01) and often showed a longer period of ventilation >1 day (5.6% versus 10.5% versus 7.4%; P<0.01). Perioperative mortality rate was highest in this group (0.9% versus 2.4% versus 1.4%; P<0.01). CONCLUSIONS: This study is the first to publish the prevalence of undiagnosed diabetes mellitus in cardiac surgery. During the perioperative and postoperative courses, these patients displayed a substantially higher morbidity and mortality rate.

ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1.

OBJECTIVE: Chemokines play an important role in the pathogenesis of diabetic nephropathy. Angiotensin II induces several fibrogenic chemokines, namely monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta. The progression of diabetic nephropathy can be retarded by ACE inhibitors (ACEIs) in patients with type 1 and type 2 diabetes. We examined if blockade of the renin-angiotensin system lowered urinary levels of the chemokine MCP-1 and correlated urinary MCP-1 (uMCP-1) with parameters of renal function and glucose and lipid metabolism before and after 1 year of treatment with an ACE inhibitor. RESEARCH DESIGN AND METHODS: In 22 patients with type 2 diabetes and diabetic nephropathy in stages 3-5, treatment with the ACEI lisinopril was initiated. Before treatment and after 12 months of continuous therapy, proteinuria, creatinine clearance, uMCP-1 levels, BMI, HbA(1c), and serum cholesterol were assessed. RESULTS: Lisinopril treatment improved renal function. Proteinuria decreased from 410 +/- 662 mg per 24 h to 270 +/- 389 mg per 24 h. Creatinine clearance rose from 61 +/- 26 to 77 +/- 41 ml/min. Urinary MCP-1 levels decreased from 0.456 +/- 0.22 ng/mg creatinine to 0.08 +/- 0.096 ng/mg creatinine. The change in uMCP-1 correlated significantly (r = 0.61, P < 0.001) with the change in proteinuria. No other parameter correlated with the improvement in renal function. CONCLUSIONS: Blockade of the renin-angiotensin system in type 2 diabetic patients with diabetic nephropathy reduces uMCP-1 levels and improves renal function. Because MCP-1 induces monocyte immigration and differentiation to macrophages, which augment extracellular matrix production and tubulointerstitial fibrosis, pharmacological reduction of angiotensin II may also exert its beneficial effects in diabetic nephropathy by downregulation of renal MCP-1.

Non-Hematopoietic Essential Functions of Bone Marrow Cells: A Review of Scientific and Clinical Literature and Rationale for Treating Bone Defects.

Hematopoiesis as the only essential function of bone marrow cells has been challenged for several decades through basic science (in vitro and in vivo) and clinical data. Such work has shed light on two other essential functions of bone marrow cells: osteopoiesis and angio-genesis/vasculogenesis. Clinical utility of autologous concentrated bone marrow aspirate (CBMA) has demonstrated both safety and efficacy in treating bone defects. Moreover, CBMA has been shown to be comparable to the gold standard of iliac crest bone graft (ICBG), or autograft, with regard to being osteogenic and osteoinductive. ICBG is not considered an advanced therapy medicinal product (ATMP), but CBMA may become regulated as an ATMP. The European Medicines Agency Committee for Advanced Therapies (EMA:CAT) has issued a reflection paper (20 June 2014) in which reversal of the 2013 ruling that CBMA is a non-ATMP has been proposed. We review bone marrow cell involvement in osteopoiesis and angiogenesis/vasculogenesis to examine EMA:CAT 2013 decision to use CBMA for treatment of osteonecrosis (e.g, of the femoral head) should be considered a non-ATMP. This paper is intended to provide discussion on the 20 June 2014 reflection paper by reviewing two non-hematopoietic essential functions of bone marrow cells. Additionally, we provide clinical and scientific rationale for treating osteonecrosis with CBMA.

Stem cell and progenitor cell therapy in peripheral artery disease. A critical appraisal.

Atherosclerotic peripheral artery disease (PAD) is a common manifestation of atherosclerosis. The occlusion of large limb arteries leads to ischaemia with claudication which can progress to critical limb ischaemia (CLI) with pain at rest, and to tissue loss. At present, common therapy for CLI is either surgical or endovascular revascularisation aimed at improving blood flow to the affected extremity. However, major amputation and death are still frequent complications. Exploring new strategies for revascularisation of ischaemic limbs is thus of major importance. Bone marrow (BM)-derived stem and progenitor cells have been identified as a potential new therapeutic option to induce therapeutic angiogenesis. Encouraging results of preclinical studies have rapidly led to several small clinical trials, in which BM-derived mononuclear cells were administered to patients with limb ischaemia. Clinical benefits were reported from these trials including improvement of ankle-brachial index (ABI), transcutaneous partial pressure of oxygen (TcPO2), reduction of pain, and decreased need for amputation. Nonetheless, large randomised, placebo-controlled, double-blind studies are necessary and currently ongoing (BONMOT-CLI, JUVENTUS and NCT00498069). Further research relates to the optimal cell type and dosage, the isolation method, the role of colony-stimulating factors, administration route, and the supportive stimulation of cells with reduced functioning due to advanced PAD. Autologous stem cell therapy for ischaemic peripheral disease seems to be a promising new tool for the treatment of severe limb ischaemia. Preliminary evidence has established its safety, feasibility and effectiveness on several important endpoints. Several large endpoints studies are underway to further consolidate this evidence.

Diabetes mellitus as a risk factor for pulmonary complications after coronary bypass surgery.

OBJECTIVES: In the past few years there has been increasing evidence that the respiratory function of patients with diabetes is impaired in the course of their disease. The objective of this article was to investigate whether patients with diabetes are particularly at risk of pulmonary complications during the perioperative stage of coronary bypass surgery. METHODS: The data of 8555 patients who had undergone coronary bypass operations in the years between 1996 and 2004 were analyzed. Depending on their diagnosis on admission and their fasting plasma glucose levels, these patients were classified as having "no diabetes" (fasting plasma glucose level < 126 mg/dL), "undiagnosed diabetes" (glucose level > or = 126 mg/dL), "oral therapy diabetes," or "insulin-treated diabetes." The 3 diabetic groups were compared with the nondiabetic group in terms of the preoperative and postoperative characteristics. RESULTS: The reintubation rate among patients with undiagnosed diabetes (4.6%) and among those with insulin-treated diabetes (4.5%) was significantly higher than that of nondiabetic patients (1.8%; P < .01). The proportion of patients who required respiration for periods longer than 1 day was also significantly higher among patients with undiagnosed diabetes (9.9%) and those with insulin-treated diabetes (8.6%) than among the nondiabetic patients (4.8%; P < .01). The regression models show that unidentified diabetes and insulin-treated diabetes constitute independent risk factors for perioperative pulmonary complications. CONCLUSIONS: Patients with undiagnosed and insulin-treated diabetes have a higher risk of having pulmonary complications in the perioperative course of coronary bypass operations than do nondiabetic patients. These results may be explained if one considers the lung as another target organ of the diabetic disease.