Teresa L. Carman

A Randomized, Controlled Pilot Study of Autologous CD34+ Cell Therapy for Critical Limb Ischemia

Background—Critical limb ischemia portends a risk of major amputation of 25% to 35% within 1 year of diagnosis. Preclinical studies provide evidence that intramuscular injection of autologous CD34+ cells improves limb perfusion and reduces amputation risk. In this randomized, double-blind, placebo-controlled pilot study, we evaluated the safety and efficacy of intramuscular injections of autologous CD34+ cells in subjects with moderate or high-risk critical limb ischemia, who were poor or noncandidates for surgical or percutaneous revascularization (ACT34-CLI). Methods and Results—Twenty-eight critical limb ischemia subjects were randomized and treated: 7 to 1×105 (low-dose) and 9 to 1×106 (high-dose) autologous CD34+ cells/kg; and 12 to placebo (control). Intramuscular injections were distributed into 8 sites within the ischemic lower extremity. At 6 months postinjection, 67% of control subjects experienced a major or minor amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.137). This trend continued at 12 months, with 75% of control subjects experiencing any amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.058). Amputation incidence was lower in the combined cell-treated groups compared with control group (6 months: P=0.125; 12 months: P=0.054), with the low-dose and high-dose groups individually showing trends toward improved amputation-free survival at 6 months and 12 months. No adverse safety signal was associated with cell administration. Conclusions—This study provides evidence that intramuscular administration of autologous CD34+ cells was safe in this patient population. Favorable trends toward reduced amputation rates in cell-treated versus control subjects were observed. These findings warrant further exploration in later-phase clinical trials. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00616980

Vitamin D supplementation and endothelial function in vitamin D deficient HIV-infected patients: a randomized placebo-controlled trial.

BACKGROUND Studies suggest that vitamin D deficiency is a risk factor for cardiovascular disease and diabetes. Vitamin D deficiency is prevalent in HIV patients but the effect of vitamin D supplementation on cardiovascular risk in this population is unknown. METHODS We conducted a randomized, double-blind, placebo-controlled trial among 45 HIV-infected adults in Cleveland (OH, USA) on stable antiretroviral therapy with durable virological suppression and a baseline serum 25-hydroxyvitamin D level of ≤20 ng/ml. Participants were randomized 2:1 to vitamin D3 4,000 IU daily or placebo for 12 weeks. The primary outcome was a change in flow-mediated brachial artery dilation (FMD). RESULTS Baseline demographics were similar except for age (vitamin D versus placebo, mean ±sd 47 ±8 versus 40 ±10 years; P=0.009). Both groups had reduced FMD at baseline (median values 2.9% [IQR 1.6-4.8] for vitamin D versus 2.5% [IQR 1.7-6.4] for placebo; P=0.819). Despite an increase in the concentration of serum 25-hydroxyvitamin D from baseline to 12 weeks (5.0 ng/ml [IQR -0.9-7.4] versus -1.9 ng/ml [IQR -4.0-0.1] for vitamin D versus placebo, respectively; P=0.003), there was no difference in FMD change (0.55% [IQR -1.05-2.13] versus 0.29% [IQR -1.61-1.77]; P=0.748). Vitamin D supplementation was associated with a decrease in total and non-high-density lipoprotein cholesterol, and an increase in indices of insulin resistance. CONCLUSIONS Among HIV-infected individuals with vitamin D deficiency, supplementation with 4,000 IU vitamin D3 daily for 12 weeks modestly improved vitamin D status and cholesterol but worsened insulin resistance without change in endothelial function. The mechanisms of resistance to standard doses of vitamin D and the complex role of vitamin D in glucose metabolism in this population require further investigation.

Prevention of thromboembolism after neurosurgery for brain and spinal tumors

Objective Deep venous thrombosis (DVT) is a major cause of morbidity and mortality after surgery for primary and metastatic brain tumors. Methods We conducted a confidential survey of American neurosurgeons interested in tumor surgery to assess DVT risk awareness and thromboprophylaxis patterns. Results Of the 172 respondents, 108 (63%) underestimated the DVT risk after brain tumor surgery. After operating on patients who had brain or spinal tumors, 81.4 and 78.5% of respondents, respectively, reported using DVT prophylaxis. After performing brain tumor surgery, 76.2% of respondents reported using solely mechanical methods of prophylaxis “always” or “most of the time.” Conclusion American neurosurgeons tend to underestimate the risk of DVT associated with brain tumor surgery and to use mechanical thromboprophylaxis despite the availability of effective pharmacologic antithrombotics. A better appreciation of the risk of thrombosis, combined with clinical studies to address safety, may enhance the use of prophylaxis and the perceived safety of antithrombotics in this setting.

Heparin-induced thrombocytopenia: natural history, diagnosis, and management.

Heparin-induced thrombocytopenia (HIT) is an under-recognized, limb- and life-threatening complication of pharmacologic heparin administration. Antibody formation against heparin complexed to platelet factor 4 (PF4) is central to the pathogenesis of HIT. Heparin: PF4 antibodies promote platelet activation and aggregation as well as excess thrombin generation which may lead to clinical thrombosis. HIT should be suspected in patients who develop thrombocytopenia with or without associated arterial or venous thrombosis while on heparin. HIT is a clinical diagnosis. Specialized HIT assays should be interpreted with care. The cornerstone of HIT management is the discontinuation of all forms of heparin exposure and the institution of anticoagulation with an alternative agent. The direct thrombin inhibitors lepirudin and argatroban are currently available and approved for use in patients with HIT.

Elevated D-dimer is independently associated with endothelial dysfunction: a cross-sectional study in HIV-infected adults on antiretroviral therapy.

BACKGROUND D-Dimer elevations have been associated with a striking increase in mortality in HIV-infected patients. However, D-Dimer has not been directly linked to endothelial dysfunction in HIV. METHODS In this cross-sectional study, we used flow-mediated dilation (FMD) of the brachial artery to measure endothelial function and several biomarkers to measure systemic inflammation and coagulation activation in HIV-infected adults on stable antiretroviral therapy with HIV-1 RNA levels <400 copies/ml. Multivariable linear regression was used to model FMD by these markers, traditional cardiovascular risk factors and HIV-related characteristics. RESULTS Analysis included 98 subjects (88% male, median age 47.5 years, CD4(+) T-cells 578.5 cells/mm(3)); all on ART (52% on protease inhibitors). The only factors independently associated with FMD were D-Dimer and body mass index. CONCLUSIONS We show for the first time an independent association between D-Dimer and endothelial dysfunction in virologically suppressed, HIV-infected adults on stable antiretroviral therapy, potentially explaining the link between D-Dimer and mortality in HIV.

C-reactive protein predicts 96-week carotid intima media thickness progression in HIV-infected adults naive to antiretroviral therapy.

Abstract:This is a 96-week prospective cohort study of antiretroviral therapy (ART)–naive HIV-infected adults and matched healthy controls to assess progression of carotid intima media thickness (CIMT) and its relationship to inflammation. Median common carotid artery (CCA) CIMT increased significantly but similarly in both groups [CCA: 0.02 (interquartile range: 0–0.05); P < 0.01 within HIV-infected adults vs. 0.01 (0–0.05) mm; P < 0.01 within controls; and P = 0.83 between groups]. Change in bulb CIMT yielded similar results. Independent predictors of CCA CIMT progression in HIV-infected adults were higher systolic blood pressure, total cholesterol, and high sensitivity C-reactive protein. Independent predictors of bulb CIMT progression were higher non–high-density lipoprotein cholesterol and high sensitivity C-reactive protein. Other inflammation markers were not associated with CIMT progression.

Medical management for chronic atherosclerotic peripheral arterial disease.

The generalized term ‘peripheral vascular disease’ (PVD) may be used to refer to vascular disorders in any non-coronary arterial bed. The more specific term ‘peripheral arterial disease’ (PAD) is used to refer to a more specific process, atherosclerotic disease of the lower extremities. PAD is common. Conservative estimates suggest more than 8 million Americans may be affected by PAD. Since atherosclerosis is a systemic process, PAD should be identified as a coronary heart disease risk equivalent. However, PAD remains an under-diagnosed and under-recognized risk for cardiovascular morbidity and mortality.PAD symptoms may range from non-specific ambulatory leg complaints, to typical symptoms of intermittent claudication to critical limb ischaemia with rest pain, gangrene or ulceration. These symptoms directly impact quality of life and may affect functional capacity. There are two therapeutic goals for patients with PAD: first, to reduce the risk of cardiovascular events and second, to manage the lower extremity symptoms. This manuscript reviews the medical management of patients with PAD, briefly discussing the goals of cardiovascular risk factor modification and then focusing on pharmacological management strategies for patients with intermittent claudication and critical limb ischaemia.

Salsalate is poorly tolerated and fails to improve endothelial function in virologically suppressed HIV-infected adults

In this 13-week, open-label, randomized study of the anti-inflammatory salsalate versus usual care, there were no significant improvements in flow-mediated dilation of the brachial artery, endothelial activation, inflammation or coagulation markers, homeostasis model assessment of insulin resistance or lipoproteins with salsalate or between groups in virologically suppressed, HIV-infected adults on antiretrovirals. Tinnitus and transaminitis occurred frequently in the salsalate group. Dose reduction due to toxicities encountered and low level of inflammation may explain these results.

Relationship between total bilirubin and endothelial function, inflammation and oxidative stress in HIV‐infected adults on stable antiretroviral therapy

Enhanced inflammation is evident in HIV infection, even with virological suppression. Outside HIV infection, studies show an independent association between higher total bilirubin and better endothelial function as well as a lower prevalence of coronary heart disease, possibly as a consequence of the anti‐inflammatory and antioxidant effect of bilirubin. The aim of this study was to determine whether such an association exists in HIV‐infected individuals.

Rate and predictors of carotid artery intima media thickness progression in antiretroviral-naive HIV-infected and uninfected adults: a 48-week matched prospective cohort study.

BACKGROUND Carotid intima media thickness (CIMT) progresses faster in HIV-infected adults on antiretroviral therapy (ART) than the general population. It is unclear if the rate of progression is similarly faster in ART-naive, HIV-infected adults. METHODS This was a 48-week prospective cohort study to compare change in CIMT and inflammation markers in ART-naive, HIV-infected adults in no immediate need of ART (HIV-positive/ART-naive) and age/sex/body mass index (BMI)-matched controls (HIV-negative). RESULTS A total of 85 HIV-positive/ART-naive and 45 HIV-negative participants were enrolled. In the HIV-positive/ART-naive group, median baseline CD4+ T-cell count and HIV-1 RNA were 535 cells/mm3 and 6,916 copies/ml. Baseline common carotid artery (CCA) and bulb CIMTs were similar between groups. Changes in CIMT to 48 weeks at both sites were not different within- or between-groups (median [IQR] change in HIV-positive/ART-naive versus HIV-negative CCA CIMT -0.0071 mm [-0.0267-0.0233] versus 0.0113 mm [-0.0117-0.0306]; P = 0.19 between-groups; and bulb CIMT 0.0017 mm [-0.0367-0.06167] versus 0.01 mm [-0.0383-0.0625]; P = 0.54). After adjustment for cardiovascular disease (CVD) risk factors, change in CCA CIMT was greater in HIV-negative participants (-0.0046 versus 0.0177 mm for HIV-positive/ART-naive versus HIV-negative; P = 0.01). In HIV-positive/ART-naive, interleukin (IL)-6, soluble tumour necrosis factor-α receptor (sTNFR)-II, vascular cell adhesion molecule-1 and intercellular adhesion molecule (ICAM)-1 were higher at both time points and D-dimer was higher at week 48 (P < 0.01 for all). IL-6, sTNFR-I and D-dimer increased over 48 weeks in HIV-positive/ART-naive participants (P < 0.01 for all). In HIV-positive/ART-naive participants, independent predictors of greater change in CCA CIMT were higher BMI (P = 0.05) and family history of CVD (P < 0.01) and of greater change in bulb CIMT were higher sTNFR-I (P = 0.03) and higher diastolic blood pressure (P < 0.01). CONCLUSIONS In ART-naive HIV-infected adults at low risk of HIV disease progression and low cardiovascular risk, CIMT progression rate was similar to matched controls. In addition to traditional CVD risk factors, higher levels of sTNFR-I predicted greater bulb CIMT changes.