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Biomedical subjects

Emile R Mohler

Publications and source records attributed to Emile R Mohler.

At least 19 recordsLinked to original sources
PubMed2006

Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging cardiovascular risk marker. To explore the biologic role of Lp-PLA2 in atherosclerosis, we examined its expression and contribution to leukocyte activation under proatherogenic conditions. METHODS AND RESULTS: Following the induction of diabetes and hypercholesterolemia in a porcine model, a rapid increase in plasma Lp-PLA2 activity was observed at 1 month. This was accompanied by upregulated Lp-PLA2 mRNA expression by peripheral blood mononuclear cells (PBMC) at 3 months, and elevated Lp-PLA2 mRNA expression in coronary arteries at 6 months. These changes were paralleled by increased inflammatory responses by circulating PBMC (ICAM-1, IL-6), in coronary tissues (ICAM-1, VCAM-1), and the subsequent accumulation of inflammatory cells. In human PBMC, proinflammatory mediators augmented the synthesis and release of functional Lp-PLA2. Furthermore, lysophosphatidylcholine (lysoPC), a product of Lp-PLA2 activity, induced an increase in several inflammatory cytokines (IL-1beta, IL-6, TNF-alpha) in a concentration-dependent manner. In contrast, Lp-PLA2 inhibition (SB677116; 1 microM) abrogated the inflammatory response elicited by oxidized LDL. CONCLUSIONS: In an experimental model of diabetes and hypercholesterolemia, leukocyte activation was associated with augmented Lp-PLA2 expression. In vitro, Lp-PLA2 activity mediated leukocyte activation and inflammatory responses, whereas Lp-PLA2 inhibition abolished inflammatory responses induced by oxidized LDL. Collectively, these observations support a proatherogenic role for Lp-PLA2.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2006

Hypercholesterolemia suppresses inwardly rectifying K+ channels in aortic endothelium in vitro and in vivo.

Inwardly rectifying K+ (Kir) channels are responsible for maintaining endothelial membrane potential and play a key role in endothelium-dependent vasorelaxation. In this study, we show that endothelial Kir channels are suppressed by hypercholesterolemic levels of lipoproteins in vitro and by serum hypercholesterolemia in vivo. Specifically, exposing human aortic endothelial cells to acetylated low-density lipoprotein or very low density lipoprotein resulted in a time- and concentration-dependent decrease in Kir current that correlated with the degree of cholesterol loading. The suppression was fully reversible by cholesterol depletion. Furthermore, a decrease in Kir current resulted in depolarization of endothelial membrane potential. Most important, the flow sensitivity of Kir currents was also impaired by cholesterol loading. Specifically, flow-induced increase in Kir current was suppressed by 70%, and flow-induced hyperpolarization was almost completely abrogated. Furthermore, we show that hypercholesterolemia in vivo also strongly suppresses endothelial Kir currents and causes a shift in endothelial membrane potential, as determined by comparing the currents in aortic endothelial cells freshly isolated from healthy or hypercholesterolemic pigs. Therefore, we suggest that suppression of Kir current is one of the important factors in hypercholesterolemia-induced endothelial dysfunction.

Animals↗
PubMed2006

Flow cytometric measurement of circulating endothelial cells: the effect of age and peripheral arterial disease on baseline levels of mature and progenitor populations.

BACKGROUND: Age and cardiovascular disease status appear to alter numbers and function of circulating endothelial progenitor cells (EPCs). Despite no universal phenotypic definition, numerous studies have implicated progenitors with apparent endothelial potential in local responses to vascular injury and with cardiovascular disease in general. To further define the role of this lineage in peripheral artery disease (PAD), we developed a multiparameter flow cytometry assay to analyze multiple phenotypic definitions of progenitor cells (PCs), EPCs, and mature endothelial cells (ECs) and evaluate effects of age and PAD on baseline levels of each subset. METHODS: Blood was collected from young healthy subjects (N = 9, mean age 33 +/- 8 years), older healthy subjects (N = 13, mean age 66 +/- 8 years), and older subjects with PAD (N = 15, mean age 69 +/- 8 years). After ammonium chloride lysis, cells were stained and analyzed on a Becton-Dickinson LSR II with a 5-color antibody panel: FITC-anti-CD31, PE-anti-CD146, PE-anti-CD133, PerCP-Cy5.5-anti-CD3,-CD19,-CD33 (lineage panel), PE-Cy7-anti-CD34, and APC-anti-VEGF-R2. Viability was assessed by propidium iodide exclusion, and only viable, low to medium side scatter lineage-negative singlets were analyzed. In some studies, cells were sorted for morphological studies. Subsets were defined as indicated later. RESULTS: Our results, using a comprehensive flow cytometric panel, indicate that CD133+, CD34+, and CD133+/CD34+ PCs are elevated in younger healthy individuals compared to older individuals, both healthy and with PAD. However, the number of EPCs and mature ECs did not significantly differ among the three groups. Assessment of endothelial colony forming units and dual acLDL-lectin staining supported the flow cytometric findings. CONCLUSIONS: We describe a comprehensive flow cytometric method to detect circulating mature and progenitor endothelial populations confirmed by conventional morphological and functional assays. Our findings suggest that aging may influence circulating levels of PCs, but not EPCs or ECs; PAD had no effect on baseline levels of any populations investigated. This study provides the basis for evaluating the potential effects of acute stress and therapeutic intervention on circulating progenitor and endothelial populations as a biomarker for cardiovascular status.

AC133 Antigen↗
PubMed2006

A randomized, double-blind trial comparing the effects of amlodipine besylate/benazepril HCl vs amlodipine on endothelial function and blood pressure.

Evidence suggests that renin-angiotensin-aldosterone system inhibition ameliorates endothelial dysfunction. The authors examined the effect of amlodipine besylate/benazepril HCl combination treatment compared with amlodipine besylate monotherapy in modulating endothelial dysfunction. This multicenter, double-blind, 12-week study randomized 70 hypertensive subjects with at least one other endothelial dysfunction risk factor to amlodipine besylate/benazepril HCl (5/20 mg/d force-titrated to 5/40 mg/d) or amlodipine besylate monotherapy (5 mg/d force-titrated to 10 mg/d). Both the combination and monotherapy produced significant median increases from baseline in percentage flow-mediated vasodilation (2.0% and 1.2%, respectively) and percentage change in percent flow-mediated vasodilation (25% and 16%, respectively). These improvements were numerically larger with combination treatment, but between-group differences did not achieve statistical significance. Reductions in systolic and diastolic blood pressure were significantly greater (P=.0452/P=.0297) with combination treatment (-18.6/-12.3 mm Hg) than with monotherapy (-14.8/-9.1 mm Hg). A highly positive correlation between change in systolic blood pressure and change in percent of flow-mediated vasodilation was demonstrated only for combination treatment.

Aged↗
PubMed2006

Can atorvastatin improve the response to sildenafil in men with erectile dysfunction not initially responsive to sildenafil? Hypothesis and pilot trial results.

BACKGROUND: Erectile dysfunction (ED) may be one manifestation of a generalized vascular disorder characterized by endothelial dysfunction. Statin drugs may improve endothelial function, even before altering the lipid profile. OBJECTIVE: We sought to determine whether the addition of a statin with sildenafil would improve ED in men who initially responded poorly to sildenafil. METHODS: Men with moderate-to-severe ED despite an adequate sildenafil trial were enrolled in this randomized, double-blind, placebo-controlled pilot study. ED was defined using a validated self-administered questionnaire as a score of <or=16 on the International Index of Erectile Function (erectile function domain score range of 6-30). Improvement in ED score with sildenafil was reassessed at 6 and 12 weeks of treatment with atorvastatin (80 mg daily) or matching placebo. RESULTS: Twelve men (mean age 58 +/- 13 years) with a mean domain score of 8.2 +/- 6.9 and a mean duration of ED of 3.7 years were enrolled in the study. Treatment with atorvastatin decreased mean low-density lipoprotein cholesterol by 43% and resulted in an improvement with sildenafil in domain score of 7.8 (P = 0.036); an effect was apparent by 6 weeks. The increase in domain score in placebo patients was not statistically significant. CONCLUSIONS: Treatment with atorvastatin improved sexual function and the response to oral sildenafil in men who did not initially respond to treatment with sildenafil. The results of this pilot study support the hypothesis that vascular endothelial dysfunction contributes to ED in sildenafil nonresponders and deserves further testing in a large clinical trial.

Adult↗
PubMed2006

An unusual case of toe ulceration.

We describe an unusual presentation of toe ulceration in a 39-year-old otherwise healthy man. The left fifth toe was painful for several months with ulceration at the tip. The other toes appeared cyanotic and discolored. Foot pulses were normal. Laboratory testing revealed the platelet count at 1208 thousand/microliter, with hemoglobin 19.2g/dl and hematocrit 57%. The erythropoietin level was found to be markedly decreased at 1 mU/ml. The patient was given the diagnosis of polycythemia vera with iron deficiency. Phlebotomy was performed and aspirin and cytoreductive therapy with hydroxyurea was prescribed with resolution of the toe ulceration.

Adult↗
PubMed2006

Impaired exercise-induced blood volume in type 2 diabetes with or without peripheral arterial disease measured by continuous-wave near-infrared spectroscopy.

OBJECTIVE: Diabetes is a significant risk factor for peripheral arterial disease (PAD) and is associated with accelerated atherosclerosis and limb loss. However, the pathophysiology involved in PAD is unclear. This study was conducted to evaluate the hemodynamic response to exercise of patients with and without diabetes and PAD. RESEARCH DESIGN AND METHODS: The hemodynamic response in calf muscles of patients with diabetes, PAD, or both was determined using near-infrared spectroscopy (NIRS). Patients performed both a plantar-flexion and treadmill-walking exercise regimen. RESULTS: Skeletal muscle capillary blood volume expansion during exercise, as measured by NIRS, was significantly impaired in the lower extremities of diabetic patients with a normal ankle-brachial index. The relative deoxygenation and oxygenation recovery times measured by NIRS correlates significantly with the presence of PAD. CONCLUSIONS: Patients with diabetes have reduced capillary volume expansion even without PAD. This is likely due to impaired vasodilation secondary to endothelial dysfunction. Further studies are needed to determine whether pharmaceutical intervention improves the blood volume expansion in the diabetic state.

Aged↗
PubMed2006

Aortic valve calcium content does not predict aortic valve area.

BACKGROUND AND AIM OF THE STUDY: Aortic stenosis (AS) is a common clinical problem which frequently necessitates aortic valve replacement (AVR). The traditional view of progressive AS is a 1:1 inverse relationship between valve calcium content and aortic valve area (AVA). However, this assumption has been based on subjective estimates of calcification on chest X-radiographic images. The study aim was to evaluate the relationship between AVA as measured with echocardiography compared to calcium quantification using electron beam computed tomography (EBT). METHODS: Sixty-one patients with an AVA between 0.7 and 2.0 cm2 underwent an EBT scan to evaluate the aortic valve calcium content. RESULTS: The mean (+/- SD) aortic valve Agatston calcium score was 1,458.4 +/- 1,362.2, and for the aortic valve volume score was 1,178.8 +/- 1,066.0. The aortic valve Agatston score did not correlate strongly with AVA (r = -0.34, 95% CI -0.54, -0.09; p = 0.007). The data pattern appeared curvilinear, with the poorest correlation noted for those patients with moderate and severe aortic valve calcification. CONCLUSION: The study findings support the hypothesis that the aortic valve orifice area decreases not only due to calcium accumulation but also to sclerotic processes.

Aged↗
PubMed2005

MR angiography of aortoiliac occlusive disease: a phase III study of the safety and effectiveness of the blood-pool contrast agent MS-325.

PURPOSE: To evaluate prospectively the safety and effectiveness of aortoiliac magnetic resonance (MR) angiography enhanced with MS-325 (gadofosveset trisodium) at a dose of 0.03 mmol/kg; effectiveness was defined as accuracy relative to the reference standard, conventional angiography. MATERIALS AND METHODS: Study was approved by institutional review boards of participating institutions, and required national approvals were obtained. Study protocol conformed to Good Clinical Practice guidelines, and informed patient consent was obtained. Patients with known or suspected peripheral vascular disease received 0.03 mmol/kg MS-325 for aortoiliac MR angiography. They were also examined with conventional angiography. MS-325-enhanced MR was evaluated for safety and effectiveness. Along with unenhanced two-dimensional time-of-flight MR angiography, it was compared with conventional angiography for presence of vascular stenosis. Student t tests were used to identify significant improvement in diagnostic sensitivity, specificity, and accuracy, as well as quantitative characterization of stenoses by three blinded readers. Correlations between readers of conventional angiograms were calculated and compared with MR results. RESULTS: In 174 patients, MS-325-enhanced MR angiography showed significant improvement (P < or = .001) in sensitivity, specificity, and accuracy for diagnosis of clinically significant (> or =50%) stenosis, compared with unenhanced MR. For all readers, areas under the receiver operating characteristic curve for both quantitative and qualitative measures of significant disease increased (P < .001) for MS-325-enhanced MR compared with time-of-flight MR. All readers also expressed higher confidence in diagnosis (P < .001) and found fewer images uninterpretable with MS-325 enhancement. All measures of interpretation accuracy approached corresponding measures of correlation between readers of conventional angiograms. Incidence of severe and serious adverse events with MS-325 was low. No patients were withdrawn from study due to adverse events or abnormalities in laboratory results. There were no clinically important trends in findings at hematology, blood chemistry, urinalysis, electrocardiography, or physical examination. CONCLUSION: MR angiography with MS-325 provides significant improvement in effectiveness over unenhanced MR (and minimal and transient side effects) at a dose of 0.03 mmol/kg and was safe and effective for MR evaluation of patients with aortoiliac occlusive disease.

Adult↗
PubMed2005

Mineral volume and morphology in carotid plaque specimens using high-resolution MRI and CT.

OBJECTIVE: High-resolution MRI methods have been used to evaluate carotid artery atherosclerotic plaque content. The purpose of this study was to assess the performance of high-resolution MRI in evaluation of the quantity and pattern of mineral deposition in carotid endarterectomy (CEA) specimens, with quantitative micro-CT as the gold standard. METHODS AND RESULTS: High-resolution MRI and CT were compared in 20 CEA specimens. Linear regression comparing mineral volumes generated from CT (VCT) and MRI (VMRI) data demonstrated good correlation using simple thresholding (VMRI=-0.01+0.98VCT; R2=0.90; threshold=4xnoise) and k-means clustering methods (VMRI=-0.005+1.38VCT; R2=0.93). Bone mineral density (BMD) and bone mineral content (BMC [mineral mass]) were calculated for CT data and BMC verified with ash weight. Patterns of mineralization like particles, granules, and sheets were more clearly depicted on CT. CONCLUSIONS: Mineral volumes generated from MRI or CT data were highly correlated. CT provided a more detailed depiction of mineralization patterns and provided BMD and BMC in addition to mineral volume. The extent of mineralization as well as the morphology may ultimately be useful in assessing plaque stability.

Adult↗
PubMed2005

The unsung perils of peripheral arterial disease: a malady in search of a patient.

Peripheral arterial disease (PAD) is increasingly recognized as a strong predictor of mortality and morbidity from atherosclerotic events, especially from coronary heart disease. Since vascular disease remains the most common cause of death in the world, the substantial prevalence, ease of diagnosis, and ominous prognosis have increased interest in PAD among the prevention community. The association with coronary heart disease is strong enough that for prevention purposes, PAD should be considered a high-risk condition that demands aggressive therapy to reduce incident vascular events. Unlike other forms of atherosclerotic disease, PAD is easily diagnosed in the outpatient clinic noninvasively, using the ankle brachial index. Because its diagnosis can thus be seamlessly integrated into the routine clinical encounter, the ankle brachial index has emerged as a tool for global risk assessment. This article will review the relationship between PAD and other vascular disease, emphasizing the role of PAD in prevention efforts.

Aged↗
PubMed2004

Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease.

OBJECTIVES: We evaluated the effects of statins on aortic valve myofibroblasts (AVMFs) and osteoblast calcification in vitro. METHODS AND RESULTS: Cultured porcine AVMFs and M2-10B4 cells were treated with simvastatin and pravastatin. Mevalonate, a 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase metabolite, was added in parallel experiments. Manumycin A, which inhibits protein prenylation, was added to cultures in the absence of statins. Calcification was assessed by counting the number of calcific nodules formed and measuring alkaline phosphatase activity (APA). Statins inhibited calcific nodule formation (P<0.01) and APA (P<0.01) in AVMFs. Mevalonate reversed the statin effect on nodule formation (P<0.05) and APA (P<0.01). Manumycin A had no effect on either parameter. M2-10B4 cells treated with simvastatin formed more calcific nodules compared with controls (P<0.01), although pravastatin had no effect. Both statins, however, resulted in increased APA in M2-10B4 cells (P<0.01). Mevalonate had no impact on nodule numbers or APA in M2-10B4 cells. CONCLUSIONS: Statins inhibit calcification in AVMFs by inhibiting the cholesterol biosynthetic pathway, independent of protein prenylation, but paradoxically stimulate bone cell calcification. Because 15% of patients with end-stage valvular heart disease exhibit mature bone in their aortic valves, statins may differentially regulate calcification within a valve, limiting dystrophic calcification but promoting ossification of formed bone.

Animals↗
PubMed2004

Mechanisms of aortic valve calcification.

The calcified aortic valve lesion develops in the setting of endothelial injury and inflammation and displays hallmarks of atherosclerosis, including lipids accumulation, matrix metalloproteinase activation, and interaction with renin-angiotensin system. Current evidence indicates that modification of atherosclerotic risk factors will slow the progression of aortic valve calcification, and valve risk factors should be addressed in all patients who have aortic valve calcification.

Aortic Valve↗
PubMed2004

Utility and barriers to performance of the ankle-brachial index in primary care practice.

Peripheral arterial disease is prevalent, associated with increased cardiovascular morbidity and mortality, and is underdiagnosed. Nevertheless, systematic efforts to provide early office-based peripheral arterial disease detection are not routinely implemented in office practice. The PARTNERS Program implemented the ankle-brachial index (ABI) measurement in primary care outpatient clinics in order to model practical dissemination of this technique and thus improve office-based peripheral arterial disease detection. The objective of this study was to identify clinician-defined factors that were perceived to foster acceptance of, or create barriers to, the use of the ABI in office practice. The ABI Utilization Survey was administered to primary care clinicians who participated in the PARTNERS Program, as well as to additional primary care clinicians who participated in the PARTNERS Preceptorship. The survey assessed six parameters: pre- and post-participation office ABI utilization; perceived clinical utility of the ABI; perceived value of the ABI data relative to other commonly used office disease detection methods; feasibility of implementing office-based ABI testing; definition of factors limiting utilization of the ABI in office practice; and the role of office staff in performing the ABI test. Survey data were obtained from 886 respondents. A total of 68% of respondents did not measure the ABI prior to participation in the PARTNERS Program. After Program participation, the frequency of office ABI use increased from 12% to 43% weekly and 13% to 39% monthly. The few participants who reported using the ABI only once a year (annually) did not significantly change after the program. Most clinicians believed that the ABI was useful in the diagnosis and management of both symptomatic (96%) and asymptomatic (89%) peripheral arterial disease. Moderate to major barriers to use of the ABI included time constraints (56%), lack of reimbursement (45%), and staff availability (45%). Nearly all (88%) clinicians believed that it was feasible to incorporate ABI into daily practice. Overall, most clinicians (57-75%) believed that ABI was equal to, or more useful, than other widely available and reimbursed screening tests in preserving their patients' health. In conclusion, the ABI was perceived by primary care clinicians to be a clinically useful diagnostic test. Limited reimbursement and time were identified as the primary barriers to its widespread use. Once learned, most clinicians stated that the ABI would continue to be frequently used in their office practice. The ABI is a simple peripheral arterial disease detection tool that can be successfully applied in primary care office practices.

Ankle↗
PubMed2004

Drug treatment of intermittent claudication.

The US FDA has approved two drugs for the management of intermittent claudication: pentoxifylline and cilostazol. The mechanism of action that provides symptom relief with pentoxifylline is poorly understood but is thought to involve red blood cell deformability as well as a reduction in fibrinogen concentration, platelet adhesiveness and whole blood viscosity. The recommended dose of pentoxifylline is 400 mg three times daily with meals. Cilostazol is a potent, reversible, phosphodiesterase III inhibitor. The inhibition of phosphodiesterase allows for the increased availability of cyclic adenosine monophosphate (cAMP). cAMP mediates many agonist-induced platelet inhibitory, vasodilatory and vascular antiproliferative responses. Cilostazol, at a dose of 100 mg twice daily, is recommended to be taken 30 minutes before or 2 hours after breakfast and dinner. In addition to pentoxifylline and cilostazol, clinical trials indicate many other drugs may relieve the symptoms of intermittent claudication. Ginkgo biloba, available as an over-the-counter extract, provides symptom relief comparable to pentoxifylline. Two European agents, naftidrofuryl and buflomedil, also have efficacy that is reported to be similar to pentoxifylline. Policosanol is a mixture of fatty alcohols derived from honeybee wax which, according to very limited data, reduces symptoms of claudication. Amino acids, certain peptides and prostaglandins may have a therapeutic role. Finally, novel approaches including angiogenesis mediated by growth factors, are currently under investigation.

Animals↗
PubMed2004

The effect of risk factor changes on peripheral arterial disease and cardiovascular risk.

Peripheral arterial disease (PAD) due to atherosclerosis, although frequently ignored in clinical practice, results in significant cardiovascular morbidity and mortality and may progress due to uncontrolled atherosclerotic risk factors. Although treatment of claudication symptoms is important for improved lifestyle, treatment of risk factors will prolong life. Smoking cessation, blood pressure control, lipid modification and strict control of diabetes mellitus will reduce the risk of both macro and micro vascular disease progression. Risk factor modification in conjunction with antiplatelet treatment results in decreased heart attack, stroke and peripheral vascular events in patients with PAD.

Arteriosclerosis↗