20 results on '"Matthew A. Kluge"'
Search Results
2. Recurrent Pericarditis: a Stubborn Opponent Meets New Treatments in 2022
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Tracy Hagerty, Matthew A. Kluge, and Martin M. LeWinter
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Interleukin 1 Receptor Antagonist Protein ,Mice ,Inflammasomes ,Recurrence ,NLR Family, Pyrin Domain-Containing 3 Protein ,Quality of Life ,Animals ,Humans ,Pericarditis ,Cardiology and Cardiovascular Medicine ,Interleukin-1 - Abstract
Our goal in writing this review was to provide a comprehensive appraisal of current therapies for idiopathic recurrent pericarditis with a particular focus on the newest therapeutic agents. We sought to understand the role of the inflammasome in the pathophysiology of pericarditis and how it informs the use of interleukin-1 (IL-1)-directed therapies.The latest research on this topic has focused on the critical role of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein) inflammasome. Very recently, components of the NLRP3 inflammasome were detected by immune staining in pericardial tissue from patients with recurrent idiopathic pericarditis. In a mouse model of pericarditis, anti-IL-1 agents anakinra and rilonacept reduced NLRP3 immunostaining. Subsequent study of these drugs in human subjects with idiopathic recurrent pericarditis demonstrated their efficacy. Recurrent idiopathic pericarditis, while relatively rare, poses a continued treatment challenge and contributes to a diminished quality of life for those patients who are afflicted. Recent developments, including an animal model of the disease and the use of IL-1-directed therapies, represent an exciting leap forward in our understanding of treatment targets. These advances offer not only new tools in our fight against this disease, but also the promise of earlier intervention and attenuation of disease morbidity. As our experience with these new agents expands, we can address questions about the ideal timing of introduction of anti-IL-1 therapy and duration of therapy and better understand the potential side effect profile.
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- 2022
3. Fabricating mechanically improved silk-based vascular grafts by solution control of the gel-spinning process
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Jonathan A. Kluge, Peter S. Kim, Matthew A. Kluge, Maria J. Rodriguez, Daniel Smoot, David L. Kaplan, Daniel Schmidt, and Paetsch Christopher R
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Pore size ,Materials science ,Biophysics ,Silk ,Bioengineering ,02 engineering and technology ,Article ,Biomaterials ,Rats, Sprague-Dawley ,03 medical and health sciences ,In vivo ,Animals ,Porosity ,Spinning ,030304 developmental biology ,chemistry.chemical_classification ,Bioprosthesis ,0303 health sciences ,Biomaterial ,Polymer ,021001 nanoscience & nanotechnology ,Blood Vessel Prosthesis ,Rats ,SILK ,chemistry ,Mechanics of Materials ,Void (composites) ,Ceramics and Composites ,Vascular Grafting ,0210 nano-technology ,Biomedical engineering - Abstract
There is a large unmet need for off-the-shelf biomaterial options to supplant venous autografts in bypass and reconstructive surgical procedures. Existing graft alternatives formed from non-degradable synthetic polymers are not capable of maintaining long-term patency and are thus not indicated for
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- 2019
4. Inadequate Boston Bowel Preparation Scale Scores Predict the Risk of Missed Neoplasia on Next Colonoscopy
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Connie K. Wu, Matthew A. Kluge, David Lieberman, Audrey H. Calderwood, Brian C. Jacobson, J. Lucas Williams, and Paul C. Schroy
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Male ,Risk ,medicine.medical_specialty ,Colon ,Colonic Polyps ,Colonoscopy ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Boston bowel preparation scale ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Prospective Studies ,Diagnostic Errors ,Early Detection of Cancer ,Aged ,Quality Indicators, Health Care ,medicine.diagnostic_test ,Cathartics ,business.industry ,Odds ratio ,Middle Aged ,Triage ,United States ,Confidence interval ,digestive system diseases ,Increased risk ,030220 oncology & carcinogenesis ,Cohort ,Female ,030211 gastroenterology & hepatology ,Observational study ,business - Abstract
Background and Aims The risks of missed findings after inadequate bowel preparation are not fully characterized in a diverse cohort. We aimed to evaluate the likelihood of missed polyps after an inadequate preparation as assessed by using the Boston Bowel Preparation Scale (BBPS). Methods In this observational study of prospectively collected data within a large, national, endoscopic consortium, we identified patients aged 50 to 75 years who underwent average-risk screening colonoscopy (C1) followed by a second colonoscopy for any indication within 3 years (C2). We determined the polyp detection rates (PDRs) and advanced PDRs during C2 stratified by C1 BBPS scores. Results Among segment pairs without polyps at C1 (N = 601), those with inadequate C1 BBPS segment scores had a higher PDR at C2 (10%) compared with those with adequate bowel preparation at C1 (5%; P = .04). Among segment pairs with polyps at C1 (N = 154), segments with inadequate bowel preparation scores at C1 had higher advanced PDRs at C2 (20%) compared with those with adequate bowel preparation scores at C1 (4%; P = .03). In multivariable analysis, the presence of advanced polyps at C1 (adjusted odds ratio [OR] 3.5; 95% confidence intervals [CIs], 1.1-10.8) but not inadequate BBPS scores at C1 (adjusted OR 1.8; 95% CI, 0.6-5.1) was associated with a significantly increased risk of advanced polyps at C2. Conclusions Inadequate BBPS segment scores generally are associated with higher rates of polyps and advanced polyps at subsequent colonoscopy within a short timeframe. The presence of advanced polyps as well as inadequate BBPS segment scores can inform the risk of missed polyps and help triage which patients warrant a timely repeat colonoscopy.
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- 2017
5. Erectile dysfunction in the trajectory of cardiovascular disease
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Matthew A. Kluge and Naomi M. Hamburg
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Male ,medicine.medical_specialty ,business.industry ,Disease ,030204 cardiovascular system & hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Erectile dysfunction ,Erectile Dysfunction ,Cardiovascular Diseases ,Risk Factors ,Internal medicine ,Trajectory ,Cardiology ,Humans ,Medicine ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business - Published
- 2017
6. Predictors of Adherence to Post-Polypectomy Surveillance Colonoscopy
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Paul C. Schroy, Audrey H. Calderwood, Matthew A. Kluge, Howard Cabral, and James F. Burgess
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Adenoma ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Problem list ,Psychological intervention ,Colonoscopy ,Colonic Polyps ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Mass Screening ,Mass screening ,Aged ,medicine.diagnostic_test ,business.industry ,Public health ,Public Health, Environmental and Occupational Health ,Attendance ,Middle Aged ,medicine.disease ,Polypectomy ,030220 oncology & carcinogenesis ,Physical therapy ,Patient Compliance ,030211 gastroenterology & hepatology ,Female ,business ,Colorectal Neoplasms - Abstract
Objective . To identify predictors of adherence with surveillance colonoscopy at a safety-net hospital. Methods . We evaluated average-risk patients aged 50–75 with adenomas diagnosed at screening colonoscopy between 1/1/05–12/31/07. The primary outcome was on-time follow-up defined as attendance at surveillance colonoscopy within 5.5 years of screening colonoscopy. Results . Among 881 patients, of whom 38% were English-speaking non-Hispanic Blacks, 38.3% attended on-time surveillance colonoscopy. In unadjusted analyses, ≥3 PCP visits after baseline colonoscopy (OR 3.6 [2.5–5.0]), “adenoma” on the EMR problem list (OR 2.2 [1.6–2.9]), and Charlson Index ≥1 (OR 1.4 [1.0–1.8]) were associated with adherence. “Adenoma” on the EMR problem list remained significant in multivariable analyses (aOR 1.8 [1.3–2.5]). A significant interaction was observed between ethnicity/language and PCP visits (p=.003). Conclusion . Many adenoma-bearing patients fail to attend surveillance colonoscopy in a safety-net setting. Adding “adenomas” to the EMR problem list improved attendance, suggesting that system-level interventions can increase adherence.
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- 2016
7. Altered Mitochondrial Dynamics Contributes to Endothelial Dysfunction in Diabetes Mellitus
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Brian H Kim, Kai Chen, Mai-Ann Duess, Matthew A. Kluge, Lija Joseph, Mor-Li Hartman, Tara L. Caiano, Naomi M. Hamburg, Aaron Levit, Monika Holbrook, Joseph A. Vita, Guoquan Xu, Alissa A. Frame, Sherene M. Shenouda, Orian S. Shirihai, Michael E. Widlansky, and Corey E. Tabit
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Adult ,Dynamins ,Male ,FIS1 ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Endothelium ,Mitochondrion ,Article ,Body Mass Index ,Cell Line ,GTP Phosphohydrolases ,Mitochondrial Proteins ,chemistry.chemical_compound ,Physiology (medical) ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,Endothelial dysfunction ,Cyclic GMP ,Aorta ,Cells, Cultured ,chemistry.chemical_classification ,Reactive oxygen species ,business.industry ,Membrane Proteins ,Free Radical Scavengers ,Middle Aged ,medicine.disease ,Mitochondria ,Glucose ,Endocrinology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,chemistry ,L-Glucose ,Female ,Mitochondrial fission ,Endothelium, Vascular ,Reactive Oxygen Species ,Cardiology and Cardiovascular Medicine ,business ,Microtubule-Associated Proteins - Abstract
Background— Endothelial dysfunction contributes to the development of atherosclerosis in patients with diabetes mellitus, but the mechanisms of endothelial dysfunction in this setting are incompletely understood. Recent studies have shown altered mitochondrial dynamics in diabetes mellitus with increased mitochondrial fission and production of reactive oxygen species. We investigated the contribution of altered dynamics to endothelial dysfunction in diabetes mellitus. Methods and Results— We observed mitochondrial fragmentation ( P =0.002) and increased expression of fission-1 protein (Fis1; P Conclusion— These findings implicate increased mitochondrial fission as a contributing mechanism for endothelial dysfunction in diabetic states.
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- 2011
8. Effects of cranberry juice consumption on vascular function in patients with coronary artery disease
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Paul E. Milbury, Joseph Palmisano, Joseph A. Vita, Jeffrey B. Blumberg, William B. Chung, Matthew A. Kluge, Mustali M Dohadwala, Naomi M. Hamburg, Sherene M. Shenouda, Monika Holbrook, Megan Titas, and Na Wang
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medicine.medical_specialty ,Nutrition and Dietetics ,Endothelium ,business.industry ,CRANBERRY JUICE ,Medicine (miscellaneous) ,medicine.disease ,Crossover study ,Gastroenterology ,Surgery ,Coronary artery disease ,medicine.anatomical_structure ,Blood pressure ,food ,medicine.artery ,Internal medicine ,medicine ,Arterial stiffness ,Brachial artery ,business ,Pulse wave velocity ,food.beverage - Abstract
Background: Cranberry juice contains polyphenolic compoundsthat could improve endothelial function and reduce cardiovasculardisease risk.Objective: The objective was to examine the effects of cranberryjuice on vascular function in subjects with coronary artery disease.Design: We completed an acute pilot study with no placebo (n = 15)and a chronic placebo-controlled crossover study (n = 44) thatexamined the effects of cranberry juice on vascular function insubjects with coronary artery disease.Results: In the chronic crossover study, subjects with coronaryheart disease consumed a research preparation of double-strengthcranberry juice (54% juice, 835 mg total polyphenols, and 94 mganthocyanins) or a matched placebo beverage (480 mL/d) for 4 wkeach with a 2-wk rest period between beverages. Beverage orderwas randomized, and participants refrained from consuming otherflavonoid-containing beverages during the study. Vascular functionwas measured before and after each beverage, with the follow-uptesting 12 h after consumption of the last beverage. Mean (6SD)carotid-femoral pulse wave velocity, a measure of central aorticstiffness, decreased after cranberry juice (8.3 6 2.3 to 7.8 6 2.2m/s) in contrast with an increase (8.0 6 2.0 to 8.4 6 2.8 m/s) afterplacebo (P = 0.003). Brachial artery flow-mediated dilation, digitalpulse amplitude tonometry, blood pressure, and carotid-radial pulsewave velocity did not change. In the uncontrolled pilot study, weobserved improved brachial artery flow-mediated dilation (7.7 62.9% to 8.7 6 3.1%, P = 0.01) and digital pulse amplitude tonom-etry ratio (0.10 6 0.12 to 0.23 6 0.16, P = 0.001) 4 h after con-sumption of a single 480-mL portion of cranberry juice.Conclusions: Chronic cranberry juice consumption reduced carotidfemoral pulse wave velocity—a clinically relevant measure of arte-rial stiffness. The uncontrolled pilot study suggested an acute benefit;however, no chronic effect on measures of endothelial vasodilatorfunction was found. This trial was registered at clinicaltrials.gov asNCT00553904. Am J Clin Nutr doi: 10.3945/ajcn.110.004242.INTRODUCTIONEpidemiologic studies have shown that consumption of fla-vonoid-containing foods and beverages is associated with re-duced cardiovascular disease risk (1, 2). Whereas the mechanismsaccounting for this benefit remain incompletely defined, clinicalstudies have identified many relevant effects. For example,consumption of grapes, cocoa, and other flavonoid-containingfoods may reduce blood pressure (3), platelet aggregation (4),insulin resistance (5), and cholesterol concentrations (6). Invitroand biomarker studies suggestthat such foods have antiin-flammatory effects (2, 7). Recently, there has been particularinterest in the possibility that flavonoids also reduce cardiovas-cular disease risk by reversing endothelial dysfunction.Endothelial dysfunction is a key mechanism in the patho-genesis of atherosclerotic vascular disease (8, 9). Risk factorsdecrease the bioavailability of endothelium-derived nitric oxideand induce a proinflammatory endothelial phenotype that pro-motes atherosclerosis and arterial stiffness. Risk-reduction ther-apies and lifestyle changes improve endothelial function (9).Prior studies have shown favorable effects of tea, cocoa, grapejuice, and other dietary sources of flavonoids on endothelialfunction in patients with coronary disease and other risk factors(10–12).Cranberry juice is a rich source of polyphenolic compounds,particularly anthocyanins (13, 14). Investigators have proposedthat cranberry consumption might have protective effects againstcardiovascular disease by reducing inflammation and serumlipids (15, 16). The present study was designed to investigatewhether consumption of cranberry juice would improve vascularfunctionandreduceinflammation.Weusednoninvasivemethodsto examine the effects of cranberry juice on multiple measuresof vascular function in different vascular beds, including endo-thelium-dependent vasodilation and arterial stiffness in patientswith coronary artery disease.
- Published
- 2011
9. Long-term Successful Weight Loss Improves Vascular Endothelial Function in Severely Obese Individuals
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Caroline M. Apovian, Donald T. Hess, Noyan Gokce, Joseph A. Vita, Melanie Mott, Antonino J. Fiscale, Sherman J Bigornia, Matthew A. Kluge, Mai-Ann Duess, and Marie E. McDonnell
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Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Brachial Artery ,Endocrinology, Diabetes and Metabolism ,Medicine (miscellaneous) ,Blood sugar ,Severity of Illness Index ,Article ,Body Mass Index ,chemistry.chemical_compound ,Endocrinology ,High-density lipoprotein ,Weight loss ,medicine.artery ,Internal medicine ,Weight Loss ,medicine ,Humans ,Obesity ,Endothelial dysfunction ,Brachial artery ,Glycated Hemoglobin ,Analysis of Variance ,Nutrition and Dietetics ,biology ,business.industry ,C-reactive protein ,Weight change ,Cholesterol, LDL ,Middle Aged ,medicine.disease ,Vasodilation ,C-Reactive Protein ,chemistry ,Cardiovascular Diseases ,biology.protein ,Female ,Endothelium, Vascular ,medicine.symptom ,business ,Body mass index - Abstract
Obesity is associated with increased cardiovascular risk. Although short-term weight loss improves vascular endothelial function, longer term outcomes have not been widely investigated. We examined brachial artery endothelium-dependent vasodilation and metabolic parameters in 29 severely obese subjects who lostor =10% body weight (age 45 +/- 13 years; BMI 48 +/- 9 kg/m(2)) at baseline and after 12 months of dietary and/or surgical intervention. We compared these parameters to 14 obese individuals (age 49 +/- 11 years; BMI 39 +/- 7 kg/m(2)) who failed to lose weight. For the entire group, mean brachial artery flow-mediated dilation (FMD) was impaired at 6.7 +/- 4.1%. Following sustained weight loss, FMD increased significantly from 6.8 +/- 4.2 to 10.0 +/- 4.7%, but remained blunted in patients without weight decline from 6.5 +/- 4.0 to 5.7 +/- 4.1%, P = 0.013 by ANOVA. Endothelium-independent, nitroglycerin-mediated dilation (NMD) was unaltered. BMI fell by 13 +/- 7 kg/m(2) following successful weight intervention and was associated with reduced total and low-density lipoprotein cholesterol, glucose, hemoglobin A(1c), and high-sensitivity C-reactive protein (CRP). Vascular improvement correlated most strongly with glucose levels (r = -0.51, P = 0.002) and was independent of weight change. In this cohort of severely obese subjects, sustained weight loss at 1 year improved vascular function and metabolic parameters. The findings suggest that reversal of endothelial dysfunction and restoration of arterial homeostasis could potentially reduce cardiovascular risk. The results also demonstrate that metabolic changes in association with weight loss are stronger determinants of vascular phenotype than degree of weight reduction.
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- 2010
10. Gastric Intestinal Metaplasia and Surveillance Recommendations in an Ethnically Diverse Urban Safety-Net Population
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Matthew A. Kluge, Audrey H. Calderwood, and Harini Naidu
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medicine.medical_specialty ,education.field_of_study ,Hepatology ,business.industry ,Safety net ,Population ,Gastroenterology ,Ethnically diverse ,Gastric Intestinal Metaplasia ,Internal medicine ,medicine ,business ,education - Published
- 2017
11. Relation of mitochondrial oxygen consumption in peripheral blood mononuclear cells to vascular function in type 2 diabetes mellitus
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Alissa A. Frame, Akash K. Shah, Orian S. Shirihai, Joseph A. Vita, Guoquan Xu, Naomi M. Hamburg, Jessica L. Fetterman, Marsha Kocherla, Matthew A. Kluge, Mor-Li Hartman, and Monika Holbrook
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Adult ,Male ,medicine.medical_specialty ,Vascular smooth muscle ,Brachial Artery ,chemistry.chemical_element ,Mitochondrion ,Oxygen ,Article ,Nitroglycerin ,Oxygen Consumption ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,Endothelial dysfunction ,Aged ,chemistry.chemical_classification ,Reactive oxygen species ,business.industry ,Type 2 Diabetes Mellitus ,VO2 max ,Middle Aged ,medicine.disease ,Mitochondria ,Endocrinology ,chemistry ,Diabetes Mellitus, Type 2 ,Leukocytes, Mononuclear ,Female ,Endothelium, Vascular ,Cardiology and Cardiovascular Medicine ,business - Abstract
Recent studies have shown mitochondrial dysfunction and increased production of reactive oxygen species in peripheral blood mononuclear cells (PBMCs) and endothelial cells from patients with diabetes mellitus. Mitochondria oxygen consumption is coupled to adenosine triphosphate (ATP) production and also occurs in an uncoupled fashion during formation of reactive oxygen species by components of the electron transport chain and other enzymatic sites. We therefore hypothesized that diabetes would be associated with higher total and uncoupled oxygen consumption in PBMCs that would correlate with endothelial dysfunction. We developed a method to measure oxygen consumption in freshly isolated PBMCs and applied it to 26 patients with type 2 diabetes mellitus and 28 non-diabetic controls. Basal (192 ± 47 vs 161 ± 44 pmoles/min, p = 0.01), uncoupled (64 ± 16 vs 53 ± 13 pmoles/min, p = 0.007), and maximal (795 ± 87 vs 715 ± 128 pmoles/min, p=0.01) oxygen consumption rates were higher in diabetic patients compared to controls. There were no significant correlations between oxygen consumption rates and endothelium-dependent flow-mediated dilation measured by vascular ultrasound. Non-endothelium-dependent nitroglycerin-mediated dilation was lower in diabetics (10.1 ± 6.6 vs 15.8 ± 4.8%, p = 0.03) and correlated with maximal oxygen consumption (r = -0.64, p=0.001). In summary, we found that diabetes mellitus is associated with a pattern of mitochondrial oxygen consumption consistent with higher production of reactive oxygen species. The correlation between oxygen consumption and nitroglycerin-mediated dilation may suggest a link between mitochondrial dysfunction and vascular smooth muscle cell dysfunction that merits further study. Finally, the described method may have utility for the assessment of mitochondrial function in larger scale observational and interventional studies in humans.
- Published
- 2014
12. Mitochondria and Endothelial Function
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Jessica L. Fetterman, Joseph A. Vita, and Matthew A. Kluge
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Endothelium ,Physiology ,Mechanism (biology) ,Angiogenesis ,Autophagy ,Endothelial Cells ,Biology ,Mitochondrion ,Article ,Cell biology ,Mitochondria ,medicine.anatomical_structure ,Mitophagy ,medicine ,Animals ,Homeostasis ,Humans ,Endothelium, Vascular ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Reactive Oxygen Species ,Function (biology) ,Signal Transduction - Abstract
In contrast to their role in cell types with higher energy demands, mitochondria in endothelial cells primarily function in signaling cellular responses to environmental cues. This article provides an overview of key aspects of mitochondrial biology in endothelial cells, including subcellular location, biogenesis, dynamics, autophagy, reactive oxygen species production and signaling, calcium homeostasis, regulated cell death, and heme biosynthesis. In each section, we introduce key concepts and then review studies showing the importance of that mechanism to endothelial control of vasomotor tone, angiogenesis, and/or inflammatory activation. We particularly highlight the small number of clinical and translational studies that have investigated each mechanism in human subjects. Finally, we review interventions that target different aspects of mitochondrial function and their effects on endothelial function. The ultimate goal of such research is the identification of new approaches for therapy. The reviewed studies make it clear that mitochondria are important in endothelial physiology and pathophysiology. A great deal of work will be needed, however, before mitochondria-directed therapies are available for the prevention and treatment of cardiovascular disease.
- Published
- 2013
13. Protein Kinase-C Beta Contributes to Impaired Endothelial Insulin Signaling in Humans with Diabetes Mellitus
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Soroosh Kiani, James L. Rosenzweig, Naomi M. Hamburg, Noyan Gokce, Jessica L. Fetterman, Neil B. Ruderman, Matthew A. Kluge, Joseph A. Vita, Monica Holbrook, Corey E. Tabit, Sherene M. Shenouda, Melissa G. Farb, Alissa A. Frame, Mustali M Dohadwala, and Aaron Held
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Adult ,Male ,medicine.medical_specialty ,Endothelium ,Nitric Oxide Synthase Type III ,medicine.medical_treatment ,Nitric Oxide ,Article ,Insulin resistance ,Physiology (medical) ,Internal medicine ,Diabetes mellitus ,Protein Kinase C beta ,medicine ,Hypoglycemic Agents ,Humans ,Insulin ,Pyrroles ,Cells, Cultured ,Protein Kinase C ,Mesylates ,biology ,business.industry ,NF-kappa B ,Type 2 Diabetes Mellitus ,Endothelial Cells ,Middle Aged ,medicine.disease ,Vascular endothelial growth factor B ,Insulin receptor ,Vascular endothelial growth factor A ,Oxidative Stress ,Endocrinology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,biology.protein ,Female ,Insulin Resistance ,Cardiology and Cardiovascular Medicine ,business ,Diabetic Angiopathies ,Signal Transduction - Abstract
Background— Abnormal endothelial function promotes atherosclerotic vascular disease in diabetes. Experimental studies indicate that disruption of endothelial insulin signaling, through the activity of protein kinase C-β (PKCβ) and nuclear factor κB, reduces nitric oxide availability. We sought to establish whether similar mechanisms operate in the endothelium in human diabetes mellitus. Methods and Results— We measured protein expression and insulin response in freshly isolated endothelial cells from patients with type 2 diabetes mellitus (n=40) and nondiabetic controls (n=36). Unexpectedly, we observed 1.7-fold higher basal endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 in patients with diabetes mellitus ( P =0.007) without a difference in total eNOS expression. Insulin stimulation increased eNOS phosphorylation in nondiabetic subjects but not in diabetic patients ( P =0.003), consistent with endothelial insulin resistance. Nitrotyrosine levels were higher in diabetic patients, indicating endothelial oxidative stress. PKCβ expression was higher in diabetic patients and was associated with lower flow-mediated dilation (r=−0.541, P =0.02). Inhibition of PKCβ with LY379196 reduced basal eNOS phosphorylation and improved insulin-mediated eNOS activation in patients with diabetes mellitus. Endothelial nuclear factor κB activation was higher in diabetes mellitus and was reduced with PKCβ inhibition. Conclusions— We provide evidence for the presence of altered eNOS activation, reduced insulin action, and inflammatory activation in the endothelium of patients with diabetes mellitus. Our findings implicate PKCβ activity in endothelial insulin resistance.
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- 2012
14. Altered Mitochondrial Membrane Potential, Mass, and Morphology in the Mononuclear Cells of Humans with Type 2 Diabetes
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Jingli Wang, Joseph A. Vita, Tinoy J. Kizhakekuttu, Sherene M. Shenouda, Tory M. Hagen, Matthew A. Kluge, Dorothee Weihrauch, Anthony R. Smith, David D. Gutterman, and Michael E. Widlansky
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Adult ,Male ,Cardiolipins ,Mitochondrion ,Biology ,Peripheral blood mononuclear cell ,Article ,Monocytes ,chemistry.chemical_compound ,Superoxides ,Physiology (medical) ,Humans ,Lymphocytes ,Inner mitochondrial membrane ,Aged ,Fluorescent Dyes ,chemistry.chemical_classification ,Membrane potential ,Membrane Potential, Mitochondrial ,Reactive oxygen species ,Superoxide ,Aminoacridines ,Biochemistry (medical) ,Acridine orange ,Public Health, Environmental and Occupational Health ,Reproducibility of Results ,General Medicine ,Carbocyanines ,Middle Aged ,Cell biology ,Mitochondria ,Cross-Sectional Studies ,chemistry ,Biochemistry ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone ,Benzimidazoles ,Female ,Biomarkers - Abstract
Mitochondrial membrane hyperpolarization and morphologic changes are important in inflammatory cell activation. Despite the pathophysiologic relevance, no valid and reproducible method for measuring mitochondrial homeostasis in human inflammatory cells is available currently. The purpose of this study was to define and validate reproducible methods for measuring relevant mitochondrial perturbations and to determine whether these methods could discern mitochondrial perturbations in type 2 diabetes mellitus (T2DM), which is a condition associated with altered mitochondrial homeostasis. We employed 5,5′,6,6′-tetrachloro-1,1′3,3′-tetraethylbenzamidazol-carboncyanine (JC-1) to estimate mitochondrial membrane potential (Ψ m ) and acridine orange 10-nonyl bromide (NAO) to assess mitochondrial mass in human mononuclear cells isolated from blood. Both assays were reproducible. We validated our findings by electron microscopy and pharmacologic manipulation of Ψ m . We measured JC-1 and NAO fluorescence in the mononuclear cells of 27 T2DM patients and 32 controls. Mitochondria were more polarized ( P = 0.02) and mitochondrial mass was lower in T2DM ( P = 0.008). Electron microscopy demonstrated diabetic mitochondria were smaller, were more spherical, and occupied less cellular area in T2DM. Mitochondrial superoxide production was higher in T2DM ( P = 0.01). Valid and reproducible measurements of mitochondrial homeostasis can be made in human mononuclear cells using these fluorophores. Furthermore, potentially clinically relevant perturbations in mitochondrial homeostasis in T2DM human mononuclear cells can be detected.
- Published
- 2010
15. Maladaptive enlargement of the brachial artery in severe obesity is reversed with weight loss
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Naomi M. Hamburg, Donald T. Hess, Caroline M. Apovian, Noyan Gokce, Joseph A. Vita, Sherman J Bigornia, Mai-Ann Duess, Melanie Mott, and Matthew A. Kluge
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Adult ,Male ,medicine.medical_specialty ,Brachial Artery ,Systemic inflammation ,Severity of Illness Index ,Article ,Body Mass Index ,Peripheral Arterial Disease ,Weight loss ,Risk Factors ,Internal medicine ,medicine.artery ,Weight Loss ,medicine ,Humans ,Longitudinal Studies ,Obesity ,Prospective Studies ,Brachial artery ,Risk factor ,Prospective cohort study ,Ultrasonography ,Vascular disease ,business.industry ,Middle Aged ,medicine.disease ,Endocrinology ,Cross-Sectional Studies ,Female ,Stress, Mechanical ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Body mass index - Abstract
Maladaptive peripheral arterial remodeling, which leads to large arteries with low shear stress, may be associated with increased cardiovascular risk. We tested the hypothesis that arterial enlargement in severe obesity represents maladaptive remodeling and that weight reduction would reverse this process. We evaluated brachial arterial diameter and flow using ultrasound in 244 severely obese patients (age 44 ± 11 years, 80% female, body mass index (BMI) 46 ± 9 kg/m) at baseline and in a group of 67 subjects who experienced weight loss at 1 year. Higher BMI was associated with larger brachial artery diameter ( p = 0.01) and lower shear stress ( p = 0.008), indicating maladaptive remodeling. Significant (≥ 10%) weight reduction was associated with a decrease in resting arterial diameter (—0.19 ± 0.47 mm, p = 0.02) along with a trend toward increased shear stress. Decreased systemic inflammation was associated with weight loss-induced reverse remodeling of the brachial artery. Our findings demonstrate the presence of maladaptive arterial remodeling in advanced obesity that was ameliorated by significant weight loss.
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- 2010
16. Tumour Blood Flow Following Local Ultrasound Heating Computed from Thermal Clearance Curves
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Matthew A. Kluge, Peter Vaupel, Thomas K. Goldstick, F. Kallinowski, R. D. Braun, and S. C. George
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Hyperthermia ,Tumour blood flow ,medicine.medical_specialty ,business.industry ,Chemistry ,Ultrasound ,Oxygen transport ,Blood flow ,medicine.disease ,Therapeutic Hyperthermia ,medicine ,Radiology ,Short exposure ,business ,Nuclear medicine - Abstract
Thermal clearance curves following termination of ultrasound-induced hyperthermia in human mammary carcinomas implanted into the flanks of nude rats were studied. They were found to be monoexponential in form, both with and without blood flow. From the difference between the inverse time constants with and without flow, the tumour blood flow rate could be calculated. Blood flow was found to increase with very short exposure times at the therapeutic hyperthermia temperature and subsequently decrease as the exposure time increased. A higher therapeutic hyperthermia temperature augmented this effect.
- Published
- 1987
17. Response of tumour red blood cell flux to hyperthermia and/or hyperglycaemia
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Paul Okunieff, Matthew A. Kluge, and P. Vaupel
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Hyperthermia ,Male ,Cancer Research ,medicine.medical_specialty ,Physiology ,Soft Tissue Neoplasms ,Hematocrit ,Biology ,Microcirculation ,chemistry.chemical_compound ,Carcinosarcoma ,Glucose Solution, Hypertonic ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,medicine.diagnostic_test ,Lasers ,Galactose ,Rats, Inbred Strains ,Blood flow ,Hyperthermia, Induced ,medicine.disease ,Lactic acid ,Rats ,Red blood cell ,medicine.anatomical_structure ,Endocrinology ,Blood pressure ,chemistry ,Regional Blood Flow ,Hyperglycemia ,Arterial blood ,Female ,Blood Flow Velocity - Abstract
Laser Doppler flowmetry has been applied to subepidermal rat tumours during localized ultrasound hyperthermia and/or moderate, short-term hyperglycaemia. Blood glucose levels were elevated 4-fold by continuous i.v. infusion of D-glucose (4.8 g/kg/60 min). To determine whether the effects of hyperglycaemia on tumour blood flow involved increased rates of glycolysis and lactic acid production, galactose, a sugar not metabolized by the tumour, was administered using the same dose schedule. Hyperglycaemia was accompanied by a 3-fold increase in blood lactate levels and a slight hypervolaemic haemodilution without any significant systematic changes of the arterial blood pressure or respiratory blood gas parameters. pH of the arterial blood decreased only slightly. Results suggest that neither i.v. glucose nor i.v. galactose alone can cause any statistically significant changes in the red blood cell flux within superficial tumour regions. Doses of hyperthermia which had no effect on tumour microcirculation (e.g. at 40 degrees C), also had no impact on RBC flux when combined with moderate, short-term hyperglycaemia. However, hyperglycaemia (mean blood glucose levels 60 min after initiation of glucose loading: 21-25 mM) in conjunction with appropriate heating can decrease tumour blood flow to a greater extent than heat alone. This effect was more pronounced during 42 degrees C hyperthermia than during heating at 44 degrees C. Thus moderate short-term hyperglycaemia is recognized as a potentiator for hyperthermia at 42-44 degrees C. Intensified glycolysis and restricted venous drainage of lactic acid seem to play an important part in these pathogenetic events.
- Published
- 1989
18. Laser Doppler flowmetry in subepidermal tumours and in normal skin of rats during localized ultrasound hyperthermia
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Peter Vaupel, Matthew A. Kluge, and M C Ambroz
- Subjects
Hyperthermia ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Physiology ,Nuclear magnetic resonance ,Carcinosarcoma ,Physiology (medical) ,Experimental therapy ,medicine ,Animals ,Laser doppler flow ,Skin ,business.industry ,Lasers ,Ultrasound ,Rats, Inbred Strains ,Periodic flow ,Hyperthermia, Induced ,Neoplasms, Experimental ,Laser Doppler velocimetry ,medicine.disease ,Rats ,Female ,Sarcoma, Experimental ,business ,Normal skin ,Blood Flow Velocity - Abstract
Laser Doppler flowmetry has been applied to normal skin and to subepidermal tumours during localized ultrasound hyperthermia in the rat. In normal skin, 40 degrees C hyperthermia only induced a marginal increase in the red blood cell flux. Significant increases occurred after 20 min at 42 degrees C and after 4 min at 44 degrees C. During 44 degrees C hyperthermia maximum fluxes were reached after 24 min. Thereafter, the flow declined and finally approached preheating values. In contrast, in subepidermal tumours 40 degrees C hyperthermia on the average induced a slight decrease of the flux. During 42 degrees C hyperthermia a significant flow decrease was found after 40 min of heating. Following a transient increase in the laser Doppler flow during the heating-up period, 44 degrees C hyperthermia led to a significant impairment of the flux after 24 min. A total shutdown of RBC flux was observed in about 30 per cent of the tumours at 44 degrees C. Upon elevated tissue temperatures, pronounced inter-tumour variabilities in the time- and temperature-dependent changes of RBC flux were observed. Rhythmic oscillations of the RBC flux were found in some subepidermal tumours (0.40 +/- 0.05 cycles/min). Upon heating, these periodic flow variations slowed down significantly (0.20 +/- 0.04 cycles/min), whereas in normal skin the frequency of the flow fluctuations increased.
- Published
- 1988
19. Microcirculatory and pH Alterations in Isotransplanted Rat and Xenotransplanted Human Tumors Associated with Hyperthermia
- Author
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Matthew A. Kluge, Peter Vaupel, H. P. Fortmeyer, E. Egelhof, and F. Kallinowski
- Subjects
Hyperthermia ,medicine.medical_specialty ,Chemistry ,Cell ,Hypoxia (medical) ,medicine.disease ,In vitro ,Microcirculation ,Endocrinology ,medicine.anatomical_structure ,In vivo ,Internal medicine ,medicine ,Cancer research ,Radiosensitivity ,medicine.symptom ,Cytotoxicity - Abstract
The rationale for considering the use of hyperthermia as an antitumor agent is based on three different mechanisms of action depending on the hyperthermia levels chosen: At moderate hyperthermia levels (40°–42.5° C) heat can increase the radiosensitivity and/or the chemosensitivity. At higher tissue temperatures ( > 42.5° C) hyperthermia acts as a cytotoxic agent since mammalian cells die after heating in a temperature-, time-, and cell cycle-dependent manner. Besides direct effects on the cell membranes, on the cytoskeleton, on metabolic processes, on DNA replication, and on RNA and protein synthesis, indirect effects distinctly modulating the anticancer action of heat have to be considered. These indirect effects are mostly mediated through the cellular microenvironment, both for in vitro and for in vivo conditions. In most solid tumors, this microenvironment is characterized by hypoxia and even anoxia, acidosis, and energy deprivation, which are known to enhance the heat effect even under in vitro conditions. These characteristic features of the cellular microenvironment are mostly determined by tumor microcirculation. It is generally accepted that nutritive blood flow in most tumors is heterogeneously distributed and on the average insufficient at larger tumor sizes. This flow pattern in solid tumors has two relevant consequences: 1. It induces the hostile microenvironment described, thus rendering the tumor cells in vivo more heat sensitive as compared with normal tissues. 2. It limits the heat dissipation from the tumor tissue and thus the energy input required to reach a therapeutic tissue temperature level. The latter fact often implies the possibility of a relatively selective heating of the tumor tissue.
- Published
- 1988
20. Pathophysiology of Tumors in Hyperthermia
- Author
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F. Kallinowski, Peter Vaupel, and Matthew A. Kluge
- Subjects
Hyperthermia ,business.industry ,In vivo ,Cancer research ,Medicine ,Distribution (pharmacology) ,Context (language use) ,Blood flow ,business ,medicine.disease ,Pathophysiology ,In vitro ,Microcirculation - Abstract
The response of tumor cells to hyperthermia is critically influenced by a number of pathophysiological factors both in vitro and in vivo. The most relevant factors in this context are tumor blood flow, tissue oxygenation, the energy status, and the pH distribution, which in turn define the cellular microenvironment.
- Published
- 1988
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