Detecting Endothelial Dysfunction in Renal Failure
Principal Investigator: Julian Stewart
Abstract: [unreadable] DESCRIPTION (provided by applicant): Cardiovascular complications of endothelial cell dysfunction (ECD) have emerged as the most serious life threatening accompaniment of end-stage renal disease (ESRD). Macrovascular detection of ECO using, ultrasound measures of flow mediated dilation (FMD) in brachial arteries or invasive measures may not relate to globally pervasive microvascular ECD underlying progressive cardiovascular disease (CVD). Based on observations from the literature, we developed cutaneous laser-Doppler flowmetry methods combined with localized thermal hyperemia measurements which can distinguish among controls and ESRD patients with known ECD, and can detect clinically silent ECD. We hypothesize that the latter patients and indeed many patients with advance chronic kidney disease (CKD) are at increased risk for developing clinical manifestations of CVD. Using local forearm thermal hyperemia (heating to 41 degrees C) and point laser-Doppler monitor for time dependence and laser Doppler perfusion imaging (scanner) for spatial dependence, we will define patterns and parameters of cutaneous flow which relate closely to nitric oxide (NO) bioavailability and therefore to microvascular endothelial function. To test these hypotheses we will study the relation of local thermal responses in control, in ESRD, and in CKD (K/DOQI3 and 4) subjects. Using intradermal microdialysis we will obtain a dose-response to the NOS inhibitor nitro-L-arginine (NLA), with and without prostaglandin inhibition with ketorolac. We will specifically test the hypothesis that abnormal laser-Doppler hyperemia measurements reflect abnormal NO bioavailability in ESRD and CKD patients with and without evident CVD. We will compare cutaneous microvascular parameters of ECD to FMD responses using ultrasound and standard reactive hyperemia flow stimuli. We will study the clinical predictive value of laser-hyperemia based ECD testing for the development of CVD in ESRD and CKD patients without evident cardiovascular disease or diabetes. The research will demonstrate our ability to noninvasively monitor ECD in ESRD and CKD, and to make clinical predictions based on ECD results. These data will form the basis of future noninvasive prognostic testing and treatment of patients at risk for ECD and can provide a means to follow treatment modalities. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-04-01 - 2009-03-31
more information: NIH RePORT
- Laser Doppler flowmetry detection of endothelial dysfunction in end-stage renal disease patients: correlation with cardiovascular riskA Kruger
Department of Medicine, New York Medical College, Valhalla, New York 10595, USA
Kidney Int 70:157-64. 2006..In conclusion, LDF parameters of microvascular reactivity offer a sensitive characterization of endothelial dysfunction, which may improve CV risk assessment through incorporation into the Framingham or Cardiorisk algorithm...
- Noninvasive measure of microvascular nitric oxide function in humans using very low-frequency cutaneous laser Doppler flow spectraJulian M Stewart
New York Medical College, Valhalla, New York, USA
Microcirculation 14:169-80. 2007..0095-0.021 Hz) do not. The authors investigated whether VLF LDF power is nitric oxide (NO) specific...
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Department of Medicine, Renal Research Institute, New York Medical College, Valhalla, NY, USA
Nephrol Dial Transplant 22:3521-6. 2007..It is becoming clear that testing functions of the vascular endothelium in conjunction with various biomarkers may better the definition of CV risk profile in CKD patients...
- Cutaneous neuronal nitric oxide is specifically decreased in postural tachycardia syndromeJulian M Stewart
The Center for Pediatric Hypotension, New York Medical College, Ste 3050, 19 Bradhurst Ave, Hawthorne, NY 10532, USA
Am J Physiol Heart Circ Physiol 293:H2161-7. 2007..The data suggest that nNO activity but not NO of endothelial NOS origin is reduced in low-flow POTS...
- Intradermal angiotensin II administration attenuates the local cutaneous vasodilator heating responseJulian M Stewart
New York Medical College, Hawthorne, NY 10532, USA
Am J Physiol Heart Circ Physiol 295:H327-34. 2008..ANG II mediates the AT(1)R blunting of local heating, which is not exclusively NO dependent, and is improved by antioxidant supplementation...
- Nitric oxide and prostaglandin inhibition during acetylcholine-mediated cutaneous vasodilation in humansMarvin S Medow
Department of Pediatrics, New York Medical College, Valhalla, New York 10532, USA
Microcirculation 15:569-79. 2008..These data suggest that cutaneous acetylcholine-mediated endothelium-dependent vasodilation is highly NO-dependent and is also strongly related to the interactions of NO with prostaglandins...