Biomedical subjects

Rajesh K Kharbanda

Publications and source records attributed to Rajesh K Kharbanda.

9 recordsLinked to original sources

PubMed2006

Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans.

OBJECTIVES: We conducted a randomized controlled trial of the effects of remote ischemic preconditioning (RIPC) in children undergoing repair of congenital heart defects. BACKGROUND: Remote ischemic preconditioning reduces injury caused by ischemia-reperfusion in distant organs. Cardiopulmonary bypass (CPB) is associated with multi-system injury. We hypothesized that RIPC would modulate injury induced by CPB. METHODS: Children undergoing repair of congenital heart defects were randomized to RIPC or control treatment. Remote ischemic preconditioning was induced by four 5-min cycles of lower limb ischemia and reperfusion using a blood pressure cuff. Measurements of lung mechanics, cytokines, and troponin I were made pre- and postoperatively. RESULTS: Thirty-seven patients were studied. There were 20 control patients and 17 patients in the RIPC group. The mean age and weight of the RIPC and control patients were not different (0.9 +/- 0.9 years vs. 2.2 +/- 3.4 years, p = 0.4; and 6.9 +/- 2.9 kg vs. 11.5 +/- 10 kg, p = 0.06). Bypass and cross-clamp times were not different (80 +/- 24 min vs. 88 +/- 25 min, p = 0.3; and 55 +/- 13 min vs. 59 +/- 13 min, p = 0.4). Levels of troponin I postoperatively were greater in the control patients compared with the RIPC group (p = 0.04), indicating greater myocardial injury in control patients. Postoperative inotropic requirement was greater in the control patients compared with RIPC patients at both 3 and 6 h (7.9 +/- 4.7 vs. 10.9 +/- 3.2, p = 0.04; and 7.3 +/- 4.9 vs. 10.8 +/- 3.9, p = 0.03, respectively). The RIPC group had significantly lower airway resistance at 6 h postoperatively (p = 0.009). CONCLUSIONS: This study demonstrates the myocardial protective effects of RIPC using a simple noninvasive technique of four 5-min cycles of lower limb ischemia and reperfusion. These novel data support the need for a larger study of RIPC in patients undergoing cardiac surgery.

Child, Preschool↗

PubMed2005

Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism.

BACKGROUND: We assess whether remote ischemic preconditioning (rIPC) of the recipient can modify ischemia-reperfusion (IR) injury in the donor heart following orthotopic heart transplantation from brain dead donors and to examine potential mechanisms of protection. METHODS: Sixteen pigs weighing from 26 to 34.2 (mean 29.2) kg, randomized to control group (n=5), ischemic preconditioning (rIPC) group (n=6), and to receive rIPC with prior glibenclamide administration (Glib + rIPC) group (n=5) underwent orthotopic heart transplantation with the support of hypothermic (32 degrees C) cardiopulmonary bypass (CPB). The hearts were harvested from donor animal rendered brain dead by balloon compression via a craniotomy. Preconditioning of the recipients was induced by four 5-min cycles of lower limb ischemia. Myocardial infarction (MI) was induced following heart transplantation by 30 min of left anterior descending (LAD) artery occlusion following by 2 hr of regional reperfusion. The extent of myocardial infarction was assessed by triphenyltetrazolium (TTC) staining. RESULTS: Preconditioning of the recipient reduced the mass of MI (6.75+/-6.3 g in rIPC vs. 18.1+/-5.8 g in control, P=0.01), MI to area at risk (ARR) mass ratio by 57% (15.6%+/-15.2% vs. 36.3%+/-13.4%, P=0.04). The protective effect of preconditioning was abolished by pretreatment with glibenclamide. CONCLUSIONS: Remote ischemic preconditioning of the recipient, decreases ischemia-reperfusion injury in the brain dead donor heart following orthotopic heart transplantation via a Katp channel-dependent mechanism. This study suggests that a circulating effector persists after the rIPC stimulus is applied, and excludes an ongoing afferent neurogenic mechanism of cardioprotection.

Animals↗

PubMed2005

Systemic Acyl-CoA:cholesterol acyltransferase inhibition reduces inflammation and improves vascular function in hypercholesterolemia.

BACKGROUND: Circulating lipids may initiate and progress atherosclerosis by causing vascular inflammation. Monocytes and tissue macrophages are involved and regulate lipid metabolism in the vascular wall through acetylation of cholesterol by acyl-CoA:cholesterol acyltransferase (ACAT). ACAT inhibition reduces atherosclerosis in animal models by mechanisms that may be independent of their effects on circulating lipids. Because endothelial dysfunction is an important factor in atherosclerosis, we tested the hypothesis that systemic ACAT inhibition would improve endothelial function in hypercholesterolemic humans and assessed its effects on circulating lipids and markers of systemic inflammation. METHODS AND RESULTS: We studied 21 hypercholesterolemic subjects in a double-blind, randomized-crossover, placebo-controlled trial with assessments of circulating lipids, markers of inflammation, resistance-vessel endothelial function (with venous occlusion plethysmography), and conduit-vessel vasoreactivity (brachial artery flow-mediated dilation at baseline and after placebo or treatment with avasimibe 750 mg QDS for 8 weeks. There was a small change in total cholesterol with treatment (326+/-25 to 311+/-22 mg/dL, P=0.04). Circulating tumor necrosis factor-alpha was significantly reduced (4.0+/-0.3 to 3.6+/-0.2 pg/mL, P=0.02); resistance vessel responses to acetylcholine, bradykinin, and verapamil were significantly enhanced; and responses to nitroglycerin and conduit-vessel vasoreactivity were unchanged after ACAT inhibition. CONCLUSIONS: Systemic ACAT inhibition reduces circulating tumor necrosis factor-alpha levels in hypercholesterolemic subjects and improves resistance-vessel endothelial function, with small effects on circulating cholesterol. This may be a novel therapeutic strategy to target vascular inflammation and endothelial dysfunction in atherosclerosis.

Acyl Coenzyme A↗

PubMed2005

Evidence for a significant myocardial contribution to total metabolic burden during hypothermic cardiopulmonary bypass: a study of continuously measured oxygen consumption and arterial lactate levels in pigs.

OBJECTIVE: We assessed the causes of imbalance of oxygen transport by continuously measuring oxygen consumption (VO2) during hypothermic cardiopulmonary bypass (CPB) in pigs. METHODS: Six pigs (17.2+/-1.6 kg) underwent hypothermic (32 degrees C) CPB for 180 min with 120 min of aortic crossclamping (ACC). An AMIS 2000 mass spectrometer was adapted for the on-line measurement of VO2. Arterial lactate was measured at the beginning of CPB, the end of hypothermia, before and 10 min after ACC release, 20 min later, and at the end of CPB. RESULTS: Arterial lactate increased from 1.8+/-0.7 to 5.1+/-1.8 mmol/L during CPB. Hypothermia reduced VO2 by 0.63+/-0.29 mlmin/kg per degrees C, but lactate increased to 4.2+/-1.5 mmol/L (p <0.05). The most rapid rise of VO2 and lactate occurred during the first 10 min after ACC removal, accounting for 26% and 68%, respectively, of the total rise during rewarming. CONCLUSIONS: Inadequate tissue oxygenation persists throughout hypothermic CPB. The rise in systemic VO2 and lactate immediately after ACC release may reflect inadequate oxygen transport within the myocardium during ischemia and manifest on reperfusion. This simple technique may be used to provide important information regarding the dynamic balance of systemic and myocardial oxygen transport during ischemia-reperfusion.

Animals↗

PubMed2004

Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism.

Local and remote ischemic preconditioning (IPC) reduce ischemia-reperfusion (I/R) injury and preserve cardiac function. In this study, we tested the hypothesis that remote preconditioning is memorized by the explanted heart and yields protection from subsequent I/R injury and that the underlying mechanism involves sarcolemmal and mitochondrial ATP-sensitive K(+) (K(ATP)) channels. Male Wistar rats (300-350 g) were randomized to a control (n = 10), a remote IPC (n = 10), and a local IPC group (n = 10). Remote IPC was induced by four cycles of 5 min of limb ischemia, followed by 5 min of reperfusion. Local IPC was induced by four cycles of 2 min of regional myocardial ischemia, followed by 3 min of reperfusion. The heart was excised within 5 min after the final cycle of preconditioning, mounted in a perfused Langendorff preparation for 40 min of stabilization, and subjected to 45 min of sustained ischemia by occluding the left coronary artery and 120 min of reperfusion. I/R injury was assessed as infarct size by triphenyltetrazolium staining. The influence of sarcolemmal and mitochondrial K(ATP) channels on remote preconditioning was assessed by the addition of glibenclamide (10 microM, a nonselective K(ATP) blocker), 5-hydroxydecanoic acid (5-HD; 100 microM, a mitochondrial K(ATP) blocker), and HMR-1098 (30 microM, a sarcolemmal K(ATP) blocker) to the Langendorff preparation before I/R. The role of mitochondrial K(ATP) channels as an effector mechanism for memorizing remote preconditioning was further studied by the effect of the specific mitochondrial K(ATP) activator diaxozide (10 mg/kg) on myocardial infarct size. Remote preconditioning reduced I/R injury in the explanted heart (0.17 +/- 0.03 vs. 0.39 +/- 0.05, P < 0.05) and improved left ventricular function during reperfusion compared with control (P < 0.05). Similar effects were obtained with diazoxide. Remote preconditioning was abolished by the addition of 5-HD and glibenclamide but not by HMR-1098. In conclusion, the protective effect of remote preconditioning is memorized in the explanted heart by a mechanism that involves mitochondrial K(ATP) channels.

Adenosine Triphosphate↗

PubMed2004

Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress.

OBJECTIVES: Our aim was to investigate mechanisms of inflammation-induced endothelial dysfunction in humans. METHODS: Endothelial function in twenty-one healthy human volunteers was measured using forearm venous plethysmography before and 8 h after administration of typhoid vaccination to generate an inflammatory response. Basal and stimulated endothelial nitric oxide (NO) bioavailability was assessed by measurement of the responses to intra-arterial N(G)-monomethyl-l-arginine (l-NMMA) and bradykinin, respectively. The effects of supplementation with l-arginine or ascorbic acid were assessed to probe the effects of substrate deficiency and oxidative stress, respectively. Systemic effects were determined by measuring cytokine response, total anti-oxidant status (TAOS) and urinary protein excretion. RESULTS: Vaccination induced a cytokine response, a fall in total anti-oxidant status and increased urinary albumin excretion (UAE). There was a reduction in the response to bradykinin (BK, P<0.005) and l-NMMA (P<0.0001) with no effect on the response to glyceryl trinitrate (GTN) and norepinephrine (NE). Following vaccination blood flow response to BK (but not GTN) was partially returned to pre-vaccine levels by infusion of ascorbic acid (P=0.01). Supplementation with l-arginine had no effect. CONCLUSION: Inflammation causes widespread endothelial dysfunction, reduces vascular NO bioavailability and increases oxidative stress. These actions are partially reversible with local anti-oxidants. These findings suggest a role for reactive oxygen species in inflammation-induced endothelial dysfunction.

Adult↗

PubMed2004

The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans.

Remote ischemic preconditioning (IPC) reduces tissue injury caused by ischemia-reperfusion (IR) in distant organs. We tested the hypothesis that remote IPC (rIPC) modifies inflammatory gene transcription in humans. Using a microarray method, we demonstrated that a simple model of brief forearm ischemia suppresses proinflammatory gene expression in circulating leukocytes. Genes encoding key proteins involved in cytokine synthesis, leukocyte chemotaxis, adhesion and migration, exocytosis, innate immunity signaling pathways, and apoptosis were all suppressed within 15 min (early phase IPC) and more so after 24 h (second window IPC). Changes in leukocyte CD11b expression measured by flow cytometry mirrored this pattern, with there being a significant (P = 0.01) reduction at 24 h. The results of this study show that the rIPC stimulus modifies leukocyte inflammatory gene expression. This effect may contribute to the protective effect of IPC against IR injury and may have broader implications in other inflammatory processes. This is the first study of human gene expression following rIPC stimulus. rIPC stimulus suppressed proinflammatory gene transcription in human leukocytes.

Adult↗

PubMed2004

Continuous measurement of oxygen consumption during cardiopulmonary bypass: description of the method and in vivo observations.

BACKGROUND: Systemic oxygen consumption is not routinely measured during cardiopulmonary bypass, despite its potential benefits. We aimed to develop a noninvasive method to continuously measure oxygen consumption using respiratory mass spectrometry during hypothermic cardiopulmonary bypass in pigs. METHODS: Nine pigs weighing 18.5 (1.6) kg underwent hypothermic (32 degrees C) cardiopulmonary bypass for 180 minutes with 120 minutes of aortic cross clamping. An AMIS 2000 mass spectrometer (Innovision A/S, Odense, Denmark) was adapted for the on-line measurement of oxygen consumption by sampling the inlet and outlet gases of the membrane oxygenator together with measurement of the "expired" gas volume. RESULTS: Active cooling for 60 minutes reduced the venous blood temperature by 2.9 (0.8) degrees C and VO(2) by 0.70 (0.33) mL/kg/min. The 40-minute active rewarming restored the venous blood temperature by 4.4 (0.4) degrees C and oxygen consumption increased by 1.36 (0.33) mL/kg/min. There was wide interanimal variability, however, particularly at higher venous blood temperatures. Immediately after the release of aortic cross clamp, there was a noticeably acute increase in oxygen consumption in all the pigs (0.64 [0.21] mL/kg/min). CONCLUSIONS: A simple and safe adaptation of mass spectrometry allows continuous measurement of oxygen consumption during hypothermic cardiopulmonary bypass. The wide interindividual variations observed in this pilot study underscore the need to more accurately describe changes in oxygen consumption and how they are affected by temperature, oxygen delivery, and other interventions during cardiopulmonary bypass. As such, the technique may have an important role in clinical research and management of oxygen transport in patients undergoing cardiac surgery.

Animals↗

PubMed2002

Prevention of inflammation-induced endothelial dysfunction: a novel vasculo-protective action of aspirin.

BACKGROUND: Inflammation and infection may initiate and promote atherosclerosis or its complications by adverse effects on the vascular endothelium. The mechanisms by which aspirin reduces cardiovascular risk might involve anti-inflammatory actions or direct effects on the endothelium in addition to its antiplatelet action. We investigated the role of aspirin in modulating endothelial dysfunction induced by an experimental inflammatory stimulus. METHODS AND RESULTS: An inflammatory response was generated in healthy volunteers by Salmonella typhi vaccination. Venous occlusion plethysmography was used to assess resistance vessel responses (16 hours before and 8 hours after vaccination) to the endothelium-dependent dilator bradykinin (BK) and the endothelium-independent dilator glyceryl-trinitrate (GTN). Twelve subjects were randomized to receive either aspirin 1.2 g orally or placebo 2 hours before vaccination. After vaccination alone there was suppression of the response to BK in the placebo group (P=0.01), with no change in response to GTN. In the aspirin group there was no change in the response to either BK or GTN after vaccination. Aspirin treatment prevented vaccine-induced elevation of interleukin-1 receptor antagonist but enhanced the generation of tumor necrosis factor-alpha compared with placebo. In an additional 5 individuals, local intrabrachial aspirin (10 mg/min for 15 minutes) failed to restore responses to BK after vaccination. CONCLUSIONS: Experimental inflammation produces endothelial dysfunction, which can be prevented by pretreatment with aspirin. Locally administered aspirin does not reverse vaccine-induced endothelial dysfunction once established. The protective effects of aspirin on inflammation-induced endothelial dysfunction may be through modulation of the cytokine cascade.

Administration, Oral↗