Ronit Lavi

The chemokine monocyte chemoattractant protein-1 contributes to renal dysfunction in swine renovascular hypertension.

Renal artery stenosis (RAS) causes renovascular hypertension and renal damage, which may result from tissue inflammation. We have previously shown that the kidney in RAS exhibits increased expression of monocyte chemoattractant protein (MCP)-1, but its contribution to renal injury remained unknown. This study tested the hypothesis that MCP-1 contributes to renal injury and dysfunction in the stenotic kidney. Methods Kidney hemodynamics, function, and endothelial function were quantified in pigs after 10 weeks of experimental RAS (n = 7), RAS supplemented with the MCP-1 inhibitor bindarit (RAS + bindarit, 50 mg/kg/day orally, n = 6), and normal controls (n = 8). Renal inflammation was assessed by the immunoreactivity of MCP-1, its receptor chemotactic cytokine receptor 2, and NFκB, and oxidative stress by nicotinamide adenine dinucleotide phosphate-oxidase expression and in-situ superoxide production. Renal microvascular density was evaluated by micro-CT and fibrosis by trichrome staining, collagen-I immunostaining, and hydroxyproline content. Results After 10 weeks of RAS, blood pressure was similarly elevated in RAS and RAS + bindarit. Compared with normal controls, stenotic RAS kidneys had decreased renal blood flow (5.4 ± 1.6 vs. 11.4 ± 1.0 ml/min/kg, P < 0.05) and glomerular filtration rate and impaired endothelial function, which were significantly improved in bindarit-treated RAS pigs (to 8.4 ± 0.8 ml/min/kg, P < 0.05 vs. RAS). Furthermore, bindarit markedly decreased tubulointerstitial (but not vascular) oxidative stress, inflammation, and fibrosis, and slightly increased renal microvascular density. The impaired renovascular endothelial function, increased oxidative-stress, and fibrosis in the contralateral kidney were also improved by bindarit. Conclusion MCP-1 contributes to functional and structural impairment in the kidney in RAS, mainly in the tubulointerstitial compartment. Its inhibition confers renoprotective effects by blunting renal inflammation and thereby preserving the kidney in chronic RAS.

Remote Ischemic Postconditioning During Percutaneous Coronary Interventions Remote Ischemic Postconditioning–Percutaneous Coronary Intervention Randomized Trial

Background—Remote ischemic preconditioning may result in reduction in infarct size during percutaneous coronary intervention (PCI). It is unclear whether remote ischemic postconditioning (RIPost) will reduce the incidence of myocardial injury after PCI, and whether ischemic conditioning of a larger remote organ (thigh versus arm) would provide further myocardial protection. Methods and Results—We randomized 360 patients presenting with stable or unstable angina (28% of patients) and negative Troponin T at baseline to 3 groups: 2 groups received RIPost (induced by ischemia to upper or lower limb), and a third was the control group. RIPost was applied during PCI immediately after stent deployment, by three 5-minute cycles of blood pressure cuff inflation to >200 mm Hg in the arm or thigh (20 mm Hg in the control) with 5-minute breaks between each cycle. The primary end-point was the proportion of patients with Troponin T levels >3×ULN postprocedure (at 6 or 18–24 hours), where ULN stands for upper limit of normal. A total of 120 patients were randomized to each group. There were no differences in baseline characteristics between the 3 groups. The primary outcome occurred in 30%, 35%, and 35% of the arm, thigh, and control groups, respectively (P=0.64). There were no differences in creatine kinase or high sensitivity C-reactive protein levels after PCI or in the incidence of acute kidney injury between the groups. Conclusions—RIPost during PCI did not reduce the incidence of periprocedural myocardial injury. Similar effect was obtained when remote ischemia was induced to the upper or lower limb. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00970827.

Lumbar Puncture: It Is Time to Change the Needle

Lumbar puncture is a frequent procedure performed by physicians from several disciplines to help establish a diagnosis and treatment for several diseases. Post-lumbar puncture headache (PLPH) is a frequent complication that typically lasts for a couple of days and can be severe enough to immobilize the patient and to require therapy. There are several risk factors identified, pain characteristics, and characteristic findings on spinal and head magnetic resonance imaging. There are several procedural factors that have been identified to be of consequence in attenuating the PLPH incidence, specifically the needle type and size used for this procedure. Once PLPH occurs, the clinician should treat it conservatively with bed rest, analgesics and increased fluids intake, especially caffeine-containing beverages, as it can dramatically affect the patient’s wellness. If the pain is severe and disabling and does not respond to conservative treatment, a blood patch should be considered at least 24–48 h following the LP. Epidural blood patch is a safe and rapidly effective treatment in experienced hands. Furthermore, patients who developed PLPH should be advised to contact the medical staff in case of changes in the characteristics of headaches. When a patient who was diagnosed with PLPH has a change in the pain character, or additional neurological manifestations appear, an urgent brain CT/head MRI should be performed to exclude rarer life-threatening intracranial complications.

Conditioning of the heart: from pharmacological interventions to local and remote protection: possible implications for clinical practice.

Ischemic preconditioning is a natural protective mechanism by which brief episodes of ischemia protect the heart or other organs from the deleterious effects of ischemia-reperfusion injury. Ischemic preconditioning was demonstrated in animals more than 20 years ago, and subsequent studies in humans showed a dramatic protective effect on the heart. This method did not translate into clinical practice partially due to difficulty in application of conditioning. At the same time, multiple drugs were assessed, but none proved to be beneficial in large scale studies for myocardial protection. Although multicenter studies are still lacking, it was recently demonstrated in reasonable sized studies that in patients undergoing percutaneous coronary interventions or suffering from myocardial infarction, remote ischemic conditioning has beneficial protective effect. With more studies we may see translation into clinical practice in the near future.

Monocyte Chemoattractant Proteins Mediate Myocardial Microvascular Dysfunction in Swine Renovascular Hypertension

Background—Monocyte chemoattractant proteins (MCPs) play an important role in mediating inflammatory processes. Hypertension (HTN) is associated with inflammation as well as impaired cardiac microcirculatory function and structure, but the contribution of MCPs to these alterations remained unclear. This study tested the hypothesis that MCPs regulate cardiac microvascular function and structure in experimental HTN. Methods and Results—Pigs (n=6 per group) were studied after 10 weeks of normal, renovascular HTN, or renovascular HTN+ bindarit (MCPs inhibitor, 50 mg/kg/d PO). Left ventricular (LV) function, myocardial microvascular permeability, and fractional vascular volume were assessed by fast computed tomography before and after adenosine infusion (400 &mgr;g/kg/min). Myocardial fibrosis, inflammation, and microvascular remodeling were determined ex vivo. Hypertension was not altered by bindarit, but LV hypertrophy and diastolic function were improved. In response to adenosine, myocardial microvascular permeability increased in HTN (from 0.0083±0.0009 to 0.0103±0.0011 AU, P =0.038 versus baseline) and fractional vascular volume decreased, whereas both remained unchanged in normal and HTN+bindarit pigs. HTN upregulated endothelin-1 expression, myocardial inflammation, and microvascular wall thickening, which were inhibited by bindarit. Conclusions—MCPs partly mediate myocardial inflammation, fibrosis, vascular remodeling, and impaired vascular integrity induced by hypertension. Inhibition of MCPs could potentially be a therapeutic target in hypertensive cardiomyopathy.

Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): a randomized controlled trial

Background: Remote ischemic preconditioning is a simple therapy that may reduce cardiac and kidney injury. We undertook a randomized controlled trial to evaluate the effect of this therapy on markers of heart and kidney injury after cardiac surgery. Methods: Patients at high risk of death within 30 days after cardiac surgery were randomly assigned to undergo remote ischemic preconditioning or a sham procedure after induction of anesthesia. The preconditioning therapy was three 5-minute cycles of thigh ischemia, with 5 minutes of reperfusion between cycles. The sham procedure was identical except that ischemia was not induced. The primary outcome was peak creatine kinase–myocardial band (CK-MB) within 24 hours after surgery (expressed as multiples of the upper limit of normal, with log transformation). The secondary outcome was change in creatinine level within 4 days after surgery (expressed as log-transformed micromoles per litre). Patient-important outcomes were assessed up to 6 months after randomization. Results: We randomly assigned 128 patients to remote ischemic preconditioning and 130 to the sham therapy. There were no significant differences in postoperative CK-MB (absolute mean difference 0.15, 95% confidence interval [CI] −0.07 to 0.36) or creatinine (absolute mean difference 0.06, 95% CI −0.10 to 0.23). Other outcomes did not differ significantly for remote ischemic preconditioning relative to the sham therapy: for myocardial infarction, relative risk (RR) 1.35 (95% CI 0.85 to 2.17); for acute kidney injury, RR 1.10 (95% CI 0.68 to 1.78); for stroke, RR 1.02 (95% CI 0.34 to 3.07); and for death, RR 1.47 (95% CI 0.65 to 3.31). Interpretation: Remote ischemic precnditioning did not reduce myocardial or kidney injury during cardiac surgery. This type of therapy is unlikely to substantially improve patient-important outcomes in cardiac surgery. Trial registration: ClinicalTrials.gov, no. NCT01071265.

Comparison of isoflurane and sevoflurane in cardiac surgery: a randomized non-inferiority comparative effectiveness trial

PurposeVolatile anesthetics possess cardioprotective properties, but it is unknown if the cardioprotective effects extend equally to all members of the class. Although sevoflurane is a relatively newer anesthetic than isoflurane, its introduction into practice was not preceded by a head-to-head comparison with isoflurane in a trial focusing on clinically important outcomes. Our objective was to determine whether sevoflurane was non-inferior to isoflurane on a clinically important primary outcome in a heterogeneous group of adults undergoing cardiac surgery.MethodsThis was a pragmatic randomized non-inferiority comparative effectiveness clinical trial in 464 adults having coronary artery bypass graft and/or single valve surgery during November 2011 to March 2014. The intervention was maintenance of anesthesia with sevoflurane (n = 231) or isoflurane (n = 233) administered at a dose of 0.5-2.0 MAC throughout the entire operation. All caregivers were blinded except for the anesthesiologist and perfusionist. The primary outcome was a composite of intensive care unit (ICU) length of stay ≥ 48 hr and all-cause 30-day mortality. We hypothesized that sevoflurane would be non-inferior to isoflurane (non-inferiority margin < 10% based on an expected event rate of 25%). Secondary outcomes included prolonged ICU stay, 30- and 365-day all-cause mortality, inotrope or vasopressor usage, new-onset hemodialysis or atrial fibrillation, stroke, and readmission to the ICU.ResultsNo losses to follow-up occurred. The primary outcome occurred in 25% of sevoflurane patients and 30% of isoflurane patients (absolute difference, −5.4%; one-sided 95% confidence interval, 1.4), thus non-inferiority was declared. Sevoflurane was not superior to isoflurane for the primary outcome (P = 0.21) or for any secondary outcomes.ConclusionSevoflurane is non-inferior to isoflurane on a composite outcome of prolonged ICU stay and all-cause 30-day mortality. Sevoflurane is not superior to isoflurane on any other of the clinically important outcomes. This trial was registered at clinicaltrials.gov; NCT01477151.RésuméObjectifLes agents anesthésiques volatils possèdent des propriétés cardioprotectrices, mais nous ne savons pas si ces effets cardioprotecteurs sont équivalents pour tous les agents de cette classe. Bien que le sévoflurane soit un anesthésique plus récent que l’isoflurane, son introduction dans notre pratique n’a pas été précédée par une comparaison directe à l’isoflurane dans une étude s’intéressant à d’importants critères d’évaluation cliniques. Notre objectif était de déterminer si le sévoflurane était non inférieur à l’isoflurane en relation à un critère d’évaluation principal important d’un point de vue clinique dans un groupe hétérogène d’adultes subissant une chirurgie cardiaque.MéthodeNous avons réalisé une étude clinique randomisée et pragmatique d’efficacité comparative et de non-infériorité auprès de 464 adultes subissant des pontages coronariens et/ou une chirurgie valvulaire unique entre novembre 2011 et mars 2014. L’intervention consistait en le maintien de l’anesthésie à l’aide de sévoflurane (n = 231) ou d’isoflurane (n = 233) administré à une dose de 0,5-2,0 MAC tout au long de l’opération. Aucun intervenant ne connaissait l’agent utilisé, à l’exception de l’anesthésiologiste et du perfusionniste. Le critère d’évaluation principal était une composée de la durée de séjour à l’unité de soins intensifs (USI) ≥ 48 h et de la mortalité, toutes causes confondues, à 30 jours. Nous avons émis l’hypothèse que le sévoflurane ne serait pas inférieur à l’isoflurane (marge de non-infériorité < 10 % sur la base d’un taux de complications attendu de 25 %). Les critères d’évaluation secondaires comprenaient un séjour prolongé à l’USI, la mortalité toutes causes confondues à 30 et à 365 jours, l’utilisation d’inotropes ou de vasopresseurs, une hémodialyse ou une fibrillation auriculaire nouvelles, un accident vasculaire cérébral et une réadmission à l’USI.RésultatsNous n’avons perdu aucun patient au suivi. Le critère d’évaluation principal est survenu chez 25 % des patients ayant reçu du sévoflurane et 30 % des patients ayant reçu de l’isoflurane (différence absolue, −5,4 %; intervalle de confiance unilatéral 95 %, 1,4): la non-infériorité a donc été déclarée. Le sévoflurane n’était pas supérieur à l’isoflurane en ce qui touchait au critère d’évaluation principal (P = 0,21) ou aux critères d’évaluation secondaires.ConclusionLe sévoflurane n’est pas inférieur à l’isoflurane selon un critère d’évaluation composé d’une durée de séjour prolongée à l’USI et de la mortalité toutes causes confondues à 30 jours. Le sévoflurane n’est pas supérieur à l’isoflurane en ce qui touche à n’importe quel autre critère clinique important. Cette étude a été enregistrée au ClinicalTrials.gov, numéro NCT01477151.

Perioperative Management of Antiplatelet Agents in Patients Undergoing Cardiac Surgery

c SURGICAL REVASCULARIZATION for coronary artery disease is one of the most common surgeries performed. ith constant aging of the world’s population and the increase n the number and complexity of percutaneous coronary interentions (PCIs), there is a shift toward performing coronary rtery bypass graft (CABG) surgery among an elderly and icker patient population. To reduce the risk of cardiovascular vents in these higher-risk patients, there is a need for more ntensive medical therapy, including the use of antiplatelet gents. The caveat is that these patients are also at an increased isk for adverse events and complications related to medical herapy. Antiplatelet medications are the most important drug therapy or patients with acute and chronic cardiovascular disease.1,2 Although their use has proven to be beneficial in reducing cardiovascular events, the administration of these medications also is associated with an increased risk of bleeding, which is an important factor in cardiovascular outcome.3,4 Because antiplatelet agents commonly are used in patients undergoing cardiovascular surgery, bleeding often occurs in these patients during the perioperative period, which significantly affects morbidity and mortality, reoperation rates, blood transfusions, intensive unit and in-hospital length of stay, and the incidence of associated complications. With the recent introduction of newer and more potent antiplatelet agents, it is particularly important to have clear guidelines for the use of these medications in patients undergoing cardiac surgery during the perioperative period.

Effect of Ticagrelor Versus Clopidogrel on Vascular Reactivity

Ticagrelor has shown superiority compared with clopidogrel in reducing cardiovascular events [(1)][1]. Although some of the clinical benefits of ticagrelor may simply reflect its potency in inhibiting platelet aggregation, the action of this drug on blood vessels may also play a role. Ticagrelor

Remote ischaemic conditioning before exercise: are we there yet?

In recent years we have witnessed substantial progress in the treatment of patients with ischaemic heart disease. Interventional techniques are improving and medical therapy is more effective. In particular, there has been dramatic progress in the treatment of patients with ST elevation myocardial infarction. These patients are being treated effectively by primary percutaneous coronary interventions, restoring flow to the ischaemic heart tissue, together with intensive medical treatment. However, in spite of this progress, ischaemia-reperfusion injury and its consequences remain a significant issue. Agents that were thought to be cardioprotective, including antioxidants and anti-inflammatory agents as well as adenosine, have not proved to be effective.1 There are some encouraging results from small studies,2 but so far none of the large trials has shown a beneficial effect of any medication in reducing ischaemia-reperfusion injury. In contrast, the results of studies involving ischaemic conditioning have shown a more powerful effect than individual medications that target only one pathway. Ischaemic conditioning is an innate protective phenomenon by which brief episodes of ischaemia protect the organs from prolonged and potentially lethal ischaemia. Ischaemic conditioning was found to be effective in different organs, but its potential to protect the heart is probably …