Publications by authors named "Luuk C Otterspoor"

17 Publications

  • Page 1 of 1

Ultrastructural Characteristics of Myocardial Reperfusion Injury and Effect of Selective Intracoronary Hypothermia: An Observational Study in Isolated Beating Porcine Hearts.

Ther Hypothermia Temp Manag 2021 Nov 29. Epub 2021 Nov 29.

Department of Cardiology, Catharina Hospital, Eindhoven, The Netherlands.

In acute myocardial infarction (AMI), myocardial reperfusion injury may undo part of the recovery after revascularization of the occluded coronary artery. Selective intracoronary hypothermia is a novel method aimed at reducing myocardial reperfusion injury, but its presumed protective effects in AMI still await further elucidation. This proof-of-concept study assesses the potential protective effects of selective intracoronary hypothermia in an , isolated beating heart model of AMI. In four isolated Langendorff perfused beating pig hearts, an anterior wall myocardial infarction was created by inflating a balloon in the mid segment of the left anterior descending (LAD) artery. After one hour, two hearts were treated with selective intracoronary hypothermia followed by normal reperfusion (cooled hearts). In the other two hearts, the balloon was deflated after one hour, allowing normal reperfusion (control hearts). Biopsies for histologic and electron microscopic evaluation were taken from the myocardium at risk at different time points: before occlusion (t = BO); 5 minutes before reperfusion (t = BR); and 10 minutes after reperfusion (t = AR). Electron microscopic analysis was performed to evaluate the condition of the mitochondria. Histological analyses included evaluation of sarcomeric collapse and intramyocardial hematoma. Electron microscopic analysis revealed intact mitochondria in the hypothermia treated hearts compared to the control hearts where mitochondria were more frequently damaged. No differences in the prespecified histological parameters were observed between cooled and control hearts at t = AR. In the isolated beating porcine heart model of AMI, reperfusion was associated with additional myocardial injury beyond ischemic injury. Selective intracoronary hypothermia preserved mitochondrial integrity compared to nontreated controls.
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http://dx.doi.org/10.1089/ther.2021.0025DOI Listing
November 2021

Diagnostic performance of echocardiography to predict cardiac tamponade after cardiac surgery.

Eur J Cardiothorac Surg 2021 Nov 17. Epub 2021 Nov 17.

Department of Intensive Care, Radboud University Medical Center, Nijmegen, Netherlands.

Objectives: Cardiac tamponade is a life-threatening complication after cardiac surgery. Echocardiography, both transthoracic (TTE) and transesophageal (TEE), may help to identify cardiac tamponade after surgery, but its diagnostic value remains unverified after cardiac surgery.

Methods: This retrospective single-centre cohort study used the electronic medical record and echocardiography database of the Catharina Hospital Eindhoven, a tertiary referral cardiothoracic centre, to identify patients who received echocardiography because they were clinically suspected of having cardiac tamponade within the 4 weeks after cardiac surgery. Overall diagnostic accuracy of both TTE and TEE was calculated (sensitivity, specificity, positive predictive value, negative predictive value, and receiver operation characteristics curves). Subgroup analyses were performed based on the timing of the echocardiography after primary surgery (<24, 24-72, >72 h).

Results: The query identified 427 echocardiographs, 373 TTEs and 54 TEEs, being performed in 414 patients (65% males, mean age 67 years). Of them, 116 patients underwent surgical re-exploration in which a cardiac tamponade was determined in 105 patients with a 30-day mortality of 8.6%. The area under the receiver operation characteristics curve for echocardiography in the 4 weeks after cardiac surgery was 0.78 [95% confidence interval (CI): 0.72-0.84, P < 0.001]. In the first 24 h after surgery was the positive predictive value of echocardiography 58.3% (95% CI: 28.6-83.5) with an area under the curve of 0.64 (95% CI: 0.49-0.80, P = 0.06). The diagnostic accuracy improved over time for both TTE and TEE.

Conclusions: Diagnostic accuracy of echocardiography in the 4 weeks after cardiac surgery for cardiac tamponade is acceptable and improves over time. However, in the early postoperative phase (<24 h), the diagnostic accuracy of echocardiography is poor.
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http://dx.doi.org/10.1093/ejcts/ezab468DOI Listing
November 2021

Safety of Selective Intracoronary Hypothermia During Primary Percutaneous Coronary Intervention in Patients With Anterior STEMI.

JACC Cardiovasc Interv 2021 09 25;14(18):2047-2055. Epub 2021 Aug 25.

Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands. Electronic address:

Objectives: The aim of this study was to determine the safety of selective intracoronary hypothermia during primary percutaneous coronary intervention (PPCI) in patients with anterior ST-segment elevation myocardial infarction (STEMI).

Background: Selective intracoronary hypothermia is a novel treatment designed to reduce myocardial reperfusion injury and is currently being investigated in the ongoing randomized controlled EURO-ICE (European Intracoronary Cooling Evaluation in Patients With ST-Elevation Myocardial Infarction) trial (NCT03447834). Data on the safety of such a procedure during PPCI are still limited.

Methods: The first 50 patients with anterior STEMI treated with selective intracoronary hypothermia during PPCI were included in this analysis and compared for safety with the first 50 patients randomized to the control group undergoing standard PPCI. In-hospital mortality, occurrence of rhythm or conduction disturbances, stent thrombosis, onset of heart failure during the procedure, and subsequent hospital admission were assessed.

Results: In-hospital mortality was 0%. One patient in both groups developed cardiogenic shock. Atrial fibrillation occurred in 0 and 3 patients (P = 0.24), and ventricular fibrillation occurred in 5 and 3 patients (P = 0.72) in the intracoronary hypothermia group and control group, respectively. Stent thrombosis occurred in 2 patients in the intracoronary hypothermia group; 1 instance was intraprocedural, and the other occurred following interruption of dual-antiplatelet therapy consequent to an intracranial hemorrhage 6 days after enrollment. No stent thrombosis was observed in the control group (P = 0.50).

Conclusions: Selective intracoronary hypothermia during PPCI in patients with anterior STEMI can be implemented within the routine of PPCI and seems to be safe. The final safety results will be reported at the end of the trial.
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http://dx.doi.org/10.1016/j.jcin.2021.06.009DOI Listing
September 2021

Hypothermia for Reduction of Myocardial Reperfusion Injury in Acute Myocardial Infarction: Closing the Translational Gap.

Circ Cardiovasc Interv 2021 08 16;14(8):e010326. Epub 2021 Jul 16.

Department of Cardiology, Catharina Hospital, Eindhoven, the Netherlands.

Myocardial reperfusion injury-triggered by an inevitable inflammatory response after reperfusion-may undo a considerable part of the myocardial salvage achieved through timely percutaneous coronary intervention in patients with acute myocardial infarction. Because infarct size is strongly correlated to mortality and risk of heart failure, the importance of endeavors for cardioprotective therapies to attenuate myocardial reperfusion injury and decrease infarct size remains undisputed. Myocardial reperfusion injury is the result of several complex nonlinear phenomena, and for a therapy to be effective, it should act on multiple targets involved in this injury. In this regard, hypothermia remains a promising treatment despite a number of negative randomized controlled trials in humans with acute myocardial infarction so far. To turn the tide for hypothermia in patients with acute myocardial infarction, sophisticated solutions for important limitations of systemic hypothermia should continue to be developed. In this review, we provide a comprehensive overview of the pathophysiology and clinical expression of myocardial reperfusion injury and discuss the current status and possible future of hypothermia for cardioprotection in patients with acute myocardial infarction.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.010326DOI Listing
August 2021

Outcome and Predictors for Mortality in Patients with Cardiogenic Shock: A Dutch Nationwide Registry-Based Study of 75,407 Patients with Acute Coronary Syndrome Treated by PCI.

J Clin Med 2021 May 11;10(10). Epub 2021 May 11.

Heart Center, Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

It is important to gain more insight into the cardiogenic shock (CS) population, as currently, little is known on how to improve outcomes. Therefore, we assessed clinical outcome in acute coronary syndrome (ACS) patients treated by percutaneous coronary intervention (PCI) with and without CS at admission. Furthermore, the incidence of CS and predictors for mortality in CS patients were evaluated. The Netherlands Heart Registration (NHR) is a nationwide registry on all cardiac interventions. We used NHR data of ACS patients treated with PCI between 2015 and 2019. Among 75,407 ACS patients treated with PCI, 3028 patients (4.1%) were identified with CS, respectively 4.3%, 3.9%, 3.5%, and 4.3% per year. Factors associated with mortality in CS were age (HR 1.02, 95%CI 1.02-1.03), eGFR (HR 0.98, 95%CI 0.98-0.99), diabetes mellitus (DM) (HR 1.25, 95%CI 1.08-1.45), multivessel disease (HR 1.22, 95%CI 1.06-1.39), prior myocardial infarction (MI) (HR 1.24, 95%CI 1.06-1.45), and out-of-hospital cardiac arrest (OHCA) (HR 1.71, 95%CI 1.50-1.94). In conclusion, in this Dutch nationwide registry-based study of ACS patients treated by PCI, the incidence of CS was 4.1% over the 4-year study period. Predictors for mortality in CS were higher age, renal insufficiency, presence of DM, multivessel disease, prior MI, and OHCA.
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http://dx.doi.org/10.3390/jcm10102047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151113PMC
May 2021

Vasopressors and Inotropes in Acute Myocardial Infarction Related Cardiogenic Shock: A Systematic Review and Meta-Analysis.

J Clin Med 2020 Jun 30;9(7). Epub 2020 Jun 30.

Heart Center, Department of Interventional Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Vasopressors and inotropes are routinely used in acute myocardial infarction (AMI) related cardiogenic shock (CS) to improve hemodynamics. We aimed to investigate the effect of routinely used vasopressor and inotropes on mortality in AMI related CS. A systematic search of MEDLINE, EMBASE and CENTRAL was performed up to 20 February 2019. Randomized and observational studies reporting mortality of AMI related CS patients were included. At least one group should have received the vasopressor/inotrope compared with a control group not exposed to the vasopressor/inotrope. Exclusion criteria were case reports, correspondence and studies including only post-cardiac surgery patients. In total, 19 studies (6 RCTs) were included, comprising 2478 CS patients. The overall quality of evidence was graded low. Treatment with adrenaline, noradrenaline, vasopressin, milrinone, levosimendan, dobutamine or dopamine was not associated with a difference in mortality between therapy and control group. We found a trend toward better outcome with levosimendan, compared with control (RR 0.69, 95% CI 0.47-1.00). In conclusion, we found insufficient evidence that routinely used vasopressors and inotropes are associated with reduced mortality in patients with AMI related CS. Considering the limited evidence, this study emphasizes the need for randomized trials with appropriate endpoints and methodology.
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http://dx.doi.org/10.3390/jcm9072051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408805PMC
June 2020

A predictive computational model to estimate myocardial temperature during intracoronary hypothermia in acute myocardial infarction.

Med Eng Phys 2019 06 18;68:65-75. Epub 2019 Apr 18.

Department of Biomedical Engineering, Eindhoven University of Technology, The Netherlands.

Hypothermia, if provided before coronary reperfusion, reduces infarct size in animal models of acute myocardial infarction (AMI). Translation to humans has failed so far, because the target temperature is not reached in time within the endangered myocardium using systemic hypothermia method. Hence, a clinically applicable method has been developed to provide intracoronary hypothermia using cold saline, selectively infused locally into the infarct area. In this study, a lumped parameter model has been designed to support the clinical method and to describe this myocardial cooling process mathematically. This model is able to predict the myocardial temperature changes over time, which cannot be measured, based on the temperature and flow of the intracoronary injected cold saline and coronary arterial blood. It was validated using data from an isolated beating porcine heart model and applied on data from patients with AMI undergoing intracoronary hypothermia. In prospect, the computational model may be used as an assistive tool to calculate the patient specific flow rate and temperature of saline required for reliable achievement of the target myocardial temperature in the hypothermia enhanced clinical treatment of AMI.
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http://dx.doi.org/10.1016/j.medengphy.2019.03.011DOI Listing
June 2019

Safety and feasibility of selective intracoronary hypothermia in acute myocardial infarction.

EuroIntervention 2017 12 8;13(12):e1475-e1482. Epub 2017 Dec 8.

Department of Cardiology, Catharina Hospital Eindhoven, Eindhoven, the Netherlands.

Aims: Hypothermia reduces reperfusion injury and infarct size in animal models of acute myocardial infarction if started before reperfusion. Human studies have not confirmed benefit, probably due to insufficient myocardial cooling and adverse systemic effects. This study sought to assess the safety and feasibility of a novel method for selective, sensor-monitored intracoronary hypothermia.

Methods And Results: Ten patients undergoing primary percutaneous coronary intervention (PPCI) were included. Saline at room temperature was administered distal to the culprit lesion through an inflated overthe- wire balloon (OTWB) in order to cool the endangered myocardium for 10 minutes (occlusion phase). Next, the OTWB was deflated and cooling continued with saline at 4°C for another 10 minutes (reperfusion phase). A sensor-tipped temperature wire in the distal coronary artery allowed titration of the infusion rate to achieve the desired coronary temperature (6°C below body temperature). Target coronary temperature was achieved within 27 seconds (median; IQR 21-46). Except for two patients with inferior wall infarction experiencing transient conduction disturbances, no side effects occurred. Systemic temperature remained unchanged. Finally, PPCI was performed as per routine.

Conclusions: Selective hypothermia of the infarct area by intracoronary infusion of saline provides a novel method to reduce coronary temperature quickly and guarantee local myocardial hypothermia. In anterior wall myocardial infarctions, the protocol appeared safe, without serious haemodynamic or systemic side effects. In inferior wall myocardial infarctions, transient conduction abnormalities of short duration occurred. Potentially, selective intracoronary delivery of hypothermia could attenuate reperfusion injury caused by traditional PPCI.
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http://dx.doi.org/10.4244/EIJ-D-17-00240DOI Listing
December 2017

Intracoronary Hypothermia Before Reperfusion to Reduce Reperfusion Injury in Acute Myocardial Infarction: A Novel Hypothesis and Technique.

Ther Hypothermia Temp Manag 2017 Dec 18;7(4):199-205. Epub 2017 May 18.

1 Department of Cardiology, Catharina Hospital , Eindhoven, the Netherlands .

Because current reperfusion strategies in acute myocardial infarction (AMI) seem to be exhausted in terms of additional mortality benefit, there remains a need for new methods to attenuate reperfusion injury and, thereby, further reduce myocardial infarct size and improve long-term survival. Therapeutic hypothermia (32-35°C) diminishes reperfusion injury and reduces infarct size in a variety of animal models of AMI if provided before reperfusion. In human studies this reduction has not been confirmed so far, most likely because systemic cooling acts slowly, and therefore, the target temperature is not reached in time or at all in a substantial number of patients. Furthermore, systemic cooling can cause adverse effects such as severe shivering, volume overload, and an enhanced adrenergic state. In most randomized clinical trials, however, subgroups of patients with anterior myocardial infarction that reached the target temperature before reperfusion did show a reduction in infarct size. To transform therapeutic hypothermia into a clinically feasible treatment for AMI, its method must be modified. An ideal technique should be quick enough to achieve sufficient myocardial hypothermia before reperfusion, without significant delay and without the adverse effects of systemic cooling. In this review, we propose a novel, potentially feasible method of selective intracoronary hypothermia to overcome the problems encountered with prior techniques.
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http://dx.doi.org/10.1089/ther.2017.0006DOI Listing
December 2017

Intracoronary hypothermia for acute myocardial infarction in the isolated beating pig heart.

Am J Transl Res 2017 15;9(2):558-568. Epub 2017 Feb 15.

Department of Cardiology, Catharina Hospital EindhovenEindhoven, The Netherlands; Department of Biomedical Engineering, Eindhoven University of TechnologyThe Netherlands.

Hypothermia may attenuate reperfusion injury and thereby improve acute myocardial infarction therapy. Systemic cooling trials failed to reduce infarct size, perhaps because the target temperature was not reached fast enough. The use of selective intracoronary hypothermia combined with intracoronary temperature monitoring allows for titrating to target temperature and optimizing the cooling rate. We aimed to the test the feasibility of intracoronary cooling for controlled, selective myocardial hypothermia in an isolated beating pig heart. In five porcine hearts the left anterior descending artery (LAD) was occluded by an over-the-wire balloon (OTWB). After occlusion, saline at 22°C was infused through the OTWB lumen for 5 minutes into the infarct area at a rate of 30 ml/min. Thereafter the balloon was deflated but infusion continued with saline at 4°C for 5 minutes. Distal coronary temperature was continuously monitored by a pressure/temperature guidewire. Myocardial temperature at several locations in the infarct and control areas was recorded using needle thermistors. In the occlusion phase, coronary temperature decreased by 11.4°C (range 9.4-12.5°C). Myocardial temperature throughout the infarct area decreased by 5.1°C (range 1.8-8.1°C) within three minutes. During the reperfusion phase, coronary temperature decreased by 6.2°C (range 4.1-10.3°C) and myocardial temperature decreased by 4.5°C (range 1.5-7.4°C). Myocardial temperature outside the infarct area was not affected. In the isolated beating pig heart with acute occlusion of the LAD, we were able to rapidly "induce, maintain, and control" a stable intracoronary and myocardial target temperature of at least 4°C below body temperature without side effects and using standard PCI equipment, justifying further studies of this technique in humans.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340690PMC
February 2017

Coronary angiography after cardiac arrest: Rationale and design of the COACT trial.

Am Heart J 2016 Oct 14;180:39-45. Epub 2016 Jul 14.

Department of Cardiology, VU University Medical Centre, Amsterdam, the Netherlands.

Background: Ischemic heart disease is a major cause of out-of-hospital cardiac arrest. The role of immediate coronary angiography (CAG) and percutaneous coronary intervention (PCI) after restoration of spontaneous circulation following cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) remains debated.

Hypothesis: We hypothesize that immediate CAG and PCI, if indicated, will improve 90-day survival in post-cardiac arrest patients without signs of STEMI.

Design: In a prospective, multicenter, randomized controlled clinical trial, 552 post-cardiac arrest patients with restoration of spontaneous circulation and without signs of STEMI will be randomized in a 1:1 fashion to immediate CAG and PCI (within 2 hours) versus initial deferral with CAG and PCI after neurological recovery. The primary end point of the study is 90-day survival. The secondary end points will include 90-day survival with good cerebral performance or minor/moderate disability, myocardial injury, duration of inotropic support, occurrence of acute kidney injury, need for renal replacement therapy, time to targeted temperature control, neurological status at intensive care unit discharge, markers of shock, recurrence of ventricular tachycardia, duration of mechanical ventilation, and reasons for discontinuation of treatment.

Summary: The COACT trial is a multicenter, randomized, controlled clinical study that will evaluate the effect of an immediate invasive coronary strategy in post-cardiac arrest patients without STEMI on 90-day survival.
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http://dx.doi.org/10.1016/j.ahj.2016.06.025DOI Listing
October 2016

Percutaneous coronary intervention of an iatrogenic occlusion of the circumflex coronary artery after mitral valve replacement.

Eur Heart J Acute Cardiovasc Care 2020 Aug 18;9(5):NP1-NP2. Epub 2015 Dec 18.

Department of Cardiology, Catharina Hospital Eindhoven, The Netherlands.

Occlusion of the circumflex coronary artery by compromising sutures is a serious complication in patients undergoing mitral valve replacement. The majority of such patients have to undergo bypass surgery or redo mitral valve replacement. We report a case of an iatrogenic occlusion of the circumflex coronary artery after mitral valve replacement that was treated by percutaneous coronary intervention.
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http://dx.doi.org/10.1177/2048872615623066DOI Listing
August 2020

Safety and feasibility of local myocardial hypothermia.

Catheter Cardiovasc Interv 2016 Apr 13;87(5):877-83. Epub 2015 Aug 13.

Department of Cardiology, Catharina Hospital, Eindhoven, The Netherlands.

Background: In ST-elevation myocardial infarction (STEMI), reduction in time to reperfusion of the occluded coronary artery reduces infarct size. In animal models, an additional reduction of infarct size was observed when hypothermia was induced before reperfusion, despite a longer ischemic time. However, several human studies did not corroborate this positive effect, which is believed to be in part due to the inability of systemic induced hypothermia to induce sufficient decrease of local myocardial temperature before reperfusion. Providing rapid local myocardial hypothermia by intracoronary infusion of saline before reperfusion in patients with STEMI may overcome this problem. In this study, we evaluate the safety and feasibility of providing rapid intracoronary myocardial hypothermia in patients undergoing intracoronary blood flow measurements based on thermodilution with continuous infusion of saline at room temperature.

Methods And Results: In 53 patients with stable angina (SA) and 20 patients with STEMI, a total of 215 measurements were performed. The measurements consisted of continuous selective intracoronary infusion of saline at room temperature with rates between 10 ml/min and 30 ml/min. Temperature changes compared to initial blood temperature (Tb ) were measured at the tip of the infusion catheter (Ti ) and distally in the coronary artery (Td ). In patients with SA, Ti was -5.65 ± 1.41°C (range -9.27 to -2.28) and Td was -0.78 ± 0.51°C (range -3.27 to -0.23°C). In patients with STEMI, Ti was -7.45 ± 0.51°C (range -8.21 to -6.56) and Td was -1.37 ± 0.82°C (range -4.62 to -0.74°C). In all patients, steady-state intracoronary hypothermia was achieved within 15 sec and could be maintained without noticeable complications.

Conclusion: This study demonstrates the safety and feasibility of inducing intracoronary hypothermia by selective infusion of saline at room temperature in patients with SA and STEMI. Steady-state hypothermia could be achieved and maintained quickly, easily, and safely using common PCI techniques. Therefore, our findings warrant further studies to the use of intracoronary hypothermia to enhance myocardial salvage in acute myocardial infarction.
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http://dx.doi.org/10.1002/ccd.26139DOI Listing
April 2016

Sepsis-related myocardial calcification.

Circ Heart Fail 2011 Sep;4(5):e16-8

Department of Intensive Care, University Medical Centre, Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.111.962183DOI Listing
September 2011

Update on the propofol infusion syndrome in ICU management of patients with head injury.

Curr Opin Anaesthesiol 2008 Oct;21(5):544-51

Department of Intensive Care, University Medical Centre Utrecht, Utrecht, The Netherlands.

Purpose Of Review: The propofol infusion syndrome is a rare condition characterized by the occurrence of lactic acidosis, rhabdomyolysis and cardiovascular collapse following high-dose propofol infusion over prolonged periods of time. Patients with traumatic brain injury are particularly at risk of developing this complication because large doses of propofol are commonly used to control intracranial pressure, whereas vasopressors are administered to augment cerebral perfusion pressure. In this review, we provide an update on the literature with particular emphasis on patients with traumatic brain injury.

Recent Findings: Several new case reports and reviews, as well as a number of experiments, have contributed significantly to our increased understanding of the cause of the syndrome. At the basis of the syndrome lies an imbalance between energy utilization and demand resulting in cell dysfunction, and ultimately necrosis of cardiac and peripheral muscle cells. Uncertainty remains whether a genetic susceptibility exists. Nonetheless, the growing number of case reports has made it possible to identify several risk factors.

Summary: Propofol infusion syndrome is a rare but frequently lethal complication of propofol use. In patients with risk factors, such as traumatic brain injury, it is suggested that an infusion rate of 4 mg/kg per hour should not be exceeded. Early warning signs include unexplained lactic acidosis, lipemia and Brugada-like ECG changes. When these occur, propofol infusion should be discontinued immediately.
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http://dx.doi.org/10.1097/ACO.0b013e32830f44fbDOI Listing
October 2008

Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Circulation 2006 Apr 27;113(13):1650-8. Epub 2006 Mar 27.

Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Background: Mutations in the plakophilin-2 gene (PKP2) have been found in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC). Hence, genetic screening can potentially be a valuable tool in the diagnostic workup of patients with ARVC.

Methods And Results: To establish the prevalence and character of PKP2 mutations and to study potential differences in the associated phenotype, we evaluated 96 index patients, including 56 who fulfilled the published task force criteria. In addition, 114 family members from 34 of these 56 ARVC index patients were phenotyped. In 24 of these 56 ARVC patients (43%), 14 different (11 novel) PKP2 mutations were identified. Four different mutations were found more than once; haplotype analyses revealed identical haplotypes in the different mutation carriers, suggesting founder mutations. No specific genotype-phenotype correlations could be identified, except that negative T waves in V(2) and V(3) occurred more often in PKP2 mutation carriers (P<0.05). Of the 34 index patients whose family members were phenotyped, 23 familial cases were identified. PKP2 mutations were identified in 16 of these 23 ARVC index patients (70%) with familial ARVC. On the other hand, no PKP2 mutations at all were found in 11 probands without additional affected family members (P<0.001).

Conclusions: PKP2 mutations can be identified in nearly half of the Dutch patients fulfilling the ARVC criteria. In familial ARVC, even the vast majority (70%) is caused by PKP2 mutations. However, nonfamilial ARVC is not related to PKP2. The high yield of mutational analysis in familial ARVC is unique in inherited cardiomyopathies.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.105.609719DOI Listing
April 2006
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