530

Letters to the Editor

In conclusion, these data provide the first evidence demonstrating that KCNQ/M-currents play an important role in neuroexcitability, especially in myelinated A-type baroreceptor neurons, through modulation of spike afterdepolarization and burst generation. However, the current data do not exclude the potential inhibition of linopirdine on HCN directly [10]. These evidences also indicate that concentration dependent bimodel effects on KCNQ/M-currents were not only observed in retigabine [6], but also confirmed with its antagonist linopirdine, while it is not seen with XE991 from this report. These data highly suggest that higher concentration of the KCNQ/M-channel blocker linopirdine contributes to down-regulation of the neuroexcitability of myelinated A-type baroreceptor neurons through KCNQ and HCN modulation, which is inconsistent with the observation seen in unmyelinated C-types from current data and the data from others [3]. This observation may open a new therapeutic potential, benefit for pharmacological convention, and bring more attentions on adverse reactions while clinically using linopirdine. This project was funded by the research grants from the National Natural Science Foundation of China (30973532; 81173051; 31171122), and partially supported by a research grant from the Ministry of Education of the People's Republic of China (20112307110008), Education Department of Heilongjiang Province (12531252), and research grant from the Heilongjiang Province Youth Science Fund (QC2012C061).

References [1] Hu H, Vervaeke K, Storm JF. M-channels (Kv7/KCNQ channels) that regulate synaptic integration, excitability, and spike pattern of CA1 pyramidal cells are located in the perisomatic region. J Neurosci 2007;27(8):1853–67. [2] Brown RD, Hilliard LM, Head GA, Jones ES, Widdop RE, Denton KM. Sex differences in the pressor and tubuloglomerular feedback response to angiotensin II. Hypertension 2012;59(1):129–35. [3] Wladyka CL, Feng B, Glazebrook PA, Schild JH, Kunze DL. The KCNQ/M-current modulates arterial baroreceptor function at the sensory terminal in rats. J Physiol 2008;586(3):795–802. [4] Jepps TA, Chadha PS, Davis AJ, et al. Downregulation of Kv7.4 channel activity in primary and secondary hypertension. Circulation 2011;124(5):602–11. [5] Lang PM, Fleckenstein J, Passmore GM, Brown DA, Grafe P. Retigabine reduces the excitability of unmyelinated peripheral human axons. Neuropharmacology 2008;54(8):1271–8. [6] Yeung S, Schwake M, Pucovsky V, Greenwood I. Bimodal effects of the Kv7 channel activator retigabine on vascular K+ currents. Br J Pharmacol 2008;155(1):62–72. [7] Wladyka CL, Kunze DL. KCNQ/M-currents contribute to the resting membrane potential in rat visceral sensory neurons. J Physiol 2006;575(Pt 1):175–89. [8] Lu XL, Xu WX, Yan ZY, et al. Subtype identification in acutely dissociated rat nodose ganglion neurons based on morphologic parameters. Int J Biol Sci 2013;9(7):716–27. [9] Li BY, Schild JH. Electrophysiological and pharmacological validation of vagal afferent fiber type of neurons enzymatically isolated from rat nodose ganglia. J Neurosci Methods 2007;164(1):75–85. [10] Han LM, Ban T, Liu Y, et al. Hyperpolarization-activated current-mediated slow afterhyperpolarization in myelinated Ah-type of baroreceptor neurons isolated from adult female rats. Int J Cardiol 2014;172(1):e106–8.

http://dx.doi.org/10.1016/j.ijcard.2014.03.033 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

Remote ischemic preconditioning reduces peri-procedural myocardial injury in elective percutaneous coronary intervention: A meta-analysis Theodoros A. Zografos a, George D. Katritsis b, Demosthenes G. Katritsis a,⁎ a b

Department of Cardiology, Athens Euroclinic, Greece Faculty of Medicine, University of Bristol, Bristol, UK

a r t i c l e

i n f o

Article history: Received 4 January 2014 Accepted 9 March 2014 Available online 15 March 2014 Keywords: Remote ischemic preconditioning Percutaneous coronary intervention Myocardial injury

Elective percutaneous coronary intervention (PCI) is the primary intervention for coronary revascularization in patients with single- or two-vessel coronary artery disease. Even though technical advances in PCI have resulted in a safe procedure with minimal complications, in several patients the procedure is complicated by peri-procedural myocardial injury (PMI), detected by elevated biomarkers of myocardial necrosis [1]. In fact, peri-procedural troponin elevation has been associated with new irreversible PMI, which can be detected by delayed-enhancement magnetic resonance imaging (MRI), and this peri-procedural injury has been associated with worst prognosis [1]. ⁎ Corresponding author at: Athens Euroclinic, 9 Athanasiadou Street, Athens 11521, Greece. Tel.: + 30 2106416600; fax: +30 2106416661. E-mail address: [email protected] (D.G. Katritsis).

One approach in reducing PMI is by utilizing an intrinsic mechanism of cardioprotection termed preconditioning, which is triggered by inducing brief, sub-lethal episodes of ischemia and reperfusion before the sustained ischemic insult [2]. Similar cardioprotection can be achieved through a non-invasive approach by subjecting a remote organ, e.g. the upper limb, to an ischemic stimulus and thereby preconditioning the myocardium, a phenomenon termed remote ischemic preconditioning (RIPC). Several studies have investigated the effects of RIPC before elective PCI, with contradictory results (Table 1) [3–10]. We therefore conducted a meta-analysis of available data to determine whether RIPC before elective PCI reduces PMI. Medline, EMBASE, Scopus, and Cochrane databases were searched independently by two investigators using the following terms: “remote ischemic preconditioning”, “remote preconditioning”, and “percutaneous coronary intervention”. Literature was searched until December 2013 and all found abstracts were screened for eligibility. Eligible trials were those in which patients undergoing PCI were randomly assigned to receive either RIPC, or no RIPC. Full paper manuscripts were obtained from all selected articles based on the assessment of abstracts. References of the retrieved articles were also screened for additional studies. The retrieved studies were examined to eliminate potential duplicates or overlapping data. Primary outcome to be assessed was PMI, detected by troponin elevation at 16 or 24 hours post-PCI. Two authors independently reviewed all full reports that could possibly meet

Letters to the Editor

531

Fig. 1. Forest plot of the relationship between remote ischemic preconditioning and post-procedural myocardial injury.

inclusion criteria. Data on the study population, inclusion and exclusion criteria, control and intervention RIPC protocol, randomization procedure, number of diseased vessels, pre-procedural and post-procedural troponin levels were collected. Results were compared and any disagreements were resolved by consensus. Data heterogeneity was analyzed using the χ2 test with the extent of heterogeneity determined using the I2 statistic. A value of I2 N50% was considered to indicate a high level of heterogeneity. A pooled odds ratio (OR) with its 95% confidence interval (CI) was calculated in a randomeffects model using DerSimonian and Laird's estimator. A significant effect of an intervention was assumed if the 95% CI did not include the value 1.0. All analyses were performed using Review Manager version 5.2.7 software (The Cochrane Collaboration, Copenhagen, DK). Our initial literature search identified 21 studies. After the exclusion of non-relevant studies, reviews and duplicates, 8 studies were retrieved for further consideration and were subsequently included in the metaanalysis. The main characteristics of these studies are shown in Table 1. The total number of patients enrolled in these studies was 1066, comprising 538 patients in the RIPC group and 528 patients in the control group. In most studies RIPC was induced with 3 cycles of 5-minute ischemia and 5-minute reperfusion, whereas in one study 3minute cycles were used. In 2 studies, RIPC was induced with less than 3 ischemia/reperfusion cycles.

According to our analysis, RIPC reduced the incidence of PMI, which occurred in 217 (40.3%) patients in the RIPC group and in 271 (51.3%) patients in the control group (OR 0.57 [95% CI: 0.36, 0.90]; test for overall effect: Z = 2.43 [P b 0.02]) (Fig. 1). Significant heterogeneity was observed between the included studies (χ2 = 16.38, P = 0.02, I2 = 57%). In sensitivity analysis, excluding the studies by Iliodromitis et al. and Prasad et al. from the analysis resulted in significantly decreased heterogeneity (I2 = 48% for excluding either, and I2 = 21% for excluding both studies). In the remaining studies, the effect of RIPC in reducing PMI was more evident (OR 0.48 [95% CI: 0.34, 0.67]; test for overall effect: Z = 4.24 [P b 0.0001]). Our analysis suggests that RIPC can be effective in reducing PMI in the setting of elective PCI. PMI can be expected in up to 50% of elective procedures. According to its pathogenesis it can be categorized into type 1 or proximal type of PMI, which is mainly attributed to sidebranch occlusion during balloon inflation or stent deployment, and type 2 or distal type of PMI, which mainly results from distal embolism of atheromatous material or platelet activation and thrombosis [1]. Since its discovery, 30 years ago, the phenomenon of preconditioning has been consistently shown to reduce myocardial infarct size [2]. Nevertheless, to directly precondition the myocardium, one must be able to predict the timing of sustained ischemia. Therefore, RIPC is ideally implemented in situations where myocardial ischemia can be readily

Table 1 Clinical trials of remote ischemic preconditioning in percutaneous coronary intervention. Reference

Study population

Remote IPC protocol

Incidence of post-PCI myocardial injury Remote IPC group

Iliodromitis et al. [6] Patients with stable angina, positive exercise treadmill test and single-vessel disease, an undefined proportion of patients had increased TnI before PCI Hoole et al. [5] Patients undergoing elective PCI, 17% multivessel disease, negative TnI in all patients before PCI Ghaemian et al. [4] Patients undergoing elective PCI, 44% multivessel disease, 7.5% of patients had increased TnT before PCI Ahmed et al. [3] Patients undergoing elective PCI, 23% multivessel disease, negative TnT in all patients before PCI Luo et al. [7] Patients undergoing elective PCI, 28% multivessel disease, negative TnI in all patients before PCI Prasad et al. [10] Patients undergoing ad hoc PCI for stable CAD or UA, 63% multivessel disease, negative TnT in all patients before PCI Xu et al. [8] Elderly, diabetic patients undergoing elective PCI for stable CAD, undefined proportion with multivessel disease, negative TnI in all patients before PCI Zografos et al. [9] Patients undergoing ad hoc PCI for stable CAD, 24% with multivessel disease, negative TnI in all patients before PCI

3 cycles of 5 min ischemia/5 min reperfusion of both upper limbs 3 cycles of 5 min ischemia/5 min reperfusion of the nondominant arm 2 cycles of 5 min ischemia/5 min reperfusion of the lower limb 3 cycles of 5 min ischemia/5 min reperfusion of the nondominant arm 3 cycles of 5 min ischemia/5 min reperfusion of the nondominant arm 3 cycles of 3 min ischemia/ 3 min reperfusion of the arm 3 cycles of 5 min ischemia/5 min reperfusion of the arm 1 cycle of 5 min ischemia/5 min reperfusion immediately before PCI

TnI, troponin I, PCI, percutaneous coronary intervention; TnT, troponin T; CAD, coronary artery disease; UA, unstable angina. a A TnI cut-off level N1 ng/mL was reported by the authors. b A TnT cut-off level N 0.03 ng/mL was reported by the authors. c A TnI cut-off level ≥0.12 (3 times the upper reference limit) was reported by the authors. d A TnI cut-off level of ≥0.20 (5 times the upper reference limit) was reported by the authors. e A TnT cut-off level N 0.042 (3 times the upper reference limit) was reported by the authors. f Fisher's exact test based on published data.

P

Control group

5/20a

0/21

0.02f

47/104c

53/98

0.23

5/40b

16/40

0.01

12/72

0.097

47/101

72/104

0.001

22/47b

19/48

0.42

76/102c

79/98

0.302

20/47

0.014

e

6/77

c

d

9/47

532

Letters to the Editor

predicted, such as elective PCI. Most of the included studies have demonstrated PMI reduction using RIPC [3–5,7–9], however two studies have produced discrepant results [6,10]. A possible explanation may be that to implement RIPC in a busy cath lab, where most PCIs are conducted ad hoc, Prasad et al. used 3 cycles of 3-minute ischemia/3 minute reperfusion [10]. Since animal models have shown that cardioprotection depends on the duration of transient ischemia, one may hypothesize that 3-minute ischemia was not a sufficient ischemic stimulus to elicit cardioprotection. In the study by Iliodromitis et al., using a Z-test it can be easily calculated that all patients in the RIPC group and 82% of patients in the control group had post-procedural troponin N5 times the mean baseline value (0.04 ng/mL), suggesting that perhaps due to analytical issues, their results may not be directly comparable [6]. In conclusion, the pooled analysis of all available studies suggests that RIPC before elective PCI is effective in reducing PMI. Even though this may not be equivalent to the reduction of major adverse cardiovascular events, RIPC is simple to apply, non-invasive, and virtually cost-free and could be incorporated into clinical practice. References [1] Babu GG, Walker JM, Yellon DM, Hausenloy DJ. Peri-procedural myocardial injury during percutaneous coronary intervention: an important target for cardioprotection. Eur Heart J 2011;32:23–31.

[2] Lim SY, Hausenloy DJ. Remote ischemic conditioning: from bench to bedside. Front Physiol 2012;3:27. [3] Ahmed RM, Mohamed el HA, Ashraf M, et al. Effect of remote ischemic preconditioning on serum troponin T level following elective percutaneous coronary intervention. Catheter Cardiovasc Interv 2013;82:E647–53. [4] Ghaemian A, Nouraei SM, Abdollahian F, Naghshvar F, Giussani DA, Nouraei SA. Remote ischemic preconditioning in percutaneous coronary revascularization: a double-blind randomized controlled clinical trial. Asian Cardiovasc Thorac Ann 2012;20:548–54. [5] Hoole SP, Heck PM, Sharples L, et al. Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) study: a prospective, randomized control trial. Circulation 2009;119:820–7. [6] Iliodromitis EK, Kyrzopoulos S, Paraskevaidis IA, et al. Increased C reactive protein and cardiac enzyme levels after coronary stent implantation. Is there protection by remote ischaemic preconditioning? Heart 2006;92:1821–6. [7] Luo SJ, Zhou YJ, Shi DM, Ge HL, Wang JL, Liu RF. Remote ischemic preconditioning reduces myocardial injury in patients undergoing coronary stent implantation. Can J Cardiol 2013;29:1084–9. [8] Xu X, Zhou Y, Luo S, et al. Effect of remote ischemic preconditioning in the elderly patients with coronary artery disease with diabetes mellitus undergoing elective drug-eluting stent implantation. Angiology 2013, http://dx.doi.org/10.1177/ 0003319713507332. [9] Zografos T, Katritsis G, Korovesis S, Giazitzoglou E, Katritsis D. Remote ischemic preconditioning is feasible in ad hoc percutaneous coronary interventions. Eur Heart J 2013;34(Suppl 1), http://dx.doi.org/10.1093/eurheartj/eht308.1049. [10] Prasad A, Gossl M, Hoyt J, et al. Remote ischemic preconditioning immediately before percutaneous coronary intervention does not impact myocardial necrosis, inflammatory response, and circulating endothelial progenitor cell counts: a single center randomized sham controlled trial. Catheter Cardiovasc Interv 2013;81:930–6.

http://dx.doi.org/10.1016/j.ijcard.2014.03.026 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

Novel MYH7 mutation associated with mild myopathy but life-threatening ventricular arrhythmias and noncompaction☆ Josef Finsterer a,⁎, Claudia Stöllberger b, Oliver Brandau c, Franco Laccone c, Katharina Bichler d, Nigel G Laing e a

Krankenanstalt Rudolfstiftung, Vienna, Austria 2nd Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria c Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria d Landesklinikum Mödling, Sr-M. Restitutagasse 12, A-2340 Mödling, Austria e Centre for Medical Research, University of Western Australia and Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia b

a r t i c l e

i n f o

Article history: Received 4 January 2014 Accepted 9 March 2014 Available online 15 March 2014 Keywords: Cardiac involvement Arrhythmias Implantable cardioverter defibrillator Non-compaction Hypertrabeculation

Myopathy due to MYH7 mutations has been well recognised during recent years [1] and it has been also established that in the majority of the cases the heart is additionally affected [1–6]. Cardiac manifestations of MYH7 myopathies so far reported include hypertrophic cardiomyopathy (hCMP) [6], dilative cardiomyopathy (dCMP) [3,4], restrictive cardiomyopathy (rCMP) [7], arrhythmias [1], or ☆ NGL was supported by Australian National Health and Medical Research Council, Principal Research Fellowship APP1002147. ⁎ Corresponding author at: Postfach 20, 1180 Vienna, Austria. Tel.: +43 1 71165 92085; fax: + 43 1 4781711. E-mail address: fifi[email protected] (J. Finsterer).

sudden cardiac death (SCD) [1]. Left ventricular hypertrabeculation/ noncompaction (LVHT) has been reported only once in association with MYH7 mutations [8,9]. (See Fig. 1.) (See Table 1.) The patient is a 43 year old Caucasian female, height 175 cm, weight 52 kg, who was taking paroxetine and alprazolam because of a reactive depression after a divorce since the age of 32 years. Since the age of 37 years, after the birth of her first son, she recognised recurrent palpitations. At the age of 40 years she experienced recurrent syncopes, initially of unknown origin. Work-up revealed recurrent, mostly selflimiting ventricular tachycardias necessitating cardio-pulmonary resuscitation (CPR) once. Echocardiography revealed LVHT (Fig. 1). No echocardiographies were carried out before the age of 40 years. An implantable cardioverter defibrillator (ICD) was implanted and repeated interrogations since then showed the persistence of ventricular arrhythmias without triggering a discharge so far. In addition to alprazolam and paroxetine, she was regularly taking bisoprolol, enalapril, magnesium, and propafenone. Echocardiography at the age of 42 years revealed a fractional shortening of 21% and confirmed LVHT. LVHT was absent in all other family members who had undergone echocardiography. At the age of 42 years she was found to carry the MYH7 mutation c.5566GNA (p.E1856K), which had been recently detected in her mother, who manifested with a mild distal myopathy since the age of 49 years. At the age of 43 years she underwent an electrophysiologic investigation which could not induce any tachycardia. Reviewing the