Prevention of ventricular arrhythmia complicating acute myocardial infarction by local cardiac denervation

International Journal of Cardiology 184 (2015) 667–673

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Prevention of ventricular arrhythmia complicating acute myocardial infarction by local cardiac denervation Jugang Chen a,1, Min Li b, Yanwei Yu a,1, Xiuli Wu a,1, Rui Jiang a,1, Yingying Jin a,1, Jingjie Li a,⁎,1 a b

Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, PR China Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

a r t i c l e

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Article history: Received 15 October 2014 Received in revised form 27 December 2014 Accepted 3 March 2015 Available online 5 March 2015 Keywords: Coronary sinus Denervation Acute myocardial infarction Ventricular electrical instability Ventricular arrhythmia

a b s t r a c t Background: Augmentation of sympathetic nerve activity after acute myocardial infarction (AMI) contributes to fatal arrhythmia. In this study, we investigated whether local ablation of the coronary sinus (CS) and great cardiac vein (GCV) peripheral nerves could reduce ventricular arrhythmias (VA) in a canine AMI model. Methods: Twenty-one anesthetized dogs were randomly assigned into the sham-operated, MI and MI-ablation groups, respectively. The incidence and duration of VA were monitored among different groups. The ventricular effective refractory period (ERP), the ERP dispersion and the ventricular fibrillation threshold (VFT) were measured during the experiments. Norepinephrine (NE) levels in CS blood and cardiac tissue were also detected in this study. Results: The incidence and duration of VA in MI-ablation group were significantly reduced as compared to the MI dogs (p b 0.05). Furthermore, local cardiac denervation drastically prolonged the ventricular ERP in the ischemia area, decreased the ERP dispersion, and reduced NE levels in CS blood (P b 0.05). VFT also showed an increased trend in the AMI-ablation group. Conclusions: The results of this study indicate that, in the canine AMI model, local ablation of CS and GCV peripheral nerves reduces VA occurrence and improves ventricular electrical stability with no obvious effects on heart rate, mean arterial pressure and infarct size. This study suggests that local cardiac denervation may prevent ventricular arrhythmias complicating AMI. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Ventricular arrhythmia (VA) is a common complication of acute myocardial infarction (AMI), and primary VA is a major cause of sudden cardiac death (SCD) in AMI patients [1–5]. Prevention and management of primary VA after AMI is a key regimen to decrease SCD incidence. However, in terms of the overall survival rate, antiarrhythmic drugs fail to prevent VA-induced SCD in patients without an ICD (implantable cardioverter defibrillator) [6–8]. Novel methodologies are needed to prevent the occurrence of VA complicating AMI. Beta-blockers significantly improve outcome of AMI patients partially due to inhibiting sympathetic nerve activity [9–12]. This suggests that the sympathetic nervous system might play an important role in the genesis and maintenance of VA in AMI patients. Direct inhibition of sympathetic nerve activity, for instance, by renal denervation or high thoracic epidural anesthesia, drastically decreases VA incidence after AMI in animal models and in clinical patients [13–16]. These studies

⁎ Corresponding author at: Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, 23Youzheng Street, Nangang District, Harbin 150001, PR China. E-mail address: [email protected] (J. Li). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

http://dx.doi.org/10.1016/j.ijcard.2015.03.057 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.

indicate that, in beta-blocker intolerant or contraindicated patients, denervation is an alternative approach to prevent VA occurrence. Although inhibition of autonomous nerve fibers at sites far from the heart clearly shows anti-arrhythmia effects, the potential damage to other organs limits its application in clinical practice. To overcome the limitations of previous methodologies, in this study, we tested whether local ablation of cardiac sympathetic nerves reduces VA incidence after AMI. In humans and animals, major sympathetic nerve fibers course toward the heart alongside the great vessels, and cross over the coronary sinus (CS) [17–19]. Using the canine AMI model, we directly ablated the CS and GCV peripheral nerves with radiofrequency ablation. Local cardiac denervation was found to significantly reduce VA occurrence and improved ventricular electrical stability without obvious effects on heart rate, mean arterial pressure and ischemia area. 2. Materials and methods 2.1. Experimental animals Mongrel dogs of both sexes were obtained from the experimental animal center at the First Affiliated Hospital, Harbin Medical University, China. All experimental protocols were approved by the Animal

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Experimentation Ethics Committee under the declaration of Helsinki and the guiding principles in the care and use of animals. Twenty-one dogs, weighing between 15 and 25 kg, were anesthetized with sodium pentobarbital (25 mg/kg induction; 1.0 mg/kg/h with intermittent boluses, as needed), and then intubated and mechanically ventilated (Electrical Animal Ventilator, Medical Equipment Factory, Shanghai, China) to maintain the arterial pCO2 between 35 and 40 mm Hg. Fluid resuscitation was established with 0.9 N NaCl at 10 ml/kg/h. The systemic arterial pressure was monitored during the experiment with a computer-based Lab System (GY-6328, Huanan Inc., China). The core body temperature of the animals was maintained at 36.5 ± 1.5 °C with heating pads. 2.2. Generation of myocardial infarction and local ablation of cardiac sympathetic nerves Twenty one animals were randomly assigned into the groups of sham-operated (n = 5), myocardial infarction (MI, n = 8) and myocardial infarction followed by nerve ablation (MI-ablation, n = 8). To establish AMI in both MI and MI-ablation group, the left anterior descending coronary artery (LAD) was permanently ligated just below the first diagonal branch by the one-stage procedure in open-chest and anesthetized dogs [20]. The animals in sham-operated group also underwent thoracotomy and pericardiotomy, but not coronary artery ligation. After successfully creating AMI, we gave the animals a 90-minute interval to recover. The dogs in the MI-ablation group then further underwent cardiac nerve ablation. The ablation sites were determined by the anatomical distribution of autonomic nerves along the CS (the distal CS, proximal 2 cm from the coronary sinus ostium) and the GCV (upper third anterior interventricular groove). To avoid potential damage to the proximal left anterior descending (LAD) and left circumflex (LCX) arteries, which distribute in the target area, the ablation sites were also chosen 0.5 cm away from these arteries. The radiofrequency (RF) energy of a cardiac ablation generator (IBI—1500T8,Irvine Biomedical Inc., USA) was set to 20 W with a cut-off temperature at 60 °C, and a saline irrigation catheter (7-F, 4.0-mm tip electrode, Irvine Biomedical Inc. USA) was applied to ablate the nerves for 2 min at both sides of the CS and GCV, respectively. An open irrigation system was set to continuously irrigate the ablation catheter at 40–60 mL/min during radiofrequency delivery. 2.3. Electrophysiological study Electrocardiogram (ECG) was recorded in all dogs during experiment to determine the incidence and duration of VA, including

ventricular premature contraction (VPC), paroxysmal ventricular tachycardia (PVT) and spontaneous VF. Before creating the MI and 2 h after cardiac denervation, multielectrode catheters with a 2 mm interelectrode distance were sutured to record the effective refractory period (ERP) of the ventricular myocardium at 6 epicardial sites. These sites were equally split into three groups which distributed respectively in the ischemia area (IA, below the first diagonal branch artery), the ischemia border area (IBA, the peripheries of the ischemia area) and the ischemia remote area (IRA, around the upper apex) (Fig. 1A). For comparison, in the shamoperated dogs which did not undergo cardiac infarction, electrodes were put on the same epicardial sites as in the MI and MI-ablation dogs. Programmed electrical stimulation was performed to measure the ERP and to induce VF threshold (VFT) in all animals. Briefly, we used an 8-beat drive train (S1, 300-ms cycle length) followed by an extra stimulus (S2), and then repeated this procedure with progressively shorter S1–S2 intervals (from 250 ms to ventricular ERP). Ventricular ERP was defined as the longest S1–S2 interval that failed to capture the ventricles. The ERP dispersion was computed as coefficient of variation (CV, standard deviation/mean) of the ERPs at all six recording sites, and the ERP dispersion was also expressed as CV-ERP [21,22]. The VFT, the minimum voltage to induce sustained VF, was determined in the dogs without spontaneous VF [21]. VF was induced at the same heart rate (200 beats/min) among animals. Followed by a 20beat drive train with a pacing cycle length of 300 ms, 100 ms S1–S1 stimuli were repeatedly applied to the right ventricular apex with an increase of stimuli intensity by 2 V each time until VF was induced. Each stimulus lasted for 10 second and was followed by a 30-second rest period before the next round of stimulation. Once a sustained VF was induced, a cardiac electric defibrillator was used to shock the heart back to normal rhythm. After a 5-minute break, the stimulation protocol was repeated to measure the second VFT. The measurements of both times were averaged as mean VFT. At the end of the experiment, all dogs died of sustained VF. 2.4. Measurement of plasma and tissue homogenates Norepinephrine (NE) Two hours after the ablation, blood samples were drawn into heparinized tubes through a modified Morawitz cannula, which was introduced into the CS through the azygos vein. All samples were placed immediately on ice after collection and centrifuged at 4 °C within 30 min. Plasma was collected and stored at −20 °C for further analysis. At the end of the experiment, ventricle tissues at the 6 epicardial electrode sites were harvested and analyzed separately. 100 mg tissue was rinsed with PBS to remove excess blood, homogenized in PBS and stored overnight at −20 °C. After two freeze–thaw cycles to break the cell membrane, the homogenates were centrifuged for 5 min at 5000 g at 4 °C, and the supernatant was collected and stored at −20 °C.

Fig. 1. A sketch of the anterior (A) and posterior (B) of a dog heart to show ablation targets, multi-electrodes, ischemia area, coronary artery and coronary sinus and its tributaries. AT, ablation target; IA, ischemia area; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; CS, coronary sinus; GCV, great cardiac vein; MCV, middle cardiac vein; SCV, small cardiac vein; LASV, left atrium slanting veins; VPVSC, vena posterior ventriculi sinistri cordis.

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Fig. 2. Immunohistochemical staining of tyrosine hydroxylase (TH) of the cardiac sympathetic nerve fibers around the coronary sinus (CS) and the great cardiac vein (GCV) (×200) in the sham-operated (A), MI (B) and MI-ablation group (C). TH positive nerve fibers are shown brown and located between myofibrils.

NE levels in plasma and tissue homogenates were measured with a Dog Norepinephrine ELISA Kit (Cusabio Biotech Co., China) according to the manufacturer's instructions [23]. 2.5. Histology immunohistochemistry At the end of the experiment, the hearts were quickly collected from 2 dogs in each group. Tissues around the CS and GCV were immediately fixed for 24 h in 4% paraformaldehyde, and were embedded in paraffin.

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4 μm transmural sections were cut perpendicularly to the epicardium and mounted onto slides. Immunohistological staining was carried out according to standard procedures. Briefly, paraffin sections were deparaffinized and rehydrated, and the antigen was retrieved with Target Unmasking Fluid (Advanced Technology & Industrial Co., Hong Kong) according to the manufacturer's protocol. Sections were incubated overnight at 4 °C with tyrosine hydroxylase (TH) antibody (1:1000, Abcam Ltd., Hong Kong), and then with IgG-HRP (Zsbio,China) for 15 min at room temperature. The immunoreactive products were

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Fig. 3. The density of TH-positive nerve fibers around the CS (A) and GCV (B) in the sham-operated, MI and MI-ablation group. CS, coronary sinus; GCV, great cardiac vein. *p b 0.05 compared with the MI group; #p b 0.05 compared with the Sham-operated group.

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Table 1 The incidence and duration of ventricular arrhythmias, and VFT in the three different groups.

VPC episodes VT episodes PVT (duration, s) Spontaneous VF episodes (%) VFT (V)

Images Advanced 3.2 software and expressed as the nerve area divided by the total area examined (μm2/mm2).

Sham-operated group

MI group

MI-ablation group

2.6. Measurement of ischemia area

26.6 ± 12.1⁎ 0.6 ± 0.9⁎ 0.7 ± 0.7⁎ 0 (0) 19.0 ± 3.2⁎

217.5 ± 35.0# 9.3 ± 1.8# 2.4 ± 0.6# 2 (25.0) 10.7 ± 2.4#

84.6 ± 14.0⁎# 2.4 ± 1.2⁎# 1.2 ± 0.5⁎ 0 13.1 ± 2.0#

Evans blue was used to distinguish the ischemic area from normal cardiac tissue according to the dye-exclusion method described previously [13]. The unstained ischemic tissue was mechanically separated from the blue-stained normal left ventricular wall. The mass of the ischemic tissue was weighed and normalized with the left ventricular tissue mass.

VPC, ventricular premature contraction; VT ventricular tachycardia; PVT, paroxysmal ventricular tachycardia; VF, ventricular fibrillation; VFT, ventricular fibrillation threshold. ⁎ p b 0.05 when compared with MI-placebo group. # p b 0.05 when compared with Sham-operated group.

visualized with Liquid DAB Substrate-Chromogen System. The density of TH-positive sympathetic nerve fibers was quantified using Motic

2.7. Statistical analysis The software SPSS 17.0 (SPSS, Chicago, IL, USA) was used in the statistical analysis. Comparisons among continuous data were performed using a one-way analysis of variance (ANOVA); whereas categorical

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Fig. 4. The effects of local cardiac denervation on ventricular ERPs and CV-ERPs. EPRs were determined before creating MI (A) and 2 h after ablation (B). CV-ERPs were measured before creating MI (C) and 2 h after ablation (D) among the six recording sites, ERP, effective refractory period; IA, ischemia area; IBA, ischemia border area; IRA, ischemia remote area; *p b 0.05 compared with MI group; #p b 0.05 compared with Sham-operated group.

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data were analyzed with the χ2-test. Values of p b 0.05 were considered statistically significant.

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As shown in Table 1, the numbers of VPC and VT episode, as well as PVT were significantly reduced by radiofrequency ablation of cardiac sympathetic nerve as compared with the MI group. These results suggested that local cardiac denervation decreases the incidence and duration of VA after AMI. Next, we determined VFT by purposely inducing VF in all live animals at the end of the electrophysiological study. In comparison with the sham-operated group, the VFT in the MI and MI-ablation dogs significantly decreased. Even though there is no significant difference, cardiac denervation did raise VFT in the MI-ablation animals (Table 1). Lastly, we investigated whether local cardiac denervation improves electrical stability after AMI, since AMI induces the electrical instability in cardiac tissue [24]. To this end, we monitored ERP at six epicardial sites, distributed in three different areas (ischemia, ischemia border and ischemia remote area), before and after AMI was induced. Before generating AMI, there were no statistical differences of the ventricular ERP and ERP dispersion among the three groups (Fig. 4A and C). Once AMI was induced by the ligation of coronary artery, ERP was significantly shortened and the ERP dispersion was increased as compared to that of the sham-operated dogs. As expected, the radiofrequency ablation of cardiac nerves drastically reversed this anomaly, prolonging EPR and decreasing the ERP dispersion, especially in the ischemia area (Fig. 4B and D). This result indicates that local cardiac denervation improves ventricular electrical stability after AMI.

3. Results 3.1. General results In order to observe the effects of local denervation on the VA occurrence after AMI, we first generated an AMI canine model by ligating the left anterior descending coronary artery. After ligation, the ECG immediately displayed ST-segment elevation and frequent VPC, and the lesion area gradually became pale. These observations suggest that we succeeded in creating the AMI model. Since short nonsustained VT was observed in 5 out of 16 ligated dogs, we gave the animals a 90minute recovery time until ECG was stable. Eight ligated dogs then underwent radiofrequency ablation of cardiac sympathetic nerves along the CS and GCV. The ablation sites, shown in Fig. 1A and B, were 0.5 cm away from LAD and LCX. Local ablation of cardiac nerves did not affect the dogs' heart rates and the mean arterial pressure. 3.2. Immunohistochemistry To evaluate the efficiency of nerve ablation, we performed immunohistological staining of cardiac tissue with an antibody against tyrosine dehydrolyse (TH) (Fig. 2), a marker of sympathetic nerve. Microscopic observations showed that TH positive nerves mainly distributed around the CS and GCV. It also showed that nerve ablation significantly decreased the numbers of cardiac TH positive nerve fibers in these areas in the MI-ablation animals as compared to the shamoperated and MI groups (Figs. 2 and 3). Histological observations also displayed that LAD and LCX arteries, which distribute around the ablation site, were kept intact after cardiac denervation.

3.4. Plasma and tissue homogenate NE analysis Since NE is a major cardiac stimulator and contributes to VA induction [25], we investigated whether local cardiac denervation affects the NE content in blood and cardiac tissue. As expected, NE levels in CS blood dramatically increased in the MI group; while local cardiac denervation significantly reversed the NE elevation induced by AMI (Fig. 5A). Furthermore, we found that AMI led to the decrease of NE levels in cardiac tissue, but denervation did not alleviate this phenotype (Fig. 5B).

3.3. Electrophysiological study To observe the anti-arrhythmic effects of local cardiac denervation, we first compared the incidence and duration of VA among the shamoperated, MI and MI-ablation groups with continuous ECG recording, which started 1 h after cardiac nerve ablation. During ECG observation, no spontaneous VF was found in the sham-operated and MI-ablation groups; however, two dogs in the MI group died of spontaneous VF.

3.5. Size of the ischemic area after MI To further evaluate the effects of local denervation on the vital signs and myocardial ischemia, we measured the heart rate, mean arterial

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Fig. 5. The effects of local cardiac denervation on NE levels in CS blood (A) and ventricular tissue (B). NE, norepinephrine; CS, coronary sinus; IA, ischemia area; IBA, ischemia border area; IRA, ischemia remote area; *p b 0.05 compared with MI group; #p b 0.05 compared with Sham-operated group.

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Table 2 The change of vital signs and ischemia area among the three different groups. After AMI

MAPs (mm Hg) HR (beat/min) IA (%)

After local cardiac denervation

MI group

MI-ablation group

MI group

MI-ablation group

83.5 ± 7.8 135.4 ± 16.2 –

86.2 ± 10.3 141.5 ± 13.8 –

81.3 ± 11.0 128.3 ± 16.5 37.1 ± 2.0

80.6 ± 8.9 122.6 ± 18.1 38.06 ± 1.18

Mean arterial pressure, MAP; heart rate, HR; IA, ischemia area.

pressure, and ischemia area. As shown in Table 2, there were no obvious differences of these indices among the three groups. 4. Discussion Our study showed that local cardiac denervation prevents VA occurrence after AMI. In the canine AMI model, frequency ablation of the CS and GCV peripheral nerves significantly reduced the incidence and duration of VA, prolonged ERP, decreased the ERP dispersion and ameliorated NE levels in CS. Furthermore, no obvious changes of the heart rate, mean arterial pressure as well as the ischemia area were observed after local ablation of cardiac sympathetic nerves. The cardiac autonomic nervous system plays an important role in the genesis of malignant ventricular arrhythmia, especially in patients with MI [7]. During the early phase of acute myocardial ischemia, the sympathetic nervous system is highly activated and releases NE into the blood [25]. Increased NE changes multiple ionic currents in ventricular myocytes by activating β2-adrenoceptors, and has been associated with VA and sudden death after myocardial infarction [24,26]. Therefore, intervention in the activity of cardiac sympathetic nerves may have antiarrhythmic effects in AMI patients. Consistent with these observations, we found that local ablation of cardiac nerves not only decreased the numbers of TH positive nerve fibers in ventricular tissues, but also significantly reduced NE levels in CS blood. This may be an underlying mechanism by which local cardiac denervation prevents the occurrence of VA complicating AMI, however, further mechanistic studies would be required in the future. Ventricular electrical instability, manifested by the decrease of ventricular refractoriness and VF threshold [27,28], is greatly influenced by NE levels in early infarcts [29,30]. And the ventricular electrical instability is a reliable predictor of the genesis of malignant ventricular arrhythmia and sudden cardiac death [31,32]. Our study showed that local cardiac denervation raised VFT, prolonged EPR, and decreased the ERP dispersion. These results indicate that local cardiac denervation improves ventricular electrical stability and prevents VA complicating AMI. Our methodology, locally targeting cardiac sympathetic nerves, has two advantages over other procedures of cardiac denervation at sites far from the heart, including the removal of unilateral stellate ganglion, thoracic epidural anesthesia, renal sympathetic denervation, etc. [33,13–16]. Our procedure could prevent the side effects inflicted by other methods. For example, blocking a stellate ganglion may cause Homer's syndrome, difficulty in swallowing, vocal cord paralysis and pneumothorax [16]. Also, our procedure is much easier to apply to clinical practice than others. The CS and its tributaries have been used for ablation of accessory pathways, ischemic VT, and idiopathic mitral annular VT [34,35]. It is possible that the CS and GCV peripheral nerves were ablated inside the CS and GCV with percutaneous coronary intervention (PCI) revascularization procedure. Combining PCI with local cardiac denervation together may be a feasible way to prevent VA and sudden death in AMI patients with high risk of VA; PCI reestablishes the blood transportation system in infarct areas and locally ablating sympathetic nerves in CS prevents the VA occurrence. We are testing this exciting hypothesis; however, we do acknowledge the difference of experimental infarction in our study versus coronary clinical infarction.

For example, the nature of pathological process, the performance of the uninfarcted myocardium and the degree of collateral circulation to the ischemic region are different between dogs and human beings [36,37]. These differences should be taken into consideration when translating results derived from animal studies to clinical patients. To our knowledge, our study is the first to test the feasibility of local ablation of cardiac sympathetic nerves to prevent VA occurrence after AMI. Since around 70 to 80% of primary VA complicating AMI occurs during 72 h after myocardial infarction [1,2,7], in this study, we focused on the acute antiarrhythmic effect of local cardiac denervation. The long-term efficacy and safety of this procedure is under evaluation in follow-up studies. Whether this methodology could prevent chronic MI-related VA will also be test in the future. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgments The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. We thank MedCom Asia for their valuable revision of the language of this study. This study was funded by the Natural Science Foundation of Heilongjiang Province China (D201285), Scientific Research Projects of Heilongjiang Province (201403) and the Postdoctoral Science-Research Developmental Foundation of Heilongjiang Province (LBH-Q12035). The authors declare that they have no competing interests. References [1] J.P.S. Henriques, P.J. Gheeraert, J.P. Ottervanger, et al., Ventricular fibrillation in acute myocardial infarction before and during primary PCI, Int. J. Cardiol. 105 (2005) 262–266. [2] R.H. Mehta, A.Z. Starr, R.D. Lopes, et al., Incidence of and outcomes associated with ventricular tachycardia or fibrillation in patients undergoing primary percutaneous coronary intervention, JAMA 301 (2009) 1779–1789. [3] S.M. Al-Khatib, C.B. Granger, Y. Huang, et al., Sustained ventricular arrhythmias among patients with acute coronary syndromes with no ST-segment elevation: incidence, predictors, and outcomes, Circulation 106 (2002) 309–312. [4] R.H. Mehta, K.J. Harjai, L. Grines, et al., Sustained ventricular tachycardia or fibrillation in the cardiac catheterization laboratory among patients receiving primary percutaneous coronary intervention: incidence, predictors, and outcomes, J. Am. Coll. Cardiol. 43 (2004) 1765–1772. [5] W. Bougouin, E. Marijon, E. Puymirat, et al., Incidence of sudden cardiac death after ventricular fibrillation complicating acute myocardial infarction: a 5-year cause-ofdeath analysis of the FAST-MI 2005 registry, Eur. Heart J. 35 (2014) 116–122. [6] The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators, A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias, N. Engl. J. Med. 337 (1997) 1576–1583. [7] H.V. Huikuri, A. Castellanos, R.J. Myerburg, Sudden death due to cardiac arrhythmias, N. Engl. J. Med. 345 (2001) 1473–1482. [8] D.P. Zipes, A.J. Camm, M. Borggrefe, et al., ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death):

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