- Email: [email protected]
Clinical evaluation of unselected cardiac arrest survivors in a tertiary center over a 1-year period (the LAZARUZ study)
Available online at www.sciencedirect.com
ScienceDirect Journal of Electrocardiology xx (2016) xxx – xxx www.jecgonline.com
Clinical evaluation of unselected cardiac arrest survivors in a tertiary center over a 1-year period (the LAZARUZ study)☆,☆☆ Peter Marstrand, Medical student, a, b Pernille Corell, MD, PhD, c Finn Lund Henriksen, MD, PhD, d Steen Pehrson, MD, DMSc, a Henning Bundgaard, MD, DMSc, PhD, a Juliane Theilade, MD, DMSc, PhD b,⁎ a
b
Department of Cardiology B, Copenhagen University Hospital/Rigshospitalet Department of Cardiology S, Copenhagen University Hospital/Herlev-Gentofte Hospital c Department of Cardiology, Roskilde University Hospital d Department of Cardiology B, Odense University Hospital
Abstract
Objectives: When the cause of an aborted cardiac arrest is unclear the initiation of therapy, counseling and family screening is challenging. Methods: We included 43 unselected, prospectively identified cardiac arrest survivors with or without a diagnosis. Family history for cardiac disease and supplemental electrocardiograms were evaluated for additional diagnostic information. Results: 43 cardiac arrest survivors were included, 34 (79%) were male and the average age was 48 years (range 23–64, SD 13.0). The most common etiologies identified in cardiac arrest survivors were ischemic heart disease (33%), cardiomyopathies (14%), miscellaneous (e.g. drug induced arrhythmias, coronary spasms) (12%) and channelopathies (5%). Family history of cardiac disease – even inheritable conditions – was not indicative of etiology in cardiac arrest survivors. Supplemental ECGs were abnormal in 10 of 43 patients; in the majority of these patients (7) no conclusive diagnosis was reached. Conclusions: In this study 16/43 (37%) of unselected, prospectively included cardiac arrest survivors remained without a diagnosis despite exhaustive investigations. We may extract additional diagnostic information from simple maneuvers during the recording of the electrocardiogram. We suggest that these ECG derived clues be investigated in future studies including genetic test results and data from relatives. © 2016 Elsevier Inc. All rights reserved.
Keywords:
Cardiac arrest survivor; Family history; Sudden cardiac death; Non-invasive electrophysiology
Introduction Prevention of recurrences and evaluation of risk in relatives possibly affected by an inheritable cardiac disease challenge physicians caring for cardiac arrest survivors. Optimally, provided a specific etiology is identified, disease specific therapy can be prescribed. For instance, ☆
Disclosures: no relationships. Financial support: This work was supported by A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal, Fondsbørsvekseleter Henry Hansen og Hustrus Legat, Købmand Sven Hansen og hustr u I na Han sen s F ond, The D ani sh H e ar t Found ati on (14-R97-A5314-22,886) and a grants from Odense University Hospital/ Rigshospitalet (8-A368). ⁎ Corresponding author at: Dept. Cardiology S, Herlev-Gentofte Hospital, Nordre Ringvej 75, 2730, Herlev. E-mail address: [email protected] ☆☆
http://dx.doi.org/10.1016/j.jelectrocard.2016.05.008 0022-0736/© 2016 Elsevier Inc. All rights reserved.
beta-adrenergic receptor blocking agents or sympathectomy in patients with malignant arrhythmias that are sensitive to sympathetic stimuli, avoidance of certain medications or life-style modifications in patients with altered cardiac repolarization can be recommended. In addition, a specific diagnosis in the proband allows for a focused evaluation of family members. In families with sudden cardiac death a specific diagnosis is not achieved in approx. 60% of cases in spite of extensive evaluation of the index case [1–10]. The results are somewhat better in cardiac arrest survivors (in the CASPAR registry this number was around 40%) [11]. For this reason, we initiated a prospective registry on cardiac arrest survivors (the LAZARUZ project) and in this paper we present our data including a focused family history and specific supplemental electrocardiograms (ECGs) as additional parameters to cardiac arrest survivors.
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Methods Cardiac arrest survivors aged 18–64 years admitted to Department of Cardiology at the Copenhagen University Hospital/Rigshospitalet during the period July 15th 2014– August 31st 2015 were invited to participate in the study. Inclusion was performed prospectively. We collected their history and test results from the clinical chart. In addition, a thorough review of the family history was obtained and supplementary ECGs were performed. Clinical data A family history was considered positive for sudden cardiac death if a 1st or 2nd relative had died suddenly and non-violently and unexpectedly before the age of 65 years. The family history was considered positive for ischemic heart disease (IHD) if IHD had occurred among 1st or 2nd degree relatives. Also, known inheritable cardiac conditions were noted.
performing physician when there was a suspicion of inflammatory disease. Images were analyzed with the use of CVI42 (Circle Cardiovascular Imaging Inc., Canada). Late gadolinium enhancement (LGE) images were visually assessed. Two independent investigators reviewed CMR scans. Invasive electrophysiology studies The electrophysiological (EP) studies were individually evaluated and set against the suspected electrical finding. A monomorphic sustained ventricular arrhythmia was always considered a positive finding. Endomyocardial biopsies The endomyocardial biopsies were immunohistochemically stained for myocarditis (Dallas criteria), amyloid (Prussian blue and Congo red stains) and fibrosis (Masson trichrome) followed by evaluation by a cardiac pathologist. Late potentials (LP)
The work-up included the following tests Transthoracic echocardiograms (TTE) Echocardiograms were performed according to the recommendations from the Danish Society for Cardiology (http://www.cardio.dk/rapporter/holdningspapir-menu). The first full echocardiography after the acute phase was noted in order to prevent potential myocardial stunning after cardiac arrest. A cardiologist reviewed all scans. Coronary angiogram, coronary CT-scan and stress test A coronary angiogram was considered positive if one or more stenoses with over 50% vessel lumen occlusion were found. CT-angiography was considered positive if the left main artery had a stenosis N 50% and/or a N 70% stenosis in the other large coronary arteries. Exercise stress test was performed using Bruce protocol on a bicycle and was terminated at maximum exertion, if the patient developed ≥ 1 mV ST-elevations or ventricular arrhythmia (N three premature ventricular beats). Non-ascending ST depressions N 0.1 mV combined with angina pectoris were considered significant. Cardiac magnetic resonance imaging (CMR) CMR scans were done on a 1.5 or 3 Tesla scanner (Siemens, Germany) with chest surface coils and 32-channel back. The cardiac volumes were obtained by steady-state free precession cine images with retrospective electrocardiographic gating as a short axis stack and as transversal stack covering the heart. (No interpolated gaps, slice thickness 8 mm). Late gadolinium enhancement was obtained by T1-weighted gradient echo images as a short-axis stack approximately 10–20 min. After administration of an intravenous bolus of gadolinium (0.10 mmol/kg bodyweight), (Gadovist, Bayer Schering, Germany). Inversion time was continuously determined to null the signal from the normal myocardium. T1-weighted images were obtained with prospective electrocardiographic triggering. T2-weighted images were performed at the discretion of the
Late potentials were derived from a signal-averaged electrocardiogram, using 300 beats on average (GE Medical Systems, MAC 5500 HD). A noise level b 0.3 μV (standard deviation) was obtained. LP were considered positive if N 1 of the following criteria were met: filtered QRS duration N 114 ms, terminal QRS root means square (RMS) voltage b 20 μV or low amplitude (b 40 μV) signal (LAS duration N 38 ms. Pharmacological provocation Pharmacological provocation was performed by infusion of either flecainide or isoprenaline. Flecainide in doses up to maximally 2 mg/kg was infused during continuous ECG monitoring and considered positive if a terminal R wave and a ≥ 2 mm ST-segment elevation occurred in ≥ 1 of leads V1–V3. Isoprenaline test was performed under continuous ECG recording with infusion of 0.02 μg/kg/min isoprenaline and increasing to 0.1 μg/kg/min for 10 min. Supplementary ECG recordings Patients rested in bed for 5 min before the recording of the first ECG, subsequently an ECG was recorded using upwards displacement of the V1–2 leads to intercostal areas 2 and 3. Subsequently, each patient was instructed to stand and ECGs were recorded every minute while the patient remained standing for 5 min. The corrected QT interval (QTc) was calculated using the Bazett's formula (maximal QT duration in lead V2 or V5 divided by the square-root of the RR-interval). Precordial leads were used as brisk standing inevitable induced noise on the ECGs that interfered with the determination of QTc duration in limb leads. As the QTc interval may be difficult to measure [13], two investigators (JT and PM who previously published data with low intra- and interobserver variation on the QTc duration in a prospective patient cohort) analyzed the ECGs independently and blinded from the clinical data [12,13]. The supplementary ECGs did not form part of the regular workup of the cardiac arrest survivors (described in the methods' section). Also, two investigators (blinded to the
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remaining clinical information and test results) analyzed of the supplementary ECGs. The supplementary ECGs had not been determining for the diagnoses in this cohort. Compliance from the patients was required and the ECGs were therefore all performed after discharge from the intensive care unit.
Results 53 cardiac arrest survivors were identified during a 12.5-month period. 10 patients were excluded due to poor neurological outcome/death (5), practical issues (4) and non-willingness to give consent (1). In total, 43 cardiac arrest survivors were included in this study. 34 (79%) were male. The average age was 48 years (range 23–64, SD 13.0). In the following sections we are presenting factors relating to the cardiac arrest circumstances, results from the diagnostic tests performed, diagnoses reached and whether patients were implanted with an ICD. Subsequently, we present the results from supplementary ECG recordings and reported history of familial heart disease.
Circumstances surrounding the cardiac arrest 24 patients were physically active immediately prior to the cardiac arrest (14 at moderate to high intensity, 10 with activities of daily life), whereas 19 were resting or sleeping. Three patients were in hospital when their cardiac arrest occurred (in 1 case due to syncope). No patients reported intensive psychological stress as a possible trigger. In 27 patients emergency rescue teams recorded ventricular fibrillation as the primary rhythm. In nine cases ventricular tachycardia and fibrillation were recorded. In seven cases the primary rhythm was not mentioned or documented in the chart. In 4 of these 7 cases a definitive cardiac condition was identified (coronary spasm, hypertrophic cardiomyopathy, congenital LQTS and in one case an ST-elevation myocardial infarction) and ventricular tachyarrhytmias were considered the likely mechanism for these patients' collapses. Among the remaining 3 patients, moderate coronary atheromatosis was identified in 2 patients again suggesting a cardiac cause of the cardiac arrest. The latter case was a male in his 20s with an unexplained cardiac arrest who presenting normal findings on TTE, CT-CAG, MRI, stress testing, late potentials and during stimulation with flecainide; based on the history it was impossible to clear him of a risk of recurrence and he was implanted with an ICD, but follow-up will show whether he develops a phenotype and/or further arrhythmias. In 34 cases bystander life support was initiated. In 20 cases the time to return of spontaneous circulation (ROSC) was 10 min or shorter; in 15 cases the time to ROSC was N 10 min (mean 20, range 15–67 min). Following resuscitation 19 patients were treated with targeted hypothermia (4 of 20 with ROSC b 10 min, all with ROSC N 10 min).
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Evaluation of patients A summary of the investigations performed is presented in Table 1. A coronary angiogram (performed in 35 patients) indicated no atheromatosis (13 patients), insignificant atheromatosis (6) or significant coronary stenoses (16). In addition, six patients underwent either an exercise test (1), a coronary CT-scan (2) or both an exercise test and a coronary CT-scan (3). The two patients that did not undergo testing for IHD were either diagnosed with preexcited atrial fibrillation or acquired long QT prolongation. An echocardiogram was performed in all patients; it was normal in 13 with minor abnormalities in 17 patients and major abnormalities in 13. Among these patients a subsequent CMR confirmed abnormal findings in three patients but rejected a suspected cardiomyopathy in one patient. In summary, TTE was consistent with non-ischemic cardiomyopathy (5) or ischemic cardiomyopathy (7). A cardiac MRI (CMR) was done in 12 patients. In the remainder of the patients CMR was not performed as a definitive diagnosis had been established (25), due to patient preference (1) or limited capacity in the CMR suite (5). The CMR was normal in four. CMR established a diagnosis in five patients (4 cardiomyopathies, 1 case of IHD). Borderline, non-diagnostic findings were present in the remaining three patients. An electrophysiological (EP) study was performed in four patients; in 1 patient a possible etiology was identified followed by an ablation (Wolff-Parkinson-White syndrome with likely atrial fibrillation). A myocardial biopsy (MYBI) was performed in two cases. One was normal, the other displayed discrete signs of myocardial hypertrophy (defined as myocardial disarray). Late potentials were performed in seven patients; the test was positive in two patients but did not contribute to the diagnosis in either case. Pharmacological provocation tests A flecainide test was performed in five patients; it was positive in one patient according to the 2013 consensus report on the Brugada syndrome [14]. It was borderline positive in one patient but not considered sufficient for the BrS diagnosis. An isoprenaline stimulation test performed in one patient strongly suggested the presence of the LQTS. Diagnoses and device therapy Following the clinical evaluation, 16 patients were classified as having suffered from idiopathic ventricular fibrillation and 14 were categorized as having had a cardiac arrest due to IHD (5 of these 14 suffered an acute coronary syndrome at the time of the cardiac arrest). In six cases a cardiomyopathy was identified, four of these were possibly inheritable and the two latter possibly related to previous chemotherapy and long-standing hypertension, respectively. Three patients with prolonged QTc duration were identified, in two of whom the observed QTc prolongation was considered acquired (electrolyte disturbances and
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Table 1 Evaluation of cardiac arrest survivors.
Performed Normal Significant findings
Echo
Coronary angiogram
CT coronary angiogram
Stress test, bicycle
CMR
EP study
Late potentials
Flecainide
Isopre-naline
Myocardial biopsy
43 13 13
35 13 16
5 5 0
7 6 1
12 4 5⁎
4 3 1
7 7 0
5 4 1
1 0 1
2 2 0
Table 1 presents an overview over the workup that was offered to cardiac arrest survivors in the study period. All patients were submitted to a TTE and the majority was referred for an invasive coronary angiogram. CMR, EP studies, late potentials (LP) or drug provocation tests (with flecainide to tease out BrS signs or Isoprenaline to diagnose LQTS or catecholaminergic polymorphic ventricular tachycardia) were performed in subsets of patient according to clinical presentation as indicated by clinician choice. ⁎ CMR findings consistent with either cardiomyopathy (4) or IHD (1).
antipsychotic medication, respectively). One patient was diagnosed with the Brugada syndrome. In one patient there was evidence of severe spasms of a coronary artery with ST-elevations on the telemetry immediately before the cardiac arrest. In addition, coronary spasms were presumed in a patient undergoing chemotherapy (capecitabin). Finally, in one patient ventricular pre-excitation with atrial fibrillation was identified during an invasive EP study. 36 patients accepted an implantable intracardiac cardioverter defibrillator (ICD) before discharge. The reasons for not implanting an ICD therapy in the remaining seven survivors were: reversible triggers controlled (acute coronary syndrome (3), acquired QTc prolongation (1), WPW and atrial fibrillation treated by ablation (1), congenital long QT syndrome (cLQTS) in patient where beta-receptor adrenergic blocking agents were initiated (1)) and patient preference (1).
Family history 10 patients reported at least one case of sudden cardiac death in the family earlier than age 65 years. Data on family history is presented in Table 2. These patients were subsequently diagnosed with IHD (4), cardiomyopathy (3), other (1) or received no diagnosis (2). Also, five patients reported a family history of inheritable cardiac disease; premature IHD (2), dilated cardiomyopathy (DCM) (1), hypercholesterolemia (1) or Marfan syndrome (1) – in no case were these diagnoses found to have caused the cardiac arrest in the index cases. 10 patients reported cases of IHD in the family (in 2 instances b age 60); among the index cases in these families, IHD was the presumed cause of cardiac arrest in three cases. Only one patient reported syncope in a relative.
Extended analysis of the electrocardiogram; dynamics of the QTc interval and Brugada pattern in elevated leads Five ECGs were excluded from QTc calculations and elevated lead analysis for BrS signs (due to LBBB (2), noise (2), atrial fibrillation (1)). Therefore, supplementary analyses were performed on ECGs from 38 cardiac arrest survivors. In seven cases, both investigators found that the QTc duration was N50 ms prolonged during standing when compared to ECGs in the supine position (Fig. 1). Among the cases with
standing-induced QTc prolongation was the one patient with cLQTS. In addition, in five patients with no specific cardiac diagnose and one diagnosed with IHD QTc prolongation (more than 50 ms) was induced during brisk standing. Cardiac function was normal or near normal in all of these seven patients as assessed by TTE. None of the two patients with acquired QT prolongation as the presumed cause of cardiac arrest were identified during brisk standing, possibly due to removal of the triggering factor at the time of brisk standing test performance. In three cases, coved ST elevations were observed when leads V1 and V2 were elevated to intercostal spaces 2 and 3. The patient diagnosed with the BrS was among these three patients (panel C in Fig. 2). This patient and another patient had structurally normal hearts on TTE and CMR. In contrast, a third patient with BrS like findings on the elevated ECG leads (panel A in Fig. 2) displayed regional hypokinesia and a left ventricular LVEF of 45% on TTE (no CMR was performed in this case), however, these structural abnormalities were not accepted as the cause of the cardiac arrest. None of these 3 patients had been subjected to a flecainide test during the evaluation presented in this paper; however Table 2 Family history of cardiac conditions in relatives of cardiac arrest survivors.
Family history of SCD in 1st or 2nd degrees relatives b65 years Family history of inheritable cardiac disease Family history of IHD
N
Findings in SCD victims
10
5 IHD 3 cardiomyopathy 2 unresolved None
5 10
5 unresolved 3 IHD 2 other
Table 2 shows the family history of sudden cardiac death (SCD) before the age of 65 years, inheritable cardiac disease and ischemic heart disease (IHD). 10 patients reported familial SCD b65 years, in these probands IHD and cardiomyopathy was identified in eight cases whereas two remained unresolved (without diagnosis = no dx). In five cases the proband reported familial heart disease; however, no inheritable or other specific cardiac condition was identified in the index case. Finally, IHD was common among relatives of SCD survivors being reported by 10 patients; however, only three of these 10 patients were ultimately diagnosed with IHD themselves, half (5) remained unresolved and in two cases another cause was identified (probable acquired LQTS (aLQTS) and cardiotoxic effects of antineoplastic therapy).
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5
A.
B.
C.
D.
E.
F.
G.
M 62 y, no dx 456+49 ms TTE minor abn.
M 53 y,no dx 435+66 ms TTE minor abn. CMRI normal
M 29, no dx 437+75 ms TTE and CMRI minor abn.
M 50 y, no dx 453+75 ms TTE normal
M 63 y, IHD 435+109 TTE normal
M, 59 y, no dx 411+121 ms TTE minor abn.
F 25 y, LQTS 467+127 ms TTE normal
V1 V2 V3 V4 V5 V6
Fig. 1. displays the supplementary ECGs from patients with the largest increase in QTc duration during brisk standing. For each patient the leftmost picture represents the ECG taken while resting supine, the rightmost panel show the ECG after one minute of brisk standing. Clinical information about each case is listed below the ECGs. For example; patient A is a 62 year-old male cardiac arrest survivor with no definite diagnosis. He displayed a resting QTc interval of 456 ms that increased with 49 ms during brisk standing. In cases A, B, C and F minor abnormalities were found on imaging but none of these were considered the cause of the cardiac arrest (see text for further details).
patients B and C were subsequently tested. The test was positive for Brugada syndrome in patient C whereas borderline ST-elevations were observed in patient B who remains without a certain diagnosis.
Discussion We present our findings in a cohort of prospectively identified cardiac arrest survivors. Our findings are important for the management of cardiac arrest victims as well as of possibly affected relatives. It is well known that the specific cause of a cardiac arrest is often elusive. Several studies suggest that more than half of sudden deaths may be due to definite or possible inheritable cardiac conditions [15]. However, 1/4 SCD victims are categorized as sudden unexplained deaths (defined as sudden death with a subsequent negative autopsy and toxicology screening) [15–24]. When a cause is identified, it is most often coronary artery disease (approx. 30%), cardiomyopathies (approx. 10%) and myocarditis (approx. 5%). Primary arrhythmias are extremely rarely identified post-mortem in SCD victims likely because the diagnosis depends on the electrocardiogram. When including data from cardiac arrest survivors and/or relatives of sudden death victims or survivors primary arrhythmias are identified in roughly 1/4 families evaluated [1–6,9–11]. However, even in studies reporting data from cardiac arrest survivors and/or their relatives the diagnosis is often not identified. For the reasons considered above, we decided to include all consenting long-term cardiac arrest survivors in a prospective study. We included data from the patients' clinical charts, re-interviewed patients about their family history and performed supplementary ECG analyses. In our cohort, the most common cause of the cardiac arrest was idiopathic ventricular tachyarrhythmias (37%), ischemic heart disease (33%), cardiomyopathies (14%), primary arrhythmia syndromes (5%) and other (12%). It is discour-
aging that a large proportion of cardiac arrest survivors remain unresolved despite a thorough evaluation. The lack of a definitive diagnosis complicates counseling and does not allow for a focused cascade screening. During follow-up it will be important to re-evaluate cases based on new information at subsequent outpatient visits and results from screening of possibly affected relatives. Subsequently, we evaluated the value of information about family history. In total, 10 patients reported SCD before the age of 65 years in a relative. In three of the survivors a cardiomyopathy was identified (one case of myocardial hypertrophy considered secondary to hypertension and two cases of dilated cardiomyopathies). However, in DCM the etiology may vary widely. In the end a likely familial cardiomyopathy was only identified in one among 10 patients with familial SCD because there was a specific family history of cardiac enlargement. Among none of five patients reporting a family history of inheritable cardiac disease could the familial condition be identified as the cause of the cardiac arrest in the proband. Finally, in only 3/10 of survivors (with recognized IHD in relatives) was IHD the cause of the cardiac arrest in the proband. As such, the family history was rarely predictive of the diagnosis in the index case. However, having access to more details about the familial cases would likely enhance the utility of familial cases of cardiac disease. Next, we investigated the dynamics of the QTc interval during brisk standing and ECG changes produced by alternative electrode placement. Our aim was to see, if these techniques might tease out findings suggestive of channelopathies which could warrant further evaluation in subsequent prospective studies. The testing for dynamic changes of the QT duration assayed the frequency and magnitude of QT prolongation during brisk standing (which induces a postural sinus tachycardia and on average increases heart rate with approx. 15 bpm). This is important for several reasons. Firstly, it is difficult to measure the QTc interval. In fact, even arrhythmia experts and in particular
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A.
B.
C.
V1 IC4
V2
V1 IC3
V2
V1 IC2
V2 M 58 y, no dx TTE mild abn.
M 39 y, no dx TTE & CMRI normal
M 33 y, BrS TTE & CMRI normal
Fig. 2. show excerpts of ECGs of patients in whom supplementary ECGs produced coved ST-elevations. The patient in panel C was diagnosed with the Brugada syndrome following a comprehensive review of his clinical data. To the left V1 and V2 are marked, to the right the placement of electrodes is shown for intercostal spaces 2, 3 and 4. Below the panel clinical information is included. For example, patient A is a 58 year-old male cardiac arrest survivor in whom no definite diagnosis was reached. His TTE showed septal hypokinesia with a LVEF 45% (see text). In his case no CMR was done.
general cardiologists estimate it wrong (in 40 or 75% of the cases, respectively) when subjected to systematic testing [12]. Secondly, 1/3 LQTS patients are categorized as having concealed LQTS (their QTc interval is within normal limits though they harbor a pathogenic mutation and a 10-time increased risk of SCD) [25,26]. Obviously, we are not the first to search for a solution to this challenge. It has been known for years that epinephrine infusion induce a more pronounced QTc prolongation in LQTS patients when compared to healthy controls [27]. However, infusion of epinephrine may also cause malignant arrhythmias and harm the patients and is therefore not used routinely (only performed one time in our cohort). Therefore, additional, non-invasive tests for identification of patients with pathological QT prolongation as a proxy for diseased cardiac repolarization are required. In 2010, Viskin reported that the QT interval in LQTS patients increased during brisk standing as opposed to the QT interval shortening that was seen in healthy controls during the same test. During continuous ECG recording they found an average maximum QTc stretch of 89 ± 47 ms among LQTS patients and the specificity for LQTS increased to 86% (only 61% using resting ECG). The authors suggested that this phenomenon might be exploited to enhance the diagnosis of LQTS patients [28]. However, all of these studies on the dynamic nature of the QTc interval were generally small (b 100–150 patients) and affected subjects had been identified before inclusion. Though our
cohort too is small, we are the first to report the systematic application of a ‘brisk standing’ test to search for abnormal cardiac repolarization among unselected cardiac arrest survivors. We identified seven patients with a significant and dynamic prolongation of the QTc interval following induction of sinus tachycardia by sudden standing up from a resting position. Even though, an agreement plot of the QTc intervals measured in this study cannot rule out that 4 of 7 cases with the least significantly induced QTc prolongation may be due to measurement errors, the patient who received the LQTS diagnosis (during the routine workup of cardiac arrest survivors) significantly prolonged her QTc during brisk standing. We also systematically collected ECGs in which leads V1–2 were displaced to intercostal spaces 2–3. The purpose was to chase the inconstant coved, right-sided ST-elevation that characterizes the Brugada syndrome. In fact, for unclear reasons this disease entity is exceedingly rare in Denmark. [29,30] Diagnosis is made difficult by a lack of a ‘golden standard’ and a diagnosis that is based on criteria defined by consensus [14,31]. This has resulted in reported false negative rates as high as 75%, false positive rates around 12% and precision as low as 24% [32,33]. Currently however, the BrS diagnosis requires the identification of a type 1 ECG (= coved ST-elevations ≥ 2 mm in ≥ 1 leads) either spontaneously or following elevation of ECG electrodes or stimulation with a drug that inhibits the SCN5A channel (that may be the genetic substrate for the condition). In three patients, we found a positive ECG. We correctly identified one patient already diagnosed with the BrS. Both this patient and another of the three patients with BrS ECGs presented with a structurally normal heart on TTE and CMR, whereas the latter patient presented minor structural changes in the heart on TTE (no CMR performed). Our data do not allow for firm conclusions on the value of the supplemental ECG recordings. Future data from follow-up visits and genetic test results and possibly data from relatives of the index cases will need to be also included in this evaluation. However, we are currently facing the challenge that a diagnosis is not readily identifiable in a significant proportion of cardiac arrest survivors (in this cohort around 40%). Though ICD therapy offers efficient protection (recurrence rates for aborted cardiac arrest have been reported to 20–50%) [14,31,34] additional protection through disease-specific therapies is unavailable to patients categorized as idiopathic ventricular fibrillation. The lack of definitive diagnoses in this large subgroup of cardiac arrest survivors also impacts their relatives, because as much as 50% of sudden cardiac death in younger subjects may be due to inheritable conditions. Therefore, it is considered advisable to screen relatives for disease. On the other hand, it is also very important to identify families that should not be screened. However – at least in this cohort in which the information was often limited to what had been communicated to surviving family members – family history was a poor predictor for disease among unselected cardiac arrest survivors. In conclusion, new tools to assist categorization of cardiac arrest survivors would be welcomed. As cardiac arrest survivors are rare and present a heterogenous
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population, we suggest that prospective national or international registries with the systematic reporting of findings (including as much information as possible generated from non-invasive ECG recording) may be a viable option to understand and enhance our management of these patients and definitely a way to evaluate whether the signals generated in this study have real clinical value.
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[15] Winkel BG, Holst AG, Theilade J, Kristensen IB, Thomsen JL, Ottesen GL, et al. Nationwide study of sudden cardiac death in persons aged 1–35 years. Eur Heart J 2011;32:983–90. [16] Morris VB, Keelan T, Leen E, Keating J, Magee H, O'Neill JO, et al. Sudden cardiac death in the young: A 1-year post-mortem analysis in the republic of Ireland. Med Sci 2009;178:257–61. [17] Puranik R, Chow CK, Duflou JA, Kilborn MJ, McGuire MA. Sudden death in the young. Heart Rhythm 2005;2:1277–82. [18] Quigley F, Greene M, O'Connor D, Kelly F. A survey of the causes of sudden cardiac death in the under 35-year-age group. Ir Med J 2005;98:232–5. [19] Vaartjes I, Hendrix A, Hertogh EM, Grobbee DE, Doevendans PA, Mosterd A, et al. Sudden death in persons younger than 40 years of age: Incidence and causes. Cardiovasc Prev Rehabil 2009;16:592–6. [20] Papadakis M, Sharma S, Cox S, Sheppard MN, Panoulas VF, Behr ER. The magnitude of sudden cardiac death in the young: A death certificate-based review in England and wales. Europace 2009;11:1353–8. [21] Margey R, Roy A, Tobin S, O'Keane CJ, McGorrian C, Morris V, et al. Sudden cardiac death in 14- to 35-year olds in Ireland from 2005 to 2007: A retrospective registry. Europace 2011;13:1411–8. [22] Eckart RE, Shry EA, Burke AP, McNear JA, Appel DA, Castillo-Rojas LM, et al. Sudden death in young adults: An autopsy-based series of a population undergoing active surveillance. J Am Coll Cardiol 2011;58:1254–61. [23] Meyer L, Stubbs B, Fahrenbruch C, Maeda C, Harmon K, Eisenberg M, et al. Incidence, causes, and survival trends from cardiovascularrelated sudden cardiac arrest in children and young adults 0 to 35 years of age: A 30-year review. Circulation 2012;126:1363–72. [24] Pilmer CM, Kirsh JA, Hildebrandt D, Krahn AD, Gow RM. Sudden cardiac death in children and adolescents between 1 and 19 years of age. Heart Rhythm 2014;11:239–45. [25] Theilade J, Kanters J, Henriksen FL, Gilsa-Hansen M, Svendsen JH, Eschen O, et al. Cascade screening in families with inherited cardiac diseases driven by cardiologists: Feasibility and nationwide outcome in long qt syndrome. Cardiology 2013;126:131–7. [26] Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S, et al. Risk for life-threatening cardiac events in patients with genotypeconfirmed long-qt syndrome and normal-range corrected qt intervals. J Am Coll Cardiol 2011;57:51–9. [27] Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter CB. Epinephrine-induced qt interval prolongation: A gene-specific paradoxical response in congenital long qt syndrome. Mayo Clin Proc 2002;77:413–21. [28] Viskin S, Postema PG, Bhuiyan ZA, Rosso R, Kalman JM, Vohra JK, et al. The response of the qt interval to the brief tachycardia provoked by standing: A bedside test for diagnosing long qt syndrome. J Am Coll Cardiol 2010;55:1955–61. [29] Holst AG, Jensen HK, Eschen O, Henriksen FL, Kanters J, Bundgaard H, et al. Low disease prevalence and inappropriate implantable cardioverter defibrillator shock rate in brugada syndrome: A nationwide study. Europace 2012;14:1025–9. [30] Pecini R, Cedergreen P, Theilade S, Haunso S, Theilade J, Jensen GB. The prevalence and relevance of the brugada-type electrocardiogram in the danish general population: Data from the Copenhagen City Heart study. Europace 2010;12:982–6. [31] Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, et al. Brugada syndrome: Report of the second consensus conference. Heart Rhythm 2005;2:429–40. [32] Priori SG, Napolitano C. Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation 2005;112:279–92 [discussion 279-292]. [33] Chung EH, McNeely III DE, Gehi AK, Brickner T, Evans S, Pryski E, et al. Brugada-type patterns are easily observed in high precordial lead ecgs in collegiate athletes. J Electrocardiol 2014;47:1–6. [34] Lelakowski J, Piekarz J, Rydlewska A, Majewski J, Senderek T, Zabek A, et al. Factors predisposing to ventricular tachyarrhythmia leading to appropriate icd intervention in patients with coronary artery disease or non-ischaemic dilated cardiomyopathy. Kardiol Pol 2012;70:1264–75.
ScienceDirect Journal of Electrocardiology xx (2016) xxx – xxx www.jecgonline.com
Clinical evaluation of unselected cardiac arrest survivors in a tertiary center over a 1-year period (the LAZARUZ study)☆,☆☆ Peter Marstrand, Medical student, a, b Pernille Corell, MD, PhD, c Finn Lund Henriksen, MD, PhD, d Steen Pehrson, MD, DMSc, a Henning Bundgaard, MD, DMSc, PhD, a Juliane Theilade, MD, DMSc, PhD b,⁎ a
b
Department of Cardiology B, Copenhagen University Hospital/Rigshospitalet Department of Cardiology S, Copenhagen University Hospital/Herlev-Gentofte Hospital c Department of Cardiology, Roskilde University Hospital d Department of Cardiology B, Odense University Hospital
Abstract
Objectives: When the cause of an aborted cardiac arrest is unclear the initiation of therapy, counseling and family screening is challenging. Methods: We included 43 unselected, prospectively identified cardiac arrest survivors with or without a diagnosis. Family history for cardiac disease and supplemental electrocardiograms were evaluated for additional diagnostic information. Results: 43 cardiac arrest survivors were included, 34 (79%) were male and the average age was 48 years (range 23–64, SD 13.0). The most common etiologies identified in cardiac arrest survivors were ischemic heart disease (33%), cardiomyopathies (14%), miscellaneous (e.g. drug induced arrhythmias, coronary spasms) (12%) and channelopathies (5%). Family history of cardiac disease – even inheritable conditions – was not indicative of etiology in cardiac arrest survivors. Supplemental ECGs were abnormal in 10 of 43 patients; in the majority of these patients (7) no conclusive diagnosis was reached. Conclusions: In this study 16/43 (37%) of unselected, prospectively included cardiac arrest survivors remained without a diagnosis despite exhaustive investigations. We may extract additional diagnostic information from simple maneuvers during the recording of the electrocardiogram. We suggest that these ECG derived clues be investigated in future studies including genetic test results and data from relatives. © 2016 Elsevier Inc. All rights reserved.
Keywords:
Cardiac arrest survivor; Family history; Sudden cardiac death; Non-invasive electrophysiology
Introduction Prevention of recurrences and evaluation of risk in relatives possibly affected by an inheritable cardiac disease challenge physicians caring for cardiac arrest survivors. Optimally, provided a specific etiology is identified, disease specific therapy can be prescribed. For instance, ☆
Disclosures: no relationships. Financial support: This work was supported by A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal, Fondsbørsvekseleter Henry Hansen og Hustrus Legat, Købmand Sven Hansen og hustr u I na Han sen s F ond, The D ani sh H e ar t Found ati on (14-R97-A5314-22,886) and a grants from Odense University Hospital/ Rigshospitalet (8-A368). ⁎ Corresponding author at: Dept. Cardiology S, Herlev-Gentofte Hospital, Nordre Ringvej 75, 2730, Herlev. E-mail address: [email protected] ☆☆
http://dx.doi.org/10.1016/j.jelectrocard.2016.05.008 0022-0736/© 2016 Elsevier Inc. All rights reserved.
beta-adrenergic receptor blocking agents or sympathectomy in patients with malignant arrhythmias that are sensitive to sympathetic stimuli, avoidance of certain medications or life-style modifications in patients with altered cardiac repolarization can be recommended. In addition, a specific diagnosis in the proband allows for a focused evaluation of family members. In families with sudden cardiac death a specific diagnosis is not achieved in approx. 60% of cases in spite of extensive evaluation of the index case [1–10]. The results are somewhat better in cardiac arrest survivors (in the CASPAR registry this number was around 40%) [11]. For this reason, we initiated a prospective registry on cardiac arrest survivors (the LAZARUZ project) and in this paper we present our data including a focused family history and specific supplemental electrocardiograms (ECGs) as additional parameters to cardiac arrest survivors.
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Methods Cardiac arrest survivors aged 18–64 years admitted to Department of Cardiology at the Copenhagen University Hospital/Rigshospitalet during the period July 15th 2014– August 31st 2015 were invited to participate in the study. Inclusion was performed prospectively. We collected their history and test results from the clinical chart. In addition, a thorough review of the family history was obtained and supplementary ECGs were performed. Clinical data A family history was considered positive for sudden cardiac death if a 1st or 2nd relative had died suddenly and non-violently and unexpectedly before the age of 65 years. The family history was considered positive for ischemic heart disease (IHD) if IHD had occurred among 1st or 2nd degree relatives. Also, known inheritable cardiac conditions were noted.
performing physician when there was a suspicion of inflammatory disease. Images were analyzed with the use of CVI42 (Circle Cardiovascular Imaging Inc., Canada). Late gadolinium enhancement (LGE) images were visually assessed. Two independent investigators reviewed CMR scans. Invasive electrophysiology studies The electrophysiological (EP) studies were individually evaluated and set against the suspected electrical finding. A monomorphic sustained ventricular arrhythmia was always considered a positive finding. Endomyocardial biopsies The endomyocardial biopsies were immunohistochemically stained for myocarditis (Dallas criteria), amyloid (Prussian blue and Congo red stains) and fibrosis (Masson trichrome) followed by evaluation by a cardiac pathologist. Late potentials (LP)
The work-up included the following tests Transthoracic echocardiograms (TTE) Echocardiograms were performed according to the recommendations from the Danish Society for Cardiology (http://www.cardio.dk/rapporter/holdningspapir-menu). The first full echocardiography after the acute phase was noted in order to prevent potential myocardial stunning after cardiac arrest. A cardiologist reviewed all scans. Coronary angiogram, coronary CT-scan and stress test A coronary angiogram was considered positive if one or more stenoses with over 50% vessel lumen occlusion were found. CT-angiography was considered positive if the left main artery had a stenosis N 50% and/or a N 70% stenosis in the other large coronary arteries. Exercise stress test was performed using Bruce protocol on a bicycle and was terminated at maximum exertion, if the patient developed ≥ 1 mV ST-elevations or ventricular arrhythmia (N three premature ventricular beats). Non-ascending ST depressions N 0.1 mV combined with angina pectoris were considered significant. Cardiac magnetic resonance imaging (CMR) CMR scans were done on a 1.5 or 3 Tesla scanner (Siemens, Germany) with chest surface coils and 32-channel back. The cardiac volumes were obtained by steady-state free precession cine images with retrospective electrocardiographic gating as a short axis stack and as transversal stack covering the heart. (No interpolated gaps, slice thickness 8 mm). Late gadolinium enhancement was obtained by T1-weighted gradient echo images as a short-axis stack approximately 10–20 min. After administration of an intravenous bolus of gadolinium (0.10 mmol/kg bodyweight), (Gadovist, Bayer Schering, Germany). Inversion time was continuously determined to null the signal from the normal myocardium. T1-weighted images were obtained with prospective electrocardiographic triggering. T2-weighted images were performed at the discretion of the
Late potentials were derived from a signal-averaged electrocardiogram, using 300 beats on average (GE Medical Systems, MAC 5500 HD). A noise level b 0.3 μV (standard deviation) was obtained. LP were considered positive if N 1 of the following criteria were met: filtered QRS duration N 114 ms, terminal QRS root means square (RMS) voltage b 20 μV or low amplitude (b 40 μV) signal (LAS duration N 38 ms. Pharmacological provocation Pharmacological provocation was performed by infusion of either flecainide or isoprenaline. Flecainide in doses up to maximally 2 mg/kg was infused during continuous ECG monitoring and considered positive if a terminal R wave and a ≥ 2 mm ST-segment elevation occurred in ≥ 1 of leads V1–V3. Isoprenaline test was performed under continuous ECG recording with infusion of 0.02 μg/kg/min isoprenaline and increasing to 0.1 μg/kg/min for 10 min. Supplementary ECG recordings Patients rested in bed for 5 min before the recording of the first ECG, subsequently an ECG was recorded using upwards displacement of the V1–2 leads to intercostal areas 2 and 3. Subsequently, each patient was instructed to stand and ECGs were recorded every minute while the patient remained standing for 5 min. The corrected QT interval (QTc) was calculated using the Bazett's formula (maximal QT duration in lead V2 or V5 divided by the square-root of the RR-interval). Precordial leads were used as brisk standing inevitable induced noise on the ECGs that interfered with the determination of QTc duration in limb leads. As the QTc interval may be difficult to measure [13], two investigators (JT and PM who previously published data with low intra- and interobserver variation on the QTc duration in a prospective patient cohort) analyzed the ECGs independently and blinded from the clinical data [12,13]. The supplementary ECGs did not form part of the regular workup of the cardiac arrest survivors (described in the methods' section). Also, two investigators (blinded to the
P. Marstrand et al. / Journal of Electrocardiology xx (2016) xxx–xxx
remaining clinical information and test results) analyzed of the supplementary ECGs. The supplementary ECGs had not been determining for the diagnoses in this cohort. Compliance from the patients was required and the ECGs were therefore all performed after discharge from the intensive care unit.
Results 53 cardiac arrest survivors were identified during a 12.5-month period. 10 patients were excluded due to poor neurological outcome/death (5), practical issues (4) and non-willingness to give consent (1). In total, 43 cardiac arrest survivors were included in this study. 34 (79%) were male. The average age was 48 years (range 23–64, SD 13.0). In the following sections we are presenting factors relating to the cardiac arrest circumstances, results from the diagnostic tests performed, diagnoses reached and whether patients were implanted with an ICD. Subsequently, we present the results from supplementary ECG recordings and reported history of familial heart disease.
Circumstances surrounding the cardiac arrest 24 patients were physically active immediately prior to the cardiac arrest (14 at moderate to high intensity, 10 with activities of daily life), whereas 19 were resting or sleeping. Three patients were in hospital when their cardiac arrest occurred (in 1 case due to syncope). No patients reported intensive psychological stress as a possible trigger. In 27 patients emergency rescue teams recorded ventricular fibrillation as the primary rhythm. In nine cases ventricular tachycardia and fibrillation were recorded. In seven cases the primary rhythm was not mentioned or documented in the chart. In 4 of these 7 cases a definitive cardiac condition was identified (coronary spasm, hypertrophic cardiomyopathy, congenital LQTS and in one case an ST-elevation myocardial infarction) and ventricular tachyarrhytmias were considered the likely mechanism for these patients' collapses. Among the remaining 3 patients, moderate coronary atheromatosis was identified in 2 patients again suggesting a cardiac cause of the cardiac arrest. The latter case was a male in his 20s with an unexplained cardiac arrest who presenting normal findings on TTE, CT-CAG, MRI, stress testing, late potentials and during stimulation with flecainide; based on the history it was impossible to clear him of a risk of recurrence and he was implanted with an ICD, but follow-up will show whether he develops a phenotype and/or further arrhythmias. In 34 cases bystander life support was initiated. In 20 cases the time to return of spontaneous circulation (ROSC) was 10 min or shorter; in 15 cases the time to ROSC was N 10 min (mean 20, range 15–67 min). Following resuscitation 19 patients were treated with targeted hypothermia (4 of 20 with ROSC b 10 min, all with ROSC N 10 min).
3
Evaluation of patients A summary of the investigations performed is presented in Table 1. A coronary angiogram (performed in 35 patients) indicated no atheromatosis (13 patients), insignificant atheromatosis (6) or significant coronary stenoses (16). In addition, six patients underwent either an exercise test (1), a coronary CT-scan (2) or both an exercise test and a coronary CT-scan (3). The two patients that did not undergo testing for IHD were either diagnosed with preexcited atrial fibrillation or acquired long QT prolongation. An echocardiogram was performed in all patients; it was normal in 13 with minor abnormalities in 17 patients and major abnormalities in 13. Among these patients a subsequent CMR confirmed abnormal findings in three patients but rejected a suspected cardiomyopathy in one patient. In summary, TTE was consistent with non-ischemic cardiomyopathy (5) or ischemic cardiomyopathy (7). A cardiac MRI (CMR) was done in 12 patients. In the remainder of the patients CMR was not performed as a definitive diagnosis had been established (25), due to patient preference (1) or limited capacity in the CMR suite (5). The CMR was normal in four. CMR established a diagnosis in five patients (4 cardiomyopathies, 1 case of IHD). Borderline, non-diagnostic findings were present in the remaining three patients. An electrophysiological (EP) study was performed in four patients; in 1 patient a possible etiology was identified followed by an ablation (Wolff-Parkinson-White syndrome with likely atrial fibrillation). A myocardial biopsy (MYBI) was performed in two cases. One was normal, the other displayed discrete signs of myocardial hypertrophy (defined as myocardial disarray). Late potentials were performed in seven patients; the test was positive in two patients but did not contribute to the diagnosis in either case. Pharmacological provocation tests A flecainide test was performed in five patients; it was positive in one patient according to the 2013 consensus report on the Brugada syndrome [14]. It was borderline positive in one patient but not considered sufficient for the BrS diagnosis. An isoprenaline stimulation test performed in one patient strongly suggested the presence of the LQTS. Diagnoses and device therapy Following the clinical evaluation, 16 patients were classified as having suffered from idiopathic ventricular fibrillation and 14 were categorized as having had a cardiac arrest due to IHD (5 of these 14 suffered an acute coronary syndrome at the time of the cardiac arrest). In six cases a cardiomyopathy was identified, four of these were possibly inheritable and the two latter possibly related to previous chemotherapy and long-standing hypertension, respectively. Three patients with prolonged QTc duration were identified, in two of whom the observed QTc prolongation was considered acquired (electrolyte disturbances and
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Table 1 Evaluation of cardiac arrest survivors.
Performed Normal Significant findings
Echo
Coronary angiogram
CT coronary angiogram
Stress test, bicycle
CMR
EP study
Late potentials
Flecainide
Isopre-naline
Myocardial biopsy
43 13 13
35 13 16
5 5 0
7 6 1
12 4 5⁎
4 3 1
7 7 0
5 4 1
1 0 1
2 2 0
Table 1 presents an overview over the workup that was offered to cardiac arrest survivors in the study period. All patients were submitted to a TTE and the majority was referred for an invasive coronary angiogram. CMR, EP studies, late potentials (LP) or drug provocation tests (with flecainide to tease out BrS signs or Isoprenaline to diagnose LQTS or catecholaminergic polymorphic ventricular tachycardia) were performed in subsets of patient according to clinical presentation as indicated by clinician choice. ⁎ CMR findings consistent with either cardiomyopathy (4) or IHD (1).
antipsychotic medication, respectively). One patient was diagnosed with the Brugada syndrome. In one patient there was evidence of severe spasms of a coronary artery with ST-elevations on the telemetry immediately before the cardiac arrest. In addition, coronary spasms were presumed in a patient undergoing chemotherapy (capecitabin). Finally, in one patient ventricular pre-excitation with atrial fibrillation was identified during an invasive EP study. 36 patients accepted an implantable intracardiac cardioverter defibrillator (ICD) before discharge. The reasons for not implanting an ICD therapy in the remaining seven survivors were: reversible triggers controlled (acute coronary syndrome (3), acquired QTc prolongation (1), WPW and atrial fibrillation treated by ablation (1), congenital long QT syndrome (cLQTS) in patient where beta-receptor adrenergic blocking agents were initiated (1)) and patient preference (1).
Family history 10 patients reported at least one case of sudden cardiac death in the family earlier than age 65 years. Data on family history is presented in Table 2. These patients were subsequently diagnosed with IHD (4), cardiomyopathy (3), other (1) or received no diagnosis (2). Also, five patients reported a family history of inheritable cardiac disease; premature IHD (2), dilated cardiomyopathy (DCM) (1), hypercholesterolemia (1) or Marfan syndrome (1) – in no case were these diagnoses found to have caused the cardiac arrest in the index cases. 10 patients reported cases of IHD in the family (in 2 instances b age 60); among the index cases in these families, IHD was the presumed cause of cardiac arrest in three cases. Only one patient reported syncope in a relative.
Extended analysis of the electrocardiogram; dynamics of the QTc interval and Brugada pattern in elevated leads Five ECGs were excluded from QTc calculations and elevated lead analysis for BrS signs (due to LBBB (2), noise (2), atrial fibrillation (1)). Therefore, supplementary analyses were performed on ECGs from 38 cardiac arrest survivors. In seven cases, both investigators found that the QTc duration was N50 ms prolonged during standing when compared to ECGs in the supine position (Fig. 1). Among the cases with
standing-induced QTc prolongation was the one patient with cLQTS. In addition, in five patients with no specific cardiac diagnose and one diagnosed with IHD QTc prolongation (more than 50 ms) was induced during brisk standing. Cardiac function was normal or near normal in all of these seven patients as assessed by TTE. None of the two patients with acquired QT prolongation as the presumed cause of cardiac arrest were identified during brisk standing, possibly due to removal of the triggering factor at the time of brisk standing test performance. In three cases, coved ST elevations were observed when leads V1 and V2 were elevated to intercostal spaces 2 and 3. The patient diagnosed with the BrS was among these three patients (panel C in Fig. 2). This patient and another patient had structurally normal hearts on TTE and CMR. In contrast, a third patient with BrS like findings on the elevated ECG leads (panel A in Fig. 2) displayed regional hypokinesia and a left ventricular LVEF of 45% on TTE (no CMR was performed in this case), however, these structural abnormalities were not accepted as the cause of the cardiac arrest. None of these 3 patients had been subjected to a flecainide test during the evaluation presented in this paper; however Table 2 Family history of cardiac conditions in relatives of cardiac arrest survivors.
Family history of SCD in 1st or 2nd degrees relatives b65 years Family history of inheritable cardiac disease Family history of IHD
N
Findings in SCD victims
10
5 IHD 3 cardiomyopathy 2 unresolved None
5 10
5 unresolved 3 IHD 2 other
Table 2 shows the family history of sudden cardiac death (SCD) before the age of 65 years, inheritable cardiac disease and ischemic heart disease (IHD). 10 patients reported familial SCD b65 years, in these probands IHD and cardiomyopathy was identified in eight cases whereas two remained unresolved (without diagnosis = no dx). In five cases the proband reported familial heart disease; however, no inheritable or other specific cardiac condition was identified in the index case. Finally, IHD was common among relatives of SCD survivors being reported by 10 patients; however, only three of these 10 patients were ultimately diagnosed with IHD themselves, half (5) remained unresolved and in two cases another cause was identified (probable acquired LQTS (aLQTS) and cardiotoxic effects of antineoplastic therapy).
P. Marstrand et al. / Journal of Electrocardiology xx (2016) xxx–xxx
5
A.
B.
C.
D.
E.
F.
G.
M 62 y, no dx 456+49 ms TTE minor abn.
M 53 y,no dx 435+66 ms TTE minor abn. CMRI normal
M 29, no dx 437+75 ms TTE and CMRI minor abn.
M 50 y, no dx 453+75 ms TTE normal
M 63 y, IHD 435+109 TTE normal
M, 59 y, no dx 411+121 ms TTE minor abn.
F 25 y, LQTS 467+127 ms TTE normal
V1 V2 V3 V4 V5 V6
Fig. 1. displays the supplementary ECGs from patients with the largest increase in QTc duration during brisk standing. For each patient the leftmost picture represents the ECG taken while resting supine, the rightmost panel show the ECG after one minute of brisk standing. Clinical information about each case is listed below the ECGs. For example; patient A is a 62 year-old male cardiac arrest survivor with no definite diagnosis. He displayed a resting QTc interval of 456 ms that increased with 49 ms during brisk standing. In cases A, B, C and F minor abnormalities were found on imaging but none of these were considered the cause of the cardiac arrest (see text for further details).
patients B and C were subsequently tested. The test was positive for Brugada syndrome in patient C whereas borderline ST-elevations were observed in patient B who remains without a certain diagnosis.
Discussion We present our findings in a cohort of prospectively identified cardiac arrest survivors. Our findings are important for the management of cardiac arrest victims as well as of possibly affected relatives. It is well known that the specific cause of a cardiac arrest is often elusive. Several studies suggest that more than half of sudden deaths may be due to definite or possible inheritable cardiac conditions [15]. However, 1/4 SCD victims are categorized as sudden unexplained deaths (defined as sudden death with a subsequent negative autopsy and toxicology screening) [15–24]. When a cause is identified, it is most often coronary artery disease (approx. 30%), cardiomyopathies (approx. 10%) and myocarditis (approx. 5%). Primary arrhythmias are extremely rarely identified post-mortem in SCD victims likely because the diagnosis depends on the electrocardiogram. When including data from cardiac arrest survivors and/or relatives of sudden death victims or survivors primary arrhythmias are identified in roughly 1/4 families evaluated [1–6,9–11]. However, even in studies reporting data from cardiac arrest survivors and/or their relatives the diagnosis is often not identified. For the reasons considered above, we decided to include all consenting long-term cardiac arrest survivors in a prospective study. We included data from the patients' clinical charts, re-interviewed patients about their family history and performed supplementary ECG analyses. In our cohort, the most common cause of the cardiac arrest was idiopathic ventricular tachyarrhythmias (37%), ischemic heart disease (33%), cardiomyopathies (14%), primary arrhythmia syndromes (5%) and other (12%). It is discour-
aging that a large proportion of cardiac arrest survivors remain unresolved despite a thorough evaluation. The lack of a definitive diagnosis complicates counseling and does not allow for a focused cascade screening. During follow-up it will be important to re-evaluate cases based on new information at subsequent outpatient visits and results from screening of possibly affected relatives. Subsequently, we evaluated the value of information about family history. In total, 10 patients reported SCD before the age of 65 years in a relative. In three of the survivors a cardiomyopathy was identified (one case of myocardial hypertrophy considered secondary to hypertension and two cases of dilated cardiomyopathies). However, in DCM the etiology may vary widely. In the end a likely familial cardiomyopathy was only identified in one among 10 patients with familial SCD because there was a specific family history of cardiac enlargement. Among none of five patients reporting a family history of inheritable cardiac disease could the familial condition be identified as the cause of the cardiac arrest in the proband. Finally, in only 3/10 of survivors (with recognized IHD in relatives) was IHD the cause of the cardiac arrest in the proband. As such, the family history was rarely predictive of the diagnosis in the index case. However, having access to more details about the familial cases would likely enhance the utility of familial cases of cardiac disease. Next, we investigated the dynamics of the QTc interval during brisk standing and ECG changes produced by alternative electrode placement. Our aim was to see, if these techniques might tease out findings suggestive of channelopathies which could warrant further evaluation in subsequent prospective studies. The testing for dynamic changes of the QT duration assayed the frequency and magnitude of QT prolongation during brisk standing (which induces a postural sinus tachycardia and on average increases heart rate with approx. 15 bpm). This is important for several reasons. Firstly, it is difficult to measure the QTc interval. In fact, even arrhythmia experts and in particular
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P. Marstrand et al. / Journal of Electrocardiology xx (2016) xxx–xxx
A.
B.
C.
V1 IC4
V2
V1 IC3
V2
V1 IC2
V2 M 58 y, no dx TTE mild abn.
M 39 y, no dx TTE & CMRI normal
M 33 y, BrS TTE & CMRI normal
Fig. 2. show excerpts of ECGs of patients in whom supplementary ECGs produced coved ST-elevations. The patient in panel C was diagnosed with the Brugada syndrome following a comprehensive review of his clinical data. To the left V1 and V2 are marked, to the right the placement of electrodes is shown for intercostal spaces 2, 3 and 4. Below the panel clinical information is included. For example, patient A is a 58 year-old male cardiac arrest survivor in whom no definite diagnosis was reached. His TTE showed septal hypokinesia with a LVEF 45% (see text). In his case no CMR was done.
general cardiologists estimate it wrong (in 40 or 75% of the cases, respectively) when subjected to systematic testing [12]. Secondly, 1/3 LQTS patients are categorized as having concealed LQTS (their QTc interval is within normal limits though they harbor a pathogenic mutation and a 10-time increased risk of SCD) [25,26]. Obviously, we are not the first to search for a solution to this challenge. It has been known for years that epinephrine infusion induce a more pronounced QTc prolongation in LQTS patients when compared to healthy controls [27]. However, infusion of epinephrine may also cause malignant arrhythmias and harm the patients and is therefore not used routinely (only performed one time in our cohort). Therefore, additional, non-invasive tests for identification of patients with pathological QT prolongation as a proxy for diseased cardiac repolarization are required. In 2010, Viskin reported that the QT interval in LQTS patients increased during brisk standing as opposed to the QT interval shortening that was seen in healthy controls during the same test. During continuous ECG recording they found an average maximum QTc stretch of 89 ± 47 ms among LQTS patients and the specificity for LQTS increased to 86% (only 61% using resting ECG). The authors suggested that this phenomenon might be exploited to enhance the diagnosis of LQTS patients [28]. However, all of these studies on the dynamic nature of the QTc interval were generally small (b 100–150 patients) and affected subjects had been identified before inclusion. Though our
cohort too is small, we are the first to report the systematic application of a ‘brisk standing’ test to search for abnormal cardiac repolarization among unselected cardiac arrest survivors. We identified seven patients with a significant and dynamic prolongation of the QTc interval following induction of sinus tachycardia by sudden standing up from a resting position. Even though, an agreement plot of the QTc intervals measured in this study cannot rule out that 4 of 7 cases with the least significantly induced QTc prolongation may be due to measurement errors, the patient who received the LQTS diagnosis (during the routine workup of cardiac arrest survivors) significantly prolonged her QTc during brisk standing. We also systematically collected ECGs in which leads V1–2 were displaced to intercostal spaces 2–3. The purpose was to chase the inconstant coved, right-sided ST-elevation that characterizes the Brugada syndrome. In fact, for unclear reasons this disease entity is exceedingly rare in Denmark. [29,30] Diagnosis is made difficult by a lack of a ‘golden standard’ and a diagnosis that is based on criteria defined by consensus [14,31]. This has resulted in reported false negative rates as high as 75%, false positive rates around 12% and precision as low as 24% [32,33]. Currently however, the BrS diagnosis requires the identification of a type 1 ECG (= coved ST-elevations ≥ 2 mm in ≥ 1 leads) either spontaneously or following elevation of ECG electrodes or stimulation with a drug that inhibits the SCN5A channel (that may be the genetic substrate for the condition). In three patients, we found a positive ECG. We correctly identified one patient already diagnosed with the BrS. Both this patient and another of the three patients with BrS ECGs presented with a structurally normal heart on TTE and CMR, whereas the latter patient presented minor structural changes in the heart on TTE (no CMR performed). Our data do not allow for firm conclusions on the value of the supplemental ECG recordings. Future data from follow-up visits and genetic test results and possibly data from relatives of the index cases will need to be also included in this evaluation. However, we are currently facing the challenge that a diagnosis is not readily identifiable in a significant proportion of cardiac arrest survivors (in this cohort around 40%). Though ICD therapy offers efficient protection (recurrence rates for aborted cardiac arrest have been reported to 20–50%) [14,31,34] additional protection through disease-specific therapies is unavailable to patients categorized as idiopathic ventricular fibrillation. The lack of definitive diagnoses in this large subgroup of cardiac arrest survivors also impacts their relatives, because as much as 50% of sudden cardiac death in younger subjects may be due to inheritable conditions. Therefore, it is considered advisable to screen relatives for disease. On the other hand, it is also very important to identify families that should not be screened. However – at least in this cohort in which the information was often limited to what had been communicated to surviving family members – family history was a poor predictor for disease among unselected cardiac arrest survivors. In conclusion, new tools to assist categorization of cardiac arrest survivors would be welcomed. As cardiac arrest survivors are rare and present a heterogenous
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population, we suggest that prospective national or international registries with the systematic reporting of findings (including as much information as possible generated from non-invasive ECG recording) may be a viable option to understand and enhance our management of these patients and definitely a way to evaluate whether the signals generated in this study have real clinical value.
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