University of Groningen Phospholamban p.Arg14del cardiomyopathy te Rijdt, Wouter

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Phospholamban p.Arg14del cardiomyopathy

te Rijdt, Wouter

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te Rijdt, W. (2019). Phospholamban p.Arg14del cardiomyopathy: Clinical and morphological aspects supporting the concept of arrhythmogenic cardiomyopathy. Rijksuniversiteit Groningen.

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gadolinium enhancement in early-stage

phospholamban p.Arg14del cardiomyopathy

CHAPTER 10

Wouter P. te Rijdt MD#a-c_{, Belend Mahmoud}#a_{, Tom E. Verstraelen}d_{, Thomas M. Gorter MD, PhD}a_, Judith N. ten Sande MDb,d_{, Paul A. van der Zwaag MD, PhD}c_{, Ingrid A. van Rijsingen MD, PhD}d_,

S. Matthijs Boekholdt MD, PhDd_{, J. Peter van Tintelen MD, PhD}e_{, Toon Oomen MD, PhD}f,g_, R. Nils Planken MD, PhDh_{, Dirk J. van Veldhuisen MD, PhD}a_{, Tineke P. Willems MD, PhD}j_, Pascal F.H.M. van Dessel MD, PhDd,k_{, Arthur A.M. Wilde MD, PhD}d_{, Rudolf A. de Boer MD, PhD}a_, Maarten P. van den Berg MD, PhDa #_{These authors contributed equally}

a_{Department of Clinical and Experimental Cardiology, University of Groningen,}

University Medical Center Groningen, Groningen, the Netherlands

b_{Netherlands Heart Institute (Nl-HI), Utrecht, the Netherlands} c_{Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands} d_{Heart Center, Department of Clinical and Experimental Cardiology, University of Amsterdam,}

Academic Medical Center, Amsterdam, the Netherlands

e_{Department of Clinical Genetics, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands} f_{Department of Cardiology, Antonius Hospital, Sneek, the Netherlands} h_{Department of Radiology, University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands} j_{Department of Radiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.}

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Abstract

Background

Phospholamban (PLN) p.Arg14del cardiomyopathy is characterized by a malignant biventricular phenotype with a high mortality and poor prognosis from late adolescence. A left ventricular ejection fraction (LVEF) below 45% and documented (non-)sustained ventricular tachycardia (VT) were shown to be independent risk-factors for the development of malignant ventricular arrhythmia (VA). Myocardial fibrosis was found to be present in one third of the total population even in many mutation carriers with normal LVEF and associated with a higher risk of VA. Aims

To investigate the prognostic value of late gadolinium enhancement presence by follow-up of the PLN CMR cohort.

Methods and Results

Of the 150 PLN mutation carriers, 19 were lost to follow-up leaving a final follow-up cohort of 131 subjects. Mean age was 45 ± 15 years and 42.7% were males. LV-LGE was present in 44 (33.6%) mutation carriers. In the LV-LGE subgroup, 22.7% of mutation carriers had a reduced LVEF (<45%). Low R-waves were measured in 63 cases (48.1%) and 39 mutation carriers (29.8%) had inverted T-waves recorded in the lateral leads (V4-V6). The mean follow-up duration was 5.1 ± 1.6 years. Eight mutation carriers (6.1%) suffered malignant ventricular arrhythmia during follow- up. In the LGE subgroup, significantly more malignant ventricular arrhythmia occured. LVEF<45%, LV-LGE presence and inverted T-waves in the lateral ECG leads were all significantly associated with the occurrence of malignant ventricular arrhythmia. However, after multivariate analysis none of these risk factors proved to be an independent predictor of malignant ventricular arrhythmia. Conclusion

We observe a clear trend towards incremental value of LV-LGE in prognostication of PLN p.Arg14del mutation carriers. A longer follow-up period is required in order to show whether LV-LGE is an independent predictor of malignant ventricular arrhythmia.

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Introduction

Phoshpolamban (PLN) p.Arg14del cardiomyopathy is associated with dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM)1_{and characterized by a malignant} biventricular phenotype with a high mortality and poor prognosis from late adolescence.2_Low voltages and repolarization changes on the surface ECG, including the left lateral leads, were shown to be early hallmarks of PLN p.Arg14del cardiomyopathy.1,3_{Over 1000 carriers of the PLN} p.Arg14del mutation have been identifi ed (http://www.phorecast.nl), in the Netherlands, many other European countries (Germany, Belgium, Spain, the United Kingdom and Norway), Canada, and the USA.

Van Rijsingen et al. found a left ventricular ejection fraction (LVEF) below 45% or documented (non-)sustained ventricular tachycardia (VT) to be independent risk-factors for the development of malignant ventricular arrhythmia in PLN p.Arg14del mutation carriers.2_{In whole} heart specimens of PLN p.Arg14del mutation carriers, we observed biventricular fi brosis and fatty infi ltration.4,5_{In a recent cross-sectional study in 150 asymptomatic p.Arg14del mutation carriers,} we demonstrated that late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR), a surrogate marker for focal myocardial fi brosis, was present in one third of the total population, yet also in many mutation carriers with normal LVEF.6 _{Moreover, we found the} presence and location of LV-LGE to be associated with a higher risk of VA in PLN p.Arg14del mutation carriers, even in the setting of preserved LVEF. More in general, previous studies have shown that LV-LGE on CMR imaging is a strong risk factor for sudden cardiac death (SCD) and overall mortality in a wide range of cardiomyopathies, e.g. DCM.7-11_{Early identifi cation may guide} early therapeutic intervention and lifestyle adjustments.

We hypothesized that CMR and particularly LGE imaging has incremental value in the risk stratifi cation of PLN p.Arg14del mutation carriers. We therefore aimed to study the prognostic value of cardiac MRI in mutation carriers for the development of malignant ventricular arrhythmia and cardiac death.

Methods

Source population

Adult (>18 years old) PLN p.Arg14del mutation carriers who had undergone CMR imaging were selected from the PHORECAST registry (PHOspholamban RElated CArdiomyopathy STudy; http:// www.phorecast.nl). It comprises the same cohort as previously described cross-sectional.6 Demographic and clinical parameters at the time of CMR and all available follow-up data were collected in three Dutch hospitals: University Medical Center Groningen (UMCG), Academic Medical Center Amsterdam (AMC), and Antonius Hospital Sneek (AZS). This group included both index mutation carriers and their relatives referred to a cardiogenetics outpatient clinic for family cascade screening. Index mutation carriers in the cohort were not known to be related to each other.

Cardiovascular magnetic resonance imaging protocol and analysis (as previously described6₎ All CMR studies were performed on a 1.5-T scanner (Siemens, Erlangen, Germany) using a phased array cardiac receiver coil. Using identical slice locations, late gadolinium-enhanced (LGE) images

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were acquired 10 minutes after intravenous administration of a gadolinium-based contrast agent (Dotarem, Gorinchem, the Netherlands; 0.2 mmol/kg) with an inversion-recovery, gradient-echo pulse sequence to identify the location and extent of LGE-distribtion. The inversion time was individually set to null the signal of viable myocardium. All CMR imaging analyses were performed using QMass 7.6 (Medis medical imaging systems BV, Leiden, the Netherlands). For LGE imaging, first the presence of delayed-enhanced signal intensity was visually determined by two experienced independent observers (by agreement), who were blinded for mutation carriers’ clinical data (T.M.G.:>5 years’ experience in CMR; and T.P.W.: >15 years’ experience in CMR, Level 3 certified cardiovascular radiologist). Subsequently, the extent of LV-LGE was quantified by one observer (T.M.G.) using the full-width at half-maximum method, by defining the enhanced area using 50% of the maximum signal found within the enhanced area.12_{LV-LGE size was expressed} as a percentage of total LV mass. LV-LGE location was determined using the 17-segment model.13 Cardiac disease outcome

Cardiac disease outcome was defined as the occurrence of malignant ventricular arrhythmia. Malignant ventricular arrhythmia was defined as cardiopulmonary resuscitation (CPR), appropriate implantable cardioverter defibrillator (ICD) intervention (discharge to terminate ventricular fibrillation or VT or antitachycardia pacing to terminate VT), or SCD. CPR was defined as a basic life support for a cardiac arrest with return of stable circulation. Appropriate ICD intervention was classified as an ICD discharge to terminate ventricular fibrillation or VT or antitachycardia pacing to terminate VT. SCD was defined as death (with or without documented ventricular fibrillation) within 1 hour of acute symptoms or a nocturnal death with no antecedent history of worsening symptoms.

The occurrence of ventricular arrhythmias (ambulatory 24-h ECG, exercise ECG or ICD report) and ECG abnormalities were documented. Non-sustained ventricular tachycardia (VT) was defined as at least three consecutive ventricular complexes at a heart rate >100 beats/min with a duration of less than 30 seconds. Sustained VT was defined as an arrhythmia at a heart rate >100 beats/min that lasted ≥30 seconds and/or required termination because of hemodynamic compromise in <30 seconds.

Statistical analysis

Statistical analyses were performed using SPSS software, version 24.0 (SPSS for Windows, 2016 release 24.0.0.0, Chicago, Ill, USA). Continuous variables are presented as a mean with standard deviation (SD). Categorical variables are presented as frequencies with percentages and analyzed using the Pearson’s chi-square test. Risk factor analysis for malignant ventricular arrhythmia was performed using Cox regression. Univariate analysis was performed on potential risk factors for the malignant ventricular arrhythmia. Significant variables were subsequently analyzed in a multivariable Cox regression model. Hazard ratio’s and 95% confidence intervals were calculated. A p-value of less than 0.05 was deemed to be statistically significant.

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Table 1: Baseline characteristics and cardiac events (n=131; categorized by presence of LV-LGE).

Total population

(n=131) LV-LGE presence (n=44) No LV-LGE (n=87) p-value

Age 45±15 51±14 42±14 0.87

Men 56 (42.7%) 21 (47.7%) 35 (40.2%) 0.41

LVEF

LVEF<45% 10 (7.6%) 58.1±9.2 10 (22.7%) 51.7±11.6 61.4±5.5 0 (0.0%) <0.001 0.36

ECG abnormalities Low voltage R-waves Inverted T-waves 72 (55.0%) 63 (48.1%) 39 (29.8%) 32 (72.7%) 29 (65.9%) 25 (56.8%) 40 (46.0%) 34 (39.1%) 14 (16.1%) 0.004 0.004 <0.001 ICD implantation 26 (19.8%) 17 (38.6%) 9 (10.3%) <0.001 (ns)VT 18 (13.8%)A _{14 (32.6%)}B _{4 (4.6%)} _<0.001 Outcome events SCD

ICD shock intervention CPR 8 (6.1%) 3 (2.3%) 7 (5.4%)A 2 (1.5%)A 6 (13.6%) 3 (6.8%) 5 (11.6%)B 2 (4.7%)B 2 (2.3%) 0 (0.0%) 2 (2.3%) 0 (0.0%) 0.010 0.014 0.027 0.043

A _{based on 130 patients,}B _{based on 43 patients}

Results

Baseline characteristics (table 1 and fi gure 1)

In total, 150 PLN-mutation carriers who underwent a routine cardiac MRI were identifi ed. Nineteen mutation carriers were lost to follow-up, leaving a fi nal study sample of 131 subjects. Mean age was 45 ± 15 years and 42.7% were males. LV-LGE was present in 44 (33.6%) mutation carriers. From the mutation carriers with LV-LGE, the mean percentage of scar tissue expressed as a percentage of the total myocardium was 9.6% [range 1.3% to 44.0%]. The mean LVEF in our population was 58.1% ± 9.2%, with 10 mutation carriers (7.6%) having an LVEF below 45%. All mutation carriers with a LVEF<45% also had LV-LGE. In the LV-LGE subgroup, 22.7% of mutation carriers had a reduced LVEF (<45%). Electrocardiographically, low R-waves were measured in 63 cases (48.1%), 29 of those had a present LV-LGE. Additionally, 39 mutation carriers (29.8%) had inverted T-waves recorded in the lateral leads (V4-V6) with 25 of them having LV-LGE present on CMR.

Table 1. Baseline characteristics and cardiac events (n=131; categorized by presence of LV-LGE).

Abbreviations: LVEF, left ventricular ejection fraction; ICD, implantable cardioverter-defi brillator; nsVT, non sustained ventricular tachycardia; SCD, sudden cardiac death; CPR, cardiopulmonary resuscitation; LV-LGE, left ventricular late gadolinium enhancement.

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Figure 1. Study population: incidences of various events in our total study population categorized by LV-LGE presence

Abbreviations: LVEF, left ventricular ejection fraction; ICD, implantable cardioverter-defibrillator; nsVT, non sustained ventricular tachycardia; SCD, sudden cardiac death; CPR, cardiopulmonary resuscitation; LV-LGE, left ventricular late gadolinium enhancement.

Cardiac disease outcome (table 1 and figure 1)

The mean follow-up duration was 5.1 ± 1.6 years. Eight mutation carriers (6.1%) suffered malignant ventricular arrhythmia during follow-up. Twenty-six (19.8%) mutation carriers received an ICD, with 7 (5.4%) of them having received an ICD shock intervention at least once. Furthermore, 2 mutation carriers (1.5%) required CPR and 3 cases (2.3%) of SCD were observed. Moreover, in 18 (14.0%) mutation carriers (ns)VT was documented at baseline.

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165 Risk factors for malignant ventricular arrhythmia (table 2 and fi gure 2)

In a univariate model (table 2), LVEF<45% (HR = 16.49 [4.00-67.93], p = <0.001), inverted T-waves in the lateral ECG leads (HR = 7.77 [1.57-38.52], p = 0.012) and the presence of LV-LGE (HR = 6.36 [1.28- 31.52], p = 0.024) all signifi cantly increased the likelihood of developing malignant ventricular arrhythmia. However, when taking these signifi cant factors into account in a multivariable model (table 2), none of these risk factors proved to be an independent predictor of malignant ventricular arrhythmia.

Cumulative event-free survival of mutation carriers with and without LV-LGE are shown in Figure 2. During follow-up, signifi cantly less malignant ventricular arrhythmia occurred in individuals without LV-LGE (P<0.001). When comparing specifi cally the subgroups with and without LV-LGE in combination with a relatively preserved LVEF, a marked trend towards a longer period of cumulative event-free survival can be seen in the group without LV-LGE (fi gure 2, bottom)

Table 2. Risk factors for malignant ventricular arrhythmia

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Table 2: Risk factors for malignant ventricular arrhythmia. Malignant ventricular

arrhythmia subgroup (n=8)

Hazard ratio (95% CI)

univariate (univariate) p-value Hazard ratio (95% CI) multivariate (multivariate) p-value

LVEF<45% 4 (50.0%) 16.49 (4.00-67.93) <0.001 6.00 (0.99-36.32) 0.051

Inverted T-waves 6 (75.0%) 7.77 (1.57-38.52) 0.012 3.01 (0.44-20.87) 0.264

LV LGE 6 (75.0%) 6.36 (1.28-31.52) 0.024 1.87 (0.24-14.52) 0.551

(ns)VT 3 (37.5%) 3.73 (0.89-15.65) 0.072 - -

Female 2 (25.0%) 0.24 (0.05-1.20) 0.083 - -

Low voltage ECG 6 (75.0%) 3.16 (0.64-15.66) 0.159 - -

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Figure 2. Kaplan-Meier event-free survival stratified by the presence or absence of LV-LGE (above) and by LVEF, more or less than 45%, and the presence or absence of LV-LGE (bottom)

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Discussion

Late gadolinium-enhanced (LGE) cardiovascular magnetic resonance imaging (CMR) has become the gold standard for non-invasive in vivo assessment of ventricular myocardial fi brosis; it allows the early identifi cation and evaluation of both the extent and localization of myocardial fi brosis in diff erent forms of cardiomyopathy.14-16_{Early myocardial fi brosis, as by the presence} of LV-LGE on CMR, was identifi ed as a key clinical feature of PLN p.Arg14del cardiomyopathy.6 After a follow-up period of approximately 5 years we found the subgroup with LV-LGE to have signifi cantly more malignant ventricular arrhythmia than the mutation carriers without LV-LGE.

In current clinical practice, PLN p.Arg14del mutation carriers with an LVEF below 45% are eligible for ICD implantation, regardless of the presence of LV-LGE.2 Therefore, LV-LGE detection is of special clinical interest in the subgroup of mutation carriers with (still) a relatively preserved ejection fraction. In this subgroup, we observed a marked trend towards a longer period of cumulative event- free survival can be seen in the preserved LVEF group without LV-LGE in comparison to the group with LV-LGE. However, in the mutation carrier group without LV-LGE, we still observed 2 events, indicating the occurrence of malignant ventricular arrhythmia cannot be ruled out when there is no LV- LGE.

After multivariable analysis, the presence of LV-LGE did not prove to be an independent predictor for the development of malignant ventricular arrhythmia. Even more we found no risk factors to be an independent predictor for the development of malignant ventricular arrhythmia, including an LVEF below 45% and a history of (ns)VT.2_{We believe a lack of events power to be the} cause in our study population may be the reason why LV-LGE did come out signifi cantly in our univariate analysis, but not yet in our multivariate model. This is a known phenomenon in genetic diseases with limited malignant ventricular arrhythmia in early-stage disease, necessitating a long follow-up time.

The selection of the cohort was based on the availability of CMR imaging. CMR imaging was only performed in PLN p.Arg14del mutation carriers without a pacemaker or implantable cardioverter defi brillator, leading to a preferential inclusion of mutation carriers with early-stage disease. The majority were not index mutation carriers, but carriers identifi ed after family cascade screening often showing milder disease. However, these circumstances do provide us the opportunity to study the role of LV-LGE in early-stage disease with a relatively preserved LVEF, a subgroup of mutation carriers where risk stratifi cation and the decision to initiation treatment is often problematic.

The main limitation of the LGE technique is the inability to evaluate diff use myocardial fi brosis. The enhanced area is defi ned on the basis of the diff erence in signal intensity relative to that of the normal myocardium. If the myocardial fi brosis is diff use instead of focal, no diff erences in signal intensity will be observed. T1 mapping, a CMR sequence to visualize and quantify diff use myocardial interstitial fi brosis in the whole heart, better refl ects the total myocardial fi brosis burden17 but has only recently become available at our centers. This new technique might prove of incremental value in the risk stratifi cation of mutation carriers.

This study was designed to investigate the incremental value of LV-LGE in PLN p.Arg14del mutation carriers. In this mainly early-stage disease cohort, not enough events occurred to study this reliably. Further follow-up is needed to see whether LV-LGE is a suffi cient prognostic marker

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and, subsequently, determinant for therapeutic intervention beside known risk factors. Moreover, additional research is warranted to elaborate which alternative underlying mechanisms are responsible for the malignant ventricular arrhythmia in p.Arg14del mutation carriers whom do not have LV-LGE.

Funding

This work was supported by the Netherlands Cardiovascular Research Initiative (CVON), an initiative supported by the Dutch Heart Foundation (the Hague, the Netherlands): CVON [grant number 2012- 10] PREDICT, CVON [grant number 2014-40] DOSIS and CVON [grant number 2015-12] eDETECT projects. W.P.t.R is supported by Young Talent Program (CVON PREDICT) grant 2017T001 - Dutch Heart Foundation.

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