Publications by authors named "Maarten P van den Berg"

182 Publications

Optimal echocardiographic assessment of myocardial dysfunction for arrhythmic risk stratification in phospholamban mutation carriers.

Eur Heart J Cardiovasc Imaging 2021 Sep 13. Epub 2021 Sep 13.

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Aims : Phospholamban (PLN) p.Arg14del mutation carriers are at risk of developing malignant ventricular arrhythmias (VAs) and/or heart failure. Currently, left ventricular ejection fraction (LVEF) plays an important role in risk assessment for VA in these individuals. We aimed to study the incremental prognostic value of left ventricular mechanical dispersion (LVMD) by echocardiographic deformation imaging for prediction of sustained VA in PLN p.Arg14del mutation carriers.

Methods And Results: We included 243 PLN p.Arg14del mutation carriers, which were classified into three groups according to the '45/45' rule: (i) normal left ventricular (LV) function, defined as preserved LVEF ≥45% with normal LVMD ≤45 ms (n = 139), (ii) mechanical LV dysfunction, defined as preserved LVEF ≥45% with abnormal LVMD >45 ms (n = 63), and (iii) overt LV dysfunction, defined as reduced LVEF <45% (n = 41). During a median follow-up of 3.3 (interquartile range 1.8-6.0) years, sustained VA occurred in 35 individuals. The negative predictive value of having normal LV function at baseline was 99% [95% confidence interval (CI): 92-100%] for developing sustained VA. The positive predictive value of mechanical LV dysfunction was 20% (95% CI: 15-27%). Mechanical LV dysfunction was an independent predictor of sustained VA in multivariable analysis [hazard ratio adjusted for VA history: 20.48 (95% CI: 2.57-162.84)].

Conclusion : LVMD has incremental prognostic value on top of LVEF in PLN p.Arg14del mutation carriers, particularly in those with preserved LVEF. The '45/45' rule is a practical approach to echocardiographic risk stratification in this challenging group of patients. This approach may also have added value in other diseases where LVEF deterioration is a relative late marker of myocardial dysfunction.
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http://dx.doi.org/10.1093/ehjci/jeab178DOI Listing
September 2021

Comparing clinical performance of current implantable cardioverter-defibrillator implantation recommendations in arrhythmogenic right ventricular cardiomyopathy.

Europace 2021 Sep 1. Epub 2021 Sep 1.

Netherlands Heart Institute, PO Box 19258, 3501 DG, Utrecht, The Netherlands.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) patients have an increased risk of ventricular arrhythmias (VA). Four implantable cardioverter-defibrillator (ICD) recommendation algorithms are available The International Task Force Consensus ('ITFC'), an ITFC modification by Orgeron et al. ('mITFC'), the AHA/HRS/ACC guideline for VA management ('AHA'), and the HRS expert consensus statement ('HRS'). This study aims to validate and compare the performance of these algorithms in ARVC.

Methods And Results: We classified 617 definite ARVC patients (38.5 ± 15.1 years, 52.4% male, 39.2% prior sustained VA) according to four algorithms. Clinical performance was evaluated by sensitivity, specificity, ROC-analysis, and decision curve analysis for any sustained VA and for fast VA (>250 b.p.m.). During 6.4 [2.8-11.5] years follow-up, 282 (45.7%) patients experienced any sustained VA, and 63 (10.2%) fast VA. For any sustained VA, ITFC and mITFC provide higher sensitivity than AHA and HRS (94.0-97.8% vs. 76.7-83.5%), but lower specificity (15.9-32.0% vs. 42.7%-60.1%). Similarly, for fast VA, ITFC and mITFC provide higher sensitivity than AHA and HRS (95.2-97.1% vs. 76.7-78.4%) but lower specificity (42.7-43.1 vs. 76.7-78.4%). Decision curve analysis showed ITFC and mITFC to be superior for a 5-year sustained VA risk ICD indication threshold between 5-25% or 2-9% for fast VA.

Conclusion: The ITFC and mITFC provide the highest protection rates, whereas AHA and HRS decrease unnecessary ICD placements. ITFC or mITFC should be used if we consider the 5-year threshold for ICD indication to lie within 5-25% for sustained VA or 2-9% for fast VA. These data will inform decision-making for ICD placement in ARVC.
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http://dx.doi.org/10.1093/europace/euab162DOI Listing
September 2021

TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility.

Eur J Hum Genet 2021 Aug 30. Epub 2021 Aug 30.

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

Deletions that include the gene TAB2 and TAB2 loss-of-function variants have previously been associated with congenital heart defects and cardiomyopathy. However, other features, including short stature, facial dysmorphisms, connective tissue abnormalities and a variable degree of developmental delay, have only been mentioned occasionally in literature and thus far not linked to TAB2. In a large-scale, social media-based chromosome 6 study, we observed a shared phenotype in patients with a 6q25.1 deletion that includes TAB2. To confirm if this phenotype is caused by haploinsufficiency of TAB2 and to delineate a TAB2-related phenotype, we subsequently sequenced TAB2 in patients with matching phenotypes and recruited patients with pathogenic TAB2 variants detected by exome sequencing. This identified 11 patients with a deletion containing TAB2 (size 1.68-14.31 Mb) and 14 patients from six families with novel truncating TAB2 variants. Twenty (80%) patients had cardiac disease, often mitral valve defects and/or cardiomyopathy, 18 (72%) had short stature and 18 (72%) had hypermobility. Twenty patients (80%) had facial features suggestive for Noonan syndrome. No substantial phenotypic differences were noted between patients with deletions and those with intragenic variants. We then compared our patients to 45 patients from the literature. All literature patients had cardiac diseases, but syndromic features were reported infrequently. Our study shows that the phenotype in 6q25.1 deletions is caused by haploinsufficiency of TAB2 and that TAB2 is associated not just with cardiac disease, but also with a distinct phenotype, with features overlapping with Noonan syndrome. We propose the name "TAB2-related syndrome".
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http://dx.doi.org/10.1038/s41431-021-00948-0DOI Listing
August 2021

Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.

J Clin Invest 2021 Jul 22. Epub 2021 Jul 22.

Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands.

The start codon c.1A>G mutation in KLHL24, encoding ubiquitin-ligase KLHL24, results in the loss of 28 N-terminal amino acids (KLHL24-ΔN28) by skipping the initial start codon. In skin, KLHL24-ΔN28 leads to gain of function, excessively targeting intermediate filament keratin-14 for proteasomal degradation, ultimately causing epidermolysis bullosa simplex (EBS). The majority of these EBS-patients are also diagnosed with dilated cardiomyopathy (DCM), but the pathological mechanism in the heart is unknown. As desmin is the cardiac homologue of keratin-14, we hypothesized that KLHL24-ΔN28 leads to excessive degradation of desmin, resulting in DCM. Dynamically loaded engineered heart tissues (dyn-EHTs) were generated from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from two patients and three (non)familial controls. Ten-fold lower desmin protein levels were observed in patient-derived dyn-EHTs, in line with diminished desmin levels detected in patients' explanted heart. This was accompanied by tissue dilatation, impaired mitochondrial function, decreased force values and increased cardiomyocyte stress. HEK293 transfection studies confirmed KLHL24-mediated desmin degradation. KLHL24 RNA interference or direct desmin overexpression recovered desmin protein levels, restoring morphology and function in patient-derived dyn-EHTs. To conclude, presence of KLHL24-ΔN28 in cardiomyocytes leads to excessive degradation of desmin, affecting tissue morphology and function, that can be prevented by restoring desmin protein levels.
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http://dx.doi.org/10.1172/JCI140615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409593PMC
July 2021

Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction.

Eur Heart J 2021 07;42(29):2842-2850

Heart Center, Department of Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands.

Aims: This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model.

Methods And Results: Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27-55]. During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75).

Conclusion: This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach.
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http://dx.doi.org/10.1093/eurheartj/ehab294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325776PMC
July 2021

The Time Has Come to Explore Plasma Biomarkers in Genetic Cardiomyopathies.

Int J Mol Sci 2021 Mar 14;22(6). Epub 2021 Mar 14.

Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, AB43, 9713 GZ Groningen, The Netherlands.

For patients with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM), screening for pathogenic variants has become standard clinical practice. Genetic cascade screening also allows the identification of relatives that carry the same mutation as the proband, but disease onset and severity in mutation carriers often remains uncertain. Early detection of disease onset may allow timely treatment before irreversible changes are present. Although plasma biomarkers may aid in the prediction of disease onset, monitoring relies predominantly on identifying early clinical symptoms, on imaging techniques like echocardiography (Echo) and cardiac magnetic resonance imaging (CMR), and on (ambulatory) electrocardiography (electrocardiograms (ECGs)). In contrast to most other cardiac diseases, which are explained by a combination of risk factors and comorbidities, genetic cardiomyopathies have a clear primary genetically defined cardiac background. Cardiomyopathy cohorts could therefore have excellent value in biomarker studies and in distinguishing biomarkers related to the primary cardiac disease from those related to extracardiac, secondary organ dysfunction. Despite this advantage, biomarker investigations in cardiomyopathies are still limited, most likely due to the limited number of carriers in the past. Here, we discuss not only the potential use of established plasma biomarkers, including natriuretic peptides and troponins, but also the use of novel biomarkers, such as cardiac autoantibodies in genetic cardiomyopathy, and discuss how we can gauge biomarker studies in cardiomyopathy cohorts for heart failure at large.
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http://dx.doi.org/10.3390/ijms22062955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998409PMC
March 2021

Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy: A Multinational Collaboration.

Circ Arrhythm Electrophysiol 2021 01 9;14(1):e008509. Epub 2020 Dec 9.

Department of Medicine, Division of Cardiology (J.C.-T., W.W., A.B., C.T., B.M., S.C., J.E.C., D.P.J., H.T., H.C., C.A.J.), Johns Hopkins Hospital, Baltimore, MD.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD.

Methods: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping.

Results: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77-10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69-0.80) and calibration slope of 0.95 (95% CI, 0.94-0.98) indicating minimal over-optimism.

Conclusions: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.
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http://dx.doi.org/10.1161/CIRCEP.120.008509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834666PMC
January 2021

Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms.

JACC Cardiovasc Imaging 2021 05 18;14(5):885-896. Epub 2020 Nov 18.

Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Objectives: This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms.

Background: Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent.

Methods: PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of <500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed.

Results: The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p < 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%).

Conclusions: Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.
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http://dx.doi.org/10.1016/j.jcmg.2020.09.030DOI Listing
May 2021

Cardiac Transthyretin-derived Amyloidosis: An Emerging Target in Heart Failure with Preserved Ejection Fraction?

Card Fail Rev 2020 Mar 7;6:e21. Epub 2020 Aug 7.

Department of Cardiology, University of Groningen, University Medical Center Groningen Groningen, the Netherlands.

Heart failure with preserved ejection fraction (HFpEF) comprises half of the heart failure population. A specific, but underdiagnosed, cause for HFpEF is transthyretin-derived (ATTR) amyloidosis. This article reviews the clinical characteristics of cardiac ATTR amyloidosis. The clinical suspicion of cardiac ATTR amyloidosis is strong if pronounced left ventricular hypertrophy is present in the absence of hypertension. Scintigraphy with a diphosphonate tracer is a diagnostic tool for the early detection of cardiac ATTR amyloidosis with high sensitivity and specificity. First treatment options for ATTR amyloidosis recently emerged, and showed a reduction in morbidity and mortality, especially if treatment was started in the early stages of disease. In light of these results, screening for ATTR amyloidosis in the general HFpEF population with left ventricular hypertrophy might be useful.
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http://dx.doi.org/10.15420/cfr.2019.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479537PMC
March 2020

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 01 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes.

Int J Cardiol 2021 01 1;323:251-258. Epub 2020 Sep 1.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background - Variants within the alpha-tropomyosin gene (TPM1) cause dominantly inherited cardiomyopathies, including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathy. Here we investigated whether TPM1 variants observed in DCM and HCM patients affect cardiomyocyte physiology differently. Methods - We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM. The effects of TPM1 variants (T201M, E62Q or M281T) and of a plasmid containing both the E62Q and M281T variants on single-cell Ca transients (CaT) in HL-1 cardiomyocytes were studied. To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants. In addition, cardiomyocyte structure was studied in human cardiac biopsies with TPM1 variants. Results - Overexpression of TPM1 variants led to time-dependent progressive deterioration of CaT, with the smallest effect seen for E62Q and larger and similar effects seen for the T201M and M281T variants. Overexpression of E62Q/M281T did not exacerbate the effects seen with overexpression of a single TPM1 variant. T201M (DCM) replaced endogenous tropomyosin dose-dependently, while M281T (HCM) did not. Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures. Conclusion - All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss of sarcomeric structures. These effects may underlie pathophysiology of different cardiomyopathy phenotypes.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.101DOI Listing
January 2021

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy.

Sci Rep 2020 06 17;10(1):9819. Epub 2020 Jun 17.

Department of Experimental Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments.
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http://dx.doi.org/10.1038/s41598-020-66656-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300032PMC
June 2020

Long-term clinical outcomes of losartan in patients with Marfan syndrome: follow-up of the multicentre randomized controlled COMPARE trial.

Eur Heart J 2020 11;41(43):4181-4187

Department of Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Aims: The COMPARE trial showed a small but significant beneficial effect of 3-year losartan treatment on aortic root dilatation rate in adults with Marfan syndrome (MFS). However, no significant effect was found on clinical endpoints, possibly due to a short follow-up period. The aim of the current study was therefore to investigate the long-term clinical outcomes after losartan treatment.

Methods And Results: In the original COMPARE study (inclusion 2008-2009), adult patients with MFS (n = 233) were randomly allocated to either the angiotensin-II receptor blocker losartan® on top of regular treatment (β-blockers in 71% of the patients) or no additional medication. After the COMPARE trial period of 3 years, study subjects chose to continue their losartan medication or not. In a median follow-up period of 8 years, 75 patients continued losartan medication, whereas 78 patients, originally allocated to the control group, never used losartan after inclusion. No differences existed between baseline characteristics of the two groups except for age at inclusion [losartan 34 (interquartile range, IQR 26-43) years, control 41 (IQR 30-52) years; P = 0.031], and β-blocker use (losartan 81%, control 64%; P = 0.022). A pathological FBN1 mutation was present in 76% of patients and 58% of the patients were male. Clinical endpoints, defined as all-cause mortality, aortic dissection/rupture, elective aortic root replacement, reoperation, and vascular graft implantation beyond the aortic root, were compared between the two groups. A per-patient composite endpoint was also analysed. Five deaths, 14 aortic dissections, 23 aortic root replacements, 3 reoperations, and 3 vascular graft implantations beyond the aortic root occurred during follow-up. Except for aortic root replacement, all endpoints occurred in patients with an operated aortic root. Patients who used losartan during the entire follow-up period showed a reduced number of events compared to the control group (death: 0 vs. 5, P = 0.014; aortic dissection: 3 vs. 11, P = 0.013; elective aortic root replacement: 10 vs. 13, P = 0.264; reoperation: 1 vs. 2, P = 0.463; vascular graft implantations beyond the aortic root 0 vs. 3, P = 0.071; and composite endpoint: 14 vs. 26, P = 0.019). These results remained similar when corrected for age and β-blocker use in a multivariate analysis.

Conclusion: These results suggest a clinical benefit of combined losartan and β-blocker treatment in patients with MFS.
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http://dx.doi.org/10.1093/eurheartj/ehaa377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711887PMC
November 2020

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Circulation 2020 07 20;142(4):324-338. Epub 2020 May 20.

Masonic Medical Research Institute, Utica, NY (R.P.).

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.

Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.

Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).

Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Heart Rate Recovery After Exercise Is Associated With Arrhythmic Events in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

Circ Arrhythm Electrophysiol 2020 03 16;13(3):e007471. Epub 2020 Feb 16.

Department of Pediatrics, Children's Heart Centre, Division of Cardiology, British Columbia Children's Hospital, Vancouver, BC, Canada (T.M.R., S.S.).

Background: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias.

Methods: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1').

Results: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1' after maximal exercise (43 [interquartile range, 25-58] versus 25 [interquartile range, 19-34] beats/min; <0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1' had an odds ratio of 3.4 (95% CI, 1.6-7.4) of being symptomatic before diagnosis (<0.001). In addition, ΔHRR1' was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22-48] versus 27 [interquartile range, 20-36] beats/min; =0.01). After diagnosis, patients with a ΔHRR1' in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles (=0.045).

Conclusions: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.
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http://dx.doi.org/10.1161/CIRCEP.119.007471DOI Listing
March 2020

Regression of Bone-Tracer Uptake in Cardiac Transthyretin Amyloidosis.

Mayo Clin Proc 2020 02 26;95(2):417-418. Epub 2019 Dec 26.

Department of Rheumatology and Clinical Immunology, Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1016/j.mayocp.2019.10.036DOI Listing
February 2020

Coexistence of wild type and hereditary ATTR amyloidosis in one family.

Amyloid 2020 Mar 13;27(1):71-72. Epub 2019 Nov 13.

Rheumatology & Clinical Immunology, Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1080/13506129.2019.1690444DOI Listing
March 2020

Three female patients with Danon disease presenting with predominant cardiac phenotype: a case series.

Eur Heart J Case Rep 2019 Sep 29;3(3):ytz132. Epub 2019 Jul 29.

Department of Cardiology, Thoraxcenter, University of Groningen, University Medical Center Groningen, PO Box 30.001, RB Groningen, The Netherlands.

Background: Danon disease is a rare X-linked multisystemic disorder that has primarily been described in male patients.

Case Summary: We present three female patients with Danon disease with a predominantly cardiac phenotype in whom disease onset and expression was very different from that of male patients. Case 1 was first admitted for acute heart failure and then readmitted a few months later for cardiac shock, necessitating mechanical support, and heart transplantation. Case 2 had complex arrhythmias for which many antiarrhythmic drugs were tried with only limited success. Her disease accelerated after her first pregnancy, and she showed reduced left ventricular function and dilated cardiomyopathy. Case 3 was referred for near syncope and ablated for an accessory pathway; she had extensive left ventricular hypertrophy. In all three cases, a final diagnosis of Danon disease was only made after genetic testing that identified a causal variant in the lysosome-associated membrane protein 2 gene.

Discussion: Danon disease in female patients is a challenging diagnosis that may not be identified until genetic testing has been performed.
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http://dx.doi.org/10.1093/ehjcr/ytz132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764575PMC
September 2019

Homozygous damaging SOD2 variant causes lethal neonatal dilated cardiomyopathy.

J Med Genet 2020 01 7;57(1):23-30. Epub 2019 Sep 7.

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

Background: Idiopathic dilated cardiomyopathy (DCM) is recognised to be a heritable disorder, yet clinical genetic testing does not produce a diagnosis in >50% of paediatric patients. Identifying a genetic cause is crucial because this knowledge can affect management options, cardiac surveillance in relatives and reproductive decision-making. In this study, we sought to identify the underlying genetic defect in a patient born to consanguineous parents with rapidly progressive DCM that led to death in early infancy.

Methods And Results: Exome sequencing revealed a potentially pathogenic, homozygous missense variant, c.542G>T, p.(Gly181Val), in . This gene encodes superoxide dismutase 2 (SOD2) or manganese-superoxide dismutase, a mitochondrial matrix protein that scavenges oxygen radicals produced by oxidation-reduction and electron transport reactions occurring in mitochondria via conversion of superoxide anion (O ) into HO. Measurement of hydroethidine oxidation showed a significant increase in O levels in the patient's skin fibroblasts, as compared with controls, and this was paralleled by reduced catalytic activity of SOD2 in patient fibroblasts and muscle. Lentiviral complementation experiments demonstrated that mitochondrial SOD2 activity could be completely restored on transduction with wild type SOD2.

Conclusion: Our results provide evidence that defective SOD2 may lead to toxic increases in the levels of damaging oxygen radicals in the neonatal heart, which can result in rapidly developing heart failure and death. We propose SOD2 as a novel nuclear-encoded mitochondrial protein involved in severe human neonatal cardiomyopathy, thus expanding the wide range of genetic factors involved in paediatric cardiomyopathies.
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http://dx.doi.org/10.1136/jmedgenet-2019-106330DOI Listing
January 2020

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

J Clin Invest 2019 07 2;129(8):3171-3184. Epub 2019 Jul 2.

Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.
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http://dx.doi.org/10.1172/JCI125538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668697PMC
July 2019

Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest.

Eur Heart J 2019 09;40(35):2953-2961

Department of Cardiology, Centre for Cardiological Innovation, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, Oslo, Norway.

Aims: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated.

Methods And Results: We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including β-blockers, flecainide, and/or left cardiac sympathetic denervation. An ICD was implanted in 79 patients (58.1%). The primary outcome of the study was sudden cardiac death (SCD). The secondary outcomes were composite outcomes of SCD, SCA, appropriate ICD shocks, and syncope. After a median follow-up of 4.8 years, SCD had occurred in three patients (3.8%) with an ICD and none of the patients without an ICD (P = 0.1). SCD, SCA, or appropriate ICD shocks occurred in 37 patients (46.8%) with an ICD and 9 patients (15.8%) without an ICD (P < 0.0001). Inappropriate ICD shocks occurred in 19 patients (24.7%) and other device-related complications in 22 patients (28.9%).

Conclusion: In previously undiagnosed patients with CPVT who presented with SCA, an ICD was not associated with improved survival. Instead, the ICD was associated with both a high rate of appropriate ICD shocks and inappropriate ICD shocks along with other device-related complications. Strict adherence to guideline-directed therapy without an ICD may provide adequate protection in these patients without all the potential disadvantages of an ICD.
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http://dx.doi.org/10.1093/eurheartj/ehz309DOI Listing
September 2019

Incidence and predictors of implantable cardioverter-defibrillator therapy and its complications in idiopathic ventricular fibrillation patients.

Europace 2019 Oct;21(10):1519-1526

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Aims: Idiopathic ventricular fibrillation (IVF) is a rare cause of sudden cardiac arrest. Implantable cardioverter-defibrillator (ICD) implantation is currently the only treatment option. Limited data are available on the prevalence and complications of ICD therapy in these patients. We sought to investigate ICD therapy and its complications in patients with IVF.

Methods And Results: Patients were selected from a national registry of IVF patients. Patients in whom no underlying diagnosis was found during follow-up were eligible for inclusion. Recurrence of ventricular arrhythmia (VA) was derived from medical and ICD records, electrogram records of ICD therapies were used to differentiate between appropriate or inappropriate interventions. Independent predictors for appropriate ICD shock were calculated using cox regression. In 217 IVF patients, recurrence of sustained VAs occurred in 66 patients (30%) during a median follow-up period of 6.1 years. Ten patients died (4.6%). Thirty-eight patients (17.5%) experienced inappropriate ICD therapy, and 32 patients (14.7%) had device-related complications. Symptoms before cardiac arrest [hazard ratio (HR): 2.51, 95% confidence interval (CI): 1.48-4.24], signs of conduction disease (HR: 2.27, 95% CI: 1.15-4.47), and carrier of the DPP6 risk haplotype (HR: 3.24, 1.70-6.17) were identified as independent predictors of appropriate shock occurrence.

Conclusion: Implantable cardioverter-defibrillator therapy is an effective treatment in IVF, treating recurrences of potentially lethal VAs in approximately one-third of patients during long-term follow-up. However, device-related complications and inappropriate shocks were also frequent. We found significant predictors for appropriate ICD therapy. This may imply that these patients require additional management to prevent recurrent events.
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http://dx.doi.org/10.1093/europace/euz151DOI Listing
October 2019

Mortality Risk Associated With Truncating Founder Mutations in Titin.

Circ Genom Precis Med 2019 05;12(5):e002436

Department of Genetics (M.J., A.F.B., A.S.U., H.K.P.v.A., E.A.M.H., D.D.), University Medical Center Utrecht, Utrecht University, the Netherlands.

Background Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in ≤25% of familial cases. Moreover, TTNtv associated with dilated cardiomyopathy are estimated to be present in 0.5% of the general population. The prognosis of asymptomatic carriers of TTNtv is poorly understood because TTNtv are associated with a highly variable phenotype. We aim to assess the natural history and clinical relevance of TTNtv by analyzing standardized mortality ratios (SMR) in multigenerational pedigrees and in close relatives of present-day patients. Methods Haplotype and genealogical analyses were performed on 3 recurrent TTNtv. Subsequently, the family tree mortality ratio method was used to compare all-cause mortality of subjects at an a priori 50% risk of carrying TTNtv to the general Dutch population. SMRs were stratified for sex, age, and calendar period. Subgroups were compared with Poisson regression. Similarly, SMRs were calculated in parents of 128 present-day dilated cardiomyopathy probands with TTNtv using the reverse parent-offspring method. Results The TTNtv were established as founder mutations and traced to 18th century ancestors. In 20 522 person-years, overall mortality was not significantly increased (SMR, 1.06; 95% CI, 0.95-1.18; P=0.162). However, mortality was significantly increased in subjects living after 1965 (SMR, 1.27; 95% CI, 1.04-1.53; P=0.009) and aged ≥60 years (SMR, 1.17; 95% CI, 1.01-1.35; P=0.02). The reverse parent-offspring analysis showed overall excess mortality (SMR, 1.26; 95% CI, 1.07-1.48; P=0.003), driven by subjects aged ≥60 years. Conclusions The natural history of the analyzed TTNtv shows a relatively mild disease course with significant excess mortality in elderly patients. With increasing life expectancy, TTNtv-associated morbidity and mortality will likely become more prevalent.
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http://dx.doi.org/10.1161/CIRCGEN.118.002436DOI Listing
May 2019

Dyssynchronopathy Can be a Manifestation of Heritable Cardiomyopathy.

Circ Genom Precis Med 2019 05;12(5):e002528

Department of Cardiology (K.D., R.A.d.B., A.H.M., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, the Netherlands.

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http://dx.doi.org/10.1161/CIRCGEN.119.002528DOI Listing
May 2019

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

Eur Heart J 2019 06;40(23):1850-1858

Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, The Netherlands.

Aims: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients.

Methods And Results: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P < 0.001).

Conclusion: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).
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http://dx.doi.org/10.1093/eurheartj/ehz103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568197PMC
June 2019

Relevance of Titin Missense and Non-Frameshifting Insertions/Deletions Variants in Dilated Cardiomyopathy.

Sci Rep 2019 03 11;9(1):4093. Epub 2019 Mar 11.

Blueprint Genetics, Helsinki, Finland.

Recent advancements in next generation sequencing (NGS) technology have led to the identification of the giant sarcomere gene, titin (TTN), as a major human disease gene. Truncating variants of TTN (TTNtv) especially in the A-band region account for 20% of dilated cardiomyopathy (DCM) cases. Much attention has been focused on assessment and interpretation of TTNtv in human disease; however, missense and non-frameshifting insertions/deletions (NFS-INDELs) are difficult to assess and interpret in clinical diagnostic workflow. Targeted sequencing covering all exons of TTN was performed on a cohort of 530 primary DCM patients from three cardiogenetic centres across Europe. Using stringent bioinformatic filtering, twenty-nine and two rare TTN missense and NFS-INDELs variants predicted deleterious were identified in 6.98% and 0.38% of DCM patients, respectively. However, when compared with those identified in the largest available reference population database, no significant enrichment of such variants was identified in DCM patients. Moreover, DCM patients and reference individuals had comparable frequencies of splice-region missense variants with predicted splicing alteration. DCM patients and reference populations had comparable frequencies of rare predicted deleterious TTN missense variants including splice-region missense variants suggesting that these variants are not independently causative for DCM. Hence, these variants should be classified as likely benign in the clinical diagnostic workflow, although a modifier effect cannot be excluded at this stage.
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http://dx.doi.org/10.1038/s41598-019-39911-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412046PMC
March 2019

Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy.

Cardiovasc Pathol 2019 May - Jun;40:2-6. Epub 2018 Dec 21.

University of Groningen, University Medical Center Groningen, Department of Pathology, Groningen, The Netherlands.

Phospholamban (PLN) p.Arg14del cardiomyopathy is characterized by a distinct arrhythmogenic biventricular phenotype that can be predominantly left ventricular, right ventricular, or both. Our aim was to further elucidate distinct features of this cardiomyopathy with respect to the distribution of desmosomal proteins observed by immunofluorescence (IF) in comparison to desmosomal arrhythmogenic cardiomyopathy and co-existent genetic variants. We studied eight explanted heart specimens from PLN p.Arg14del mutation carriers. Macro- and microscopic examination revealed biventricular presence of fibrofatty replacement and interstitial fibrosis. Five out of 8 (63%) patients met consensus criteria for both arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). In four cases, targeted next-generation sequencing revealed one additional pathogenic variant and six variants of unknown significance. IF showed diminished junction plakoglobin signal intensity at the intercalated disks in 4 (67%) out of 6 cases fulfilling ARVC criteria but normal intensity in both cases fulfilling only DCM criteria. Notably, the four cases with diminished junction plakoglobin were also those where an additional gene variant was detected. IF for two proteins recently investigated in desmosomal arrhythmogenic cardiomyopathy (ACM), synapse-associated protein 97 and glycogen synthase kinase-3 beta, showed a distinct distributional pattern in comparison to desmosomal ACM. In 7 (88%) out of 8 cases we observed both a strong synapse-associated protein 97 signal at the sarcomeres and no glycogen synthase kinase-3 beta translocation to the intercalated discs. Phospholamban p.Arg14del cardiomyopathy is characterized by a distinct molecular signature compared to desmosomal ACM, specifically a different desmosomal protein distribution. This study substantiates the idea that additional genetic variants play a role in the phenotypical heterogeneity.
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http://dx.doi.org/10.1016/j.carpath.2018.12.006DOI Listing
July 2019

Heart failure with preserved ejection fraction, atrial fibrillation, and the role of senile amyloidosis.

Eur Heart J 2019 04;40(16):1287-1293

Department of Cardiology, Thorax Centre, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands.

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are very common conditions, particularly in the elderly. However, the mechanisms underlying the two disorders, including their intricate interaction have not been fully resolved. Here, our aim is to review the evidence on the role of the two types of senile amyloidosis in this connection. Two types of senile amyloidosis can be identified: wild-type transthyretin (TTR)-derived amyloidosis (ATTRwt) and isolated atrial amyloidosis (IAA). ATTRwt is an underlying condition that is being increasingly recognized in patients with HFpEF and often accompanied by AF. IAA is an established cause of AF, adding to the mechanism problem. New diagnostic and therapeutic possibilities have emerged that may facilitate clinical management of (senile) amyloidosis, which in turn may have implications for the management of HFpEF and AF.
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http://dx.doi.org/10.1093/eurheartj/ehz057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553504PMC
April 2019
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