Myocardial fibrosis as an early feature in phospholamban p.Arg14del mutation carriers: phenotypic insights from cardiovascular magnetic resonance imaging

Rijdt, Wouter P. te; Sande, Judith N. ten; Gorter, Thomas M.; Zwaag, Paul A. van der; Rijsingen, Ingrid A van; Boekholdt, S. Matthijs; Tintelen, J. Peter van; Haelst, Paul L. van; Planken, R. Nils; Boer, Rudolf A. de; Suurmeijer, Albert; Veldhuisen, Dirk J. van; Wilde, Arthur A.M.; Willems, Tineke P.; Dessel, Pascal F.H.M. van; Berg, Maarten P. van den

doi:10.1093/ehjci/jey047

Cited by 52 publications

(60 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, this pathogenic variant was described as a founder mutation in the Netherlands, and was identified in ±14% of Dutch patients with dilated cardiomyopathy (DCM) or arrhythmogenic right ventricular cardiomyopathy (ARVC), which translates into thousands of carriers 9 . PLN-R14del carriers have a high risk of developing malignant ventricular arrhythmias (VAs) and HF, and are often diagnosed with DCM or ARVC, which, given the presence of biventricular abnormalities, is better referred to as arrhythmogenic cardiomyopathy (ACM) 3,[9][10][11] . The phenotype is typically characterized by ECG abnormalities, including low QRS-potentials and inverted T-waves in precordial leads, myocardial fibrosis and fibrofatty replacement, and, ultimately, severe biventricular dysfunction and HF 3,9,10 .…”

mentioning

confidence: 99%

“…In 2021 we expect the results of the PHOspholamban RElated CArdiomyopathy STudy -Intervention (i-PHORECAST; ClinicalTrials.gov NCT01857856). As myocardial fibrosis is considered to be an early disease manifestation in this cardiomyopathy 7,11,14 , the i-PHORECAST study aims to test the efficacy of the mineralocorticoid receptor antagonist (MRA) eplerenone, which has been shown to exert anti-fibrotic effects 15 , in reducing disease progression or postponing onset of overt disease in asymptomatic mutation carriers.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Eijgenraam

Boukens

Boogerd

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca2+-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.

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Eijgenraam

Boukens

Boogerd

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The hearts showed biventricular presence of fibrofatty replacement and interstitial fibrosis, in line with our previous pathological [8][9][10] and cardiac magnetic resonance imaging findings. 20 Sepehrkhouy et al recently showed this fibrosis pattern to be distinctive for PLN p.Arg14del cardiomyopathy in comparison with other hereditary cardiomyopathies. 10 Clinically, the majority of patients (63%) in our cohort fulfilled criteria for both ARVC and DCM.…”

Section: Discussionmentioning

confidence: 94%

Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy

Rijdt

Asimaki

Jongbloed

et al. 2019

Cardiovascular Pathology

View full text Add to dashboard Cite

Phospholamban (PLN) p.Arg14del cardiomyopathy is characterized by a distinctly 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 in comparison to desmosomal arrhythmogenic cardiomyopathy and co-existent genetic variants. We studied 8 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%) of patients met consensus criteria for both arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM). In four cases, targeted NGS revealed one additional pathogenic variant and six variants of unknown significance. Immunofluorescence showed diminished junction plakoglobin signal intensity at the intercalated disks in 4/6 (67%) cases fulfilling ARVC criteria but normal intensity in both cases fulfilling only DCM criteria. Notably, the 4 cases with diminished junction plakoglobin were also those where an additional gene variant was detected.Immunofluorescence for two proteins recently investigated in desmosomal ACM, synapse-associated protein 97 and glycogen synthase kinase-3 beta, showed a distinct distributional pattern in comparison to desmosomal ACM. In 7/8 (88%) 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.

show abstract

“…Previous studies have demonstrated that phospholamban mutation carriers with T‑wave inversion were more likely to have left ventricular late gadolinium enhancement on cardiac MRI, compared to those without T‑wave inversion. In our cohort, we demonstrated a strong association between T‑wave inversion and LV dysfunction among mutation carriers [ 11 ]. Furthermore, fibrosis and fatty changes among phospholamban carriers may also occur in a distinct pattern compared to other forms of hereditary cardiomyopathies [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Phospholamban cardiomyopathy: a Canadian perspective on a unique population

et al. 2019

View full text Add to dashboard Cite

Introduction Phospholamban cardiomyopathy is an inherited cardiomyopathy, characterised by a defect in regulation of the sarcoplasmic reticulum Ca 2+ pump, often presenting with malignant arrhythmias and progressive cardiac dysfunction occurring at a young age. Methods Phospholamban R14del mutation carriers and family members were identified from inherited arrhythmia clinics at 13 sites across Canada. Cardiac investigations, including electrocardiograms, Holter monitoring (premature ventricular complexes, PVCs), and imaging results were summarised. Results Fifty patients (10 families) were identified (median age 30 years, range 3–71, 46% female). Mutation carriers were more likely to be older, have low-voltage QRS, T‑wave inversion, frequent PVCs, and cardiac dysfunction, compared to unaffected relatives. Increasing age, low-voltage QRS, T‑wave inversion, late potentials, and frequent PVCs were predictors of cardiac dysfunction ( p < 0.05 for all). Older carriers (age ≥45 years) were more likely to have disease manifestations than were their younger counterparts, with disease onset occurring at an older age in Canadian patients and their Dutch counterparts. Discussion Among Canadian patients with phospholamban cardiomyopathy, clinical manifestations resembled those of their Dutch counterparts, with increasing age a major predictor of disease manifestation. Older mutation carriers were more likely to have electrical and structural abnormalities, and may represent variable expressivity, age-dependent penetrance, or genetic heterogeneity among Canadian patients. Electronic supplementary material The online version of this article (10.1007/s12471-019-1247-0) contains supplementary material, which is available to authorized users.

show abstract

Myocardial fibrosis as an early feature in phospholamban p.Arg14del mutation carriers: phenotypic insights from cardiovascular magnetic resonance imaging

Cited by 52 publications

References 29 publications

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

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

Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy

Phospholamban cardiomyopathy: a Canadian perspective on a unique population

Contact Info

Product

Resources

About