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1. Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle

Author

McNamara, JW, Parker, BL, Voges, HK, Mehdiabadi, NR, Bolk, F, Ahmad, F, Chung, JD, Charitakis, N, Molendijk, J, Zech, ATL, Lal, S, Ramialison, M, Karavendzas, K, Pointer, HL, Syrris, P, Lopes, LR, Elliott, PM, Lynch, GS, Mills, RJ, Hudson, JE, Watt, KI, Porrello, ER, Elliott, DA, McNamara, JW, Parker, BL, Voges, HK, Mehdiabadi, NR, Bolk, F, Ahmad, F, Chung, JD, Charitakis, N, Molendijk, J, Zech, ATL, Lal, S, Ramialison, M, Karavendzas, K, Pointer, HL, Syrris, P, Lopes, LR, Elliott, PM, Lynch, GS, Mills, RJ, Hudson, JE, Watt, KI, Porrello, ER, and Elliott, DA

Abstract

Muscle contraction is driven by the molecular machinery of the sarcomere. As phosphorylation is a critical regulator of muscle function, the identification of regulatory kinases is important for understanding sarcomere biology. Pathogenic variants in alpha kinase 3 (ALPK3) cause cardiomyopathy and musculoskeletal disease, but little is known about this atypical kinase. Here we show that ALPK3 is an essential component of the M-band of the sarcomere and define the ALPK3-dependent phosphoproteome. ALPK3 deficiency impaired contractility both in human cardiac organoids and in the hearts of mice harboring a pathogenic truncating Alpk3 variant. ALPK3-dependent phosphopeptides were enriched for sarcomeric components of the M-band and the ubiquitin-binding protein sequestosome-1 (SQSTM1) (also known as p62). Analysis of the ALPK3 interactome confirmed binding to M-band proteins including SQSTM1. In human pluripotent stem cell-derived cardiomyocytes modeling cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization of SQSTM1 were abnormal suggesting that this mechanism may underly disease pathogenesis.

Published
2023

2. Clinical Features and Natural History of Preadolescent Nonsyndromic Hypertrophic Cardiomyopathy.

Author

Norrish, G, Cleary, A, Field, E, Cervi, E, Boleti, O, Ziółkowska, L, Olivotto, I, Khraiche, D, Limongelli, G, Anastasakis, A, Weintraub, R, Biagini, E, Ragni, L, Prendiville, T, Duignan, S, McLeod, K, Ilina, M, Fernandez, A, Marrone, C, Bökenkamp, R, Baban, A, Kubus, P, Daubeney, PEF, Sarquella-Brugada, G, Cesar, S, Klaassen, S, Ojala, TH, Bhole, V, Medrano, C, Uzun, O, Brown, E, Gran, F, Sinagra, G, Castro, FJ, Stuart, G, Yamazawa, H, Barriales-Villa, R, Garcia-Guereta, L, Adwani, S, Linter, K, Bharucha, T, Gonzales-Lopez, E, Siles, A, Rasmussen, TB, Calcagnino, M, Jones, CB, De Wilde, H, Kubo, T, Felice, T, Popoiu, A, Mogensen, J, Mathur, S, Centeno, F, Reinhardt, Z, Schouvey, S, Elliott, PM, Kaski, JP, Norrish, G, Cleary, A, Field, E, Cervi, E, Boleti, O, Ziółkowska, L, Olivotto, I, Khraiche, D, Limongelli, G, Anastasakis, A, Weintraub, R, Biagini, E, Ragni, L, Prendiville, T, Duignan, S, McLeod, K, Ilina, M, Fernandez, A, Marrone, C, Bökenkamp, R, Baban, A, Kubus, P, Daubeney, PEF, Sarquella-Brugada, G, Cesar, S, Klaassen, S, Ojala, TH, Bhole, V, Medrano, C, Uzun, O, Brown, E, Gran, F, Sinagra, G, Castro, FJ, Stuart, G, Yamazawa, H, Barriales-Villa, R, Garcia-Guereta, L, Adwani, S, Linter, K, Bharucha, T, Gonzales-Lopez, E, Siles, A, Rasmussen, TB, Calcagnino, M, Jones, CB, De Wilde, H, Kubo, T, Felice, T, Popoiu, A, Mogensen, J, Mathur, S, Centeno, F, Reinhardt, Z, Schouvey, S, Elliott, PM, and Kaski, JP

Abstract

BACKGROUND: Up to one-half of childhood sarcomeric hypertrophic cardiomyopathy (HCM) presents before the age of 12 years, but this patient group has not been systematically characterized. OBJECTIVES: The aim of this study was to describe the clinical presentation and natural history of patients presenting with nonsyndromic HCM before the age of 12 years. METHODS: Data from the International Paediatric Hypertrophic Cardiomyopathy Consortium on 639 children diagnosed with HCM younger than 12 years were collected and compared with those from 568 children diagnosed between 12 and 16 years. RESULTS: At baseline, 339 patients (53.6%) had family histories of HCM, 132 (20.9%) had heart failure symptoms, and 250 (39.2%) were prescribed cardiac medications. The median maximal left ventricular wall thickness z-score was 8.7 (IQR: 5.3-14.4), and 145 patients (27.2%) had left ventricular outflow tract obstruction. Over a median follow-up period of 5.6 years (IQR: 2.3-10.0 years), 42 patients (6.6%) died, 21 (3.3%) underwent cardiac transplantation, and 69 (10.8%) had life-threatening arrhythmic events. Compared with those presenting after 12 years, a higher proportion of younger patients underwent myectomy (10.5% vs 7.2%; P = 0.045), but fewer received primary prevention implantable cardioverter-defibrillators (18.9% vs 30.1%; P = 0.041). The incidence of mortality or life-threatening arrhythmic events did not differ, but events occurred at a younger age. CONCLUSIONS: Early-onset childhood HCM is associated with a comparable symptom burden and cardiac phenotype as in patients presenting later in childhood. Long-term outcomes including mortality did not differ by age of presentation, but patients presenting at younger than 12 years experienced adverse events at younger ages.

Published
2022

3. The role of the electrocardiographic phenotype in risk stratification for sudden cardiac death in childhood hypertrophic cardiomyopathy

Author

Norrish, G, Topriceanu, C, Qu, C, Field, E, Walsh, H, Ziolkowska, L, Olivotto, I, Passantino, S, Favilli, S, Anastasakis, A, Vlagkouli, V, Weintraub, R, King, I, Biagini, E, Ragni, L, Prendiville, T, Duignan, S, McLeod, K, Ilina, M, Fernandez, A, Bokenkamp, R, Baban, A, Drago, F, Kubus, P, Daubeney, PEF, Chivers, S, Sarquella-Brugada, G, Cesar, S, Marrone, C, Medrano, C, Garcia-Roves, RA, Uzun, O, Gran, F, Castro, FJ, Gimeno, JR, Barriales-Villa, R, Rueda, F, Adwani, S, Searle, J, Bharucha, T, Siles, A, Usano, A, Rasmussen, TB, Jones, CB, Kubo, T, Mogensen, J, Reinhardt, Z, Cervi, E, Elliott, PM, Omar, RZ, Kaski, JP, Norrish, G, Topriceanu, C, Qu, C, Field, E, Walsh, H, Ziolkowska, L, Olivotto, I, Passantino, S, Favilli, S, Anastasakis, A, Vlagkouli, V, Weintraub, R, King, I, Biagini, E, Ragni, L, Prendiville, T, Duignan, S, McLeod, K, Ilina, M, Fernandez, A, Bokenkamp, R, Baban, A, Drago, F, Kubus, P, Daubeney, PEF, Chivers, S, Sarquella-Brugada, G, Cesar, S, Marrone, C, Medrano, C, Garcia-Roves, RA, Uzun, O, Gran, F, Castro, FJ, Gimeno, JR, Barriales-Villa, R, Rueda, F, Adwani, S, Searle, J, Bharucha, T, Siles, A, Usano, A, Rasmussen, TB, Jones, CB, Kubo, T, Mogensen, J, Reinhardt, Z, Cervi, E, Elliott, PM, Omar, RZ, and Kaski, JP

Abstract

AIMS: The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. METHODS AND RESULTS: Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0-7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93-2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484-0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7. CONCLUSION: In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.

Published
2022

4. Relationship Between Maximal Left Ventricular Wall Thickness and Sudden Cardiac Death in Childhood Onset Hypertrophic Cardiomyopathy.

Author

Norrish, G, Ding, T, Field, E, Cervi, E, Ziółkowska, L, Olivotto, I, Khraiche, D, Limongelli, G, Anastasakis, A, Weintraub, R, Biagini, E, Ragni, L, Prendiville, T, Duignan, S, McLeod, K, Ilina, M, Fernández, A, Marrone, C, Bökenkamp, R, Baban, A, Kubus, P, Daubeney, PEF, Sarquella-Brugada, G, Cesar, S, Klaassen, S, Ojala, TH, Bhole, V, Medrano, C, Uzun, O, Brown, E, Gran, F, Sinagra, G, Castro, FJ, Stuart, G, Vignati, G, Yamazawa, H, Barriales-Villa, R, Garcia-Guereta, L, Adwani, S, Linter, K, Bharucha, T, Garcia-Pavia, P, Siles, A, Rasmussen, TB, Calcagnino, M, Jones, CB, De Wilde, H, Kubo, T, Felice, T, Popoiu, A, Mogensen, J, Mathur, S, Centeno, F, Reinhardt, Z, Schouvey, S, O'Mahony, C, Omar, RZ, Elliott, PM, Kaski, JP, Norrish, G, Ding, T, Field, E, Cervi, E, Ziółkowska, L, Olivotto, I, Khraiche, D, Limongelli, G, Anastasakis, A, Weintraub, R, Biagini, E, Ragni, L, Prendiville, T, Duignan, S, McLeod, K, Ilina, M, Fernández, A, Marrone, C, Bökenkamp, R, Baban, A, Kubus, P, Daubeney, PEF, Sarquella-Brugada, G, Cesar, S, Klaassen, S, Ojala, TH, Bhole, V, Medrano, C, Uzun, O, Brown, E, Gran, F, Sinagra, G, Castro, FJ, Stuart, G, Vignati, G, Yamazawa, H, Barriales-Villa, R, Garcia-Guereta, L, Adwani, S, Linter, K, Bharucha, T, Garcia-Pavia, P, Siles, A, Rasmussen, TB, Calcagnino, M, Jones, CB, De Wilde, H, Kubo, T, Felice, T, Popoiu, A, Mogensen, J, Mathur, S, Centeno, F, Reinhardt, Z, Schouvey, S, O'Mahony, C, Omar, RZ, Elliott, PM, and Kaski, JP

Abstract

BACKGROUND: Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort. METHODS: The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1-16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids). RESULTS: MLVWT Z score was <10 in 598 (58.1%), ≥10 to <20 in 334 (31.1%), and ≥20 in 143 (13.3%). Higher MLVWT Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3-9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores <10, ≥10 to <20, and ≥20 was 95.6%, 87.4%, and 86.0, respectively. The estimated SCD risk at 5 years had a nonlinear, inverted U-shaped relationship with MLVWT Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk. CONCLUSIONS: In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter def

Published
2022

7. Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure

Author

Akhtar, MM, Lorenzini, M, Pavlou, M, Ochoa, JP, O'Mahony, C, Restrepo-Cordoba, MA, Segura-Rodriguez, D, Bermudez-Jimenez, F, Molina, P, Cuenca, S, Ader, F, Larranaga-Moreira, JM, Sabater-Molina, M, Garcia-Alvarez, MI, Arantzamendi, LG, Truszkowska, G, Ortiz-Genga, M, Ruiz, IS, Nielsen, SK, Rasmussen, TB, Mezcua, AR, Alvarez-Rubio, J, Eiskjaer, H, Gautel, M, Garcia-Pinilla, JM, Ripoll-Vera, T, Mogensen, J, Freire, JL, Rodriguez-Palomares, JF, Pena-Pena, ML, Rangel-Sousa, D, Palomino-Doza, J, Achaga, XA, Bilinska, Z, Golvano, EZ, Climent, V, Penalver, MN, Barriales-Villa, R, Charron, P, Yotti, R, Zorio, E, Jimenez-Jaimez, J, Garcia-Pavia, P, Elliott, PM, and European Genetic Cardiomyopathies

Subjects
MUTATIONS, DILATED CARDIOMYOPATHY, DIAGNOSIS, GUIDELINES
Abstract

IMPORTANCE Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia. OBJECTIVE To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). DESIGN, SETTING, AND PARTICIPANTS This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. MAIN OUTCOMES AND MEASURES The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. RESULTS In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (>= 500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF

Published
2021

8. Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy

Author

Lopes, LR, Garcia-Hernandez, S, Lorenzini, M, Futema, M, Chumakova, O, Zateyshchikov, D, Isidoro-Garcia, M, Villacorta, E, Escobar-Lopez, L, Garcia-Pavia, P, Bilbao, R, Dobarro, D, Sandin-Fuentes, M, Catalli, C, Gener Querol, B, Mezcua, A, Garcia Pinilla, J, Rasmussen, TB, Ferreira-Aguar, A, Revilla-Marti, P, Basurte Elorz, MT, Bautista Paves, A, Ramon Gimeno, J, Figueroa, AV, Franco-Gutierrez, R, Fuentes-Canamero, ME, Martinez Moreno, M, Ortiz-Genga, M, Piqueras-Flores, J, Ramos, KA, Rudzitis, A, Ruiz-Guerrero, L, Stein, R, Triguero-Bocharan, M, de la Higuera, L, Ochoa, JP, Abu-Bonsrah, D, Kwok, CYT, Smith, JB, Porrello, ER, Akhtar, MM, Jager, J, Ashworth, M, Syrris, P, Elliott, DA, Monserrat, L, Elliott, PM, Lopes, LR, Garcia-Hernandez, S, Lorenzini, M, Futema, M, Chumakova, O, Zateyshchikov, D, Isidoro-Garcia, M, Villacorta, E, Escobar-Lopez, L, Garcia-Pavia, P, Bilbao, R, Dobarro, D, Sandin-Fuentes, M, Catalli, C, Gener Querol, B, Mezcua, A, Garcia Pinilla, J, Rasmussen, TB, Ferreira-Aguar, A, Revilla-Marti, P, Basurte Elorz, MT, Bautista Paves, A, Ramon Gimeno, J, Figueroa, AV, Franco-Gutierrez, R, Fuentes-Canamero, ME, Martinez Moreno, M, Ortiz-Genga, M, Piqueras-Flores, J, Ramos, KA, Rudzitis, A, Ruiz-Guerrero, L, Stein, R, Triguero-Bocharan, M, de la Higuera, L, Ochoa, JP, Abu-Bonsrah, D, Kwok, CYT, Smith, JB, Porrello, ER, Akhtar, MM, Jager, J, Ashworth, M, Syrris, P, Elliott, DA, Monserrat, L, and Elliott, PM

Abstract

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

Published
2021

9. Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease

Author

van der Veen, SJ, Vlietstra, Wytze, van der Dussen, L, van Kuilenburg, ABP, Dijkgraaf, MG, Lenders, M, Brand, E (Eddy), Wanner, C, Hughes, D, Elliott, PM, Hollak, CEM, Langeveld, Mirte, van der Veen, SJ, Vlietstra, Wytze, van der Dussen, L, van Kuilenburg, ABP, Dijkgraaf, MG, Lenders, M, Brand, E (Eddy), Wanner, C, Hughes, D, Elliott, PM, Hollak, CEM, and Langeveld, Mirte

Published
2020

10. Prevalence of TTR variants detected by whole-exome sequencing in hypertrophic cardiomyopathy

Author

Lopes, LR, Futema, M, Akhtar, MM, Lorenzini, M, Pittman, A, Syrris, P, and Elliott, PM

Subjects
endocrine system, nutritional and metabolic diseases
Abstract

Background: A proportion of patients with hypertrophic cardiomyopathy (HCM) have a diagnosis of cardiac amyloidosis. Hereditary transthyretin amyloid cardiomyopathy (ATTRv-CM) is caused by mutations in the TTR gene. Our aim was to study the prevalence of potentially amyloidogenic TTR variants in a whole-exome sequencing (WES) study of a large HCM cohort. Methods and results: 770 consecutive HCM probands underwent WES and clinical characterisation. Patients with rare or known pathogenic variants in TTR underwent 99mTechnetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy and were retrospectively re-assessed for clinical features of amyloidosis. Two patients had rare TTR variants of unknown significance and four had the known pathogenic V122I (p.V142I) variant (one homozygous and also heterozygous for a likely pathogenic MYL3 variant and another double heterozygous for a likely pathogenic MYBPC3 variant). Four out of 6 patients with TTR variants underwent DPD scintigraphy; the only positive study was in the patient with the homozygous V122I (p.V142I) variant. Conclusions: Pathogenic TTR variants are rare in carefully assessed HCM patients and may occur in double heterozygosity with pathogenic sarcomere variants. The lack of evidence for an amyloidosis phenotype in all but one TTR variant carrier illustrates the importance of complete clinical evaluation of HCM patients that harbour pathogenic TTR variants.

Published
2019

18. International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy (EVIDENCE-HCM)

Author

O'Mahony, C, Jichi, F, Ommen, SR, Christiaans, I, Arbustini, E, Garcia-Pavia, P, Cecchi, F, Olivotto, I, Kitaoka, H, Gotsman, I, Carr-White, G, Mogensen, J, Antoniades, L, Mohiddin, SA, Maurer, M S, Tang, HC, Geske, JB, Siontis, KC, Mahmoud, Karim, Vermeer, A, Wilde, A, Favalli, V, Guttmann, OP, Gallego-Delgado, M, Dominguez, F, Tanini, I, Kubo, T, Keren, A, Bueser, T, Waters, S, Issa, IF, Malcolmson, J, Burns, T, Sekhri, N, Hoeger, CW, Omar, RZ, Elliott, PM, O'Mahony, C, Jichi, F, Ommen, SR, Christiaans, I, Arbustini, E, Garcia-Pavia, P, Cecchi, F, Olivotto, I, Kitaoka, H, Gotsman, I, Carr-White, G, Mogensen, J, Antoniades, L, Mohiddin, SA, Maurer, M S, Tang, HC, Geske, JB, Siontis, KC, Mahmoud, Karim, Vermeer, A, Wilde, A, Favalli, V, Guttmann, OP, Gallego-Delgado, M, Dominguez, F, Tanini, I, Kubo, T, Keren, A, Bueser, T, Waters, S, Issa, IF, Malcolmson, J, Burns, T, Sekhri, N, Hoeger, CW, Omar, RZ, and Elliott, PM

Published
2018

19. 3 SPECT/CT quantification of DPD scintigraphy in cardiac amyloid

Author

Scully, PR, primary, Morris, E, additional, Burniston, M, additional, Treibel, TA, additional, Jerrum, M, additional, Bedford, K, additional, Queenan, H, additional, Hartman, N, additional, Mullen, M, additional, Ozkor, M, additional, Kennon, S, additional, Newton, J, additional, Sabharwal, N, additional, Kelion, A, additional, Elliott, PM, additional, Moon, JC, additional, Hawkins, PN, additional, and Menezes, LJ, additional

Published
2018
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20. Diagnostic work-up in cardiomyopathies: bridging the gap between clinical phenotypes and final diagnosis. A position statement from the ESC Working Group on Myocardial and Pericardial Diseases

Author

Rapezzi, C, Arbustini, E, Caforio, A, Charron, P, Gimeno-Blanes, J, Heliö, T, Linhart, A, Mogensen, J, Pinto, Y, Ristic, A, Seggewiss, H, Sinagra, Gf, Tavazzi, L, Elliott, Pm, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Rapezzi C, Arbustini E, Caforio AL, Charron P, Gimeno-Blanes J, Heliö T, Linhart A, Mogensen J, Pinto Y, Ristic A, Seggewiss H, Sinagra G, Tavazzi L, Elliott PM, Rapezzi, C, Arbustini, E, Caforio, Al, Charron, P, Gimeno Blanes, J, Heliö, T, Linhart, A, Mogensen, J, Pinto, Y, Ristic, A, Seggewiss, H, Sinagra, Gianfranco, Tavazzi, L, and Elliott, Pm

Subjects
Position statement, Diagnostic Imaging, medicine.medical_specialty, Bridging (networking), Cardiomyopathy, Myocardial Infarction, Paraproteinemias, Physical examination, Cardiomegaly, Disease, genetic analysis, DIAGNOSIS, PHENOTYPE, Autoimmune Diseases, NO, Electrocardiography, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Age of Onset, Intensive care medicine, Atrioventricular Block, Creatine Kinase, Physical Examination, Genetic testing, Cardiomyopathie, medicine.diagnostic_test, business.industry, Clinical Laboratory Techniques, Cardiomyopathies, Diagnosis, Dilated cardiomyopathy, Arrhythmias, Cardiac, medicine.disease, GENOTYPES, Work-up, Pedigree, Pericardial diseases, Cardiology, Cardiology and Cardiovascular Medicine, business, Diagnosi
Abstract

In 2008, The ESC Working Group on Myocardial and Pericardial Diseases proposed an updated classification of cardiomyopathies based on morphological and functional phenotypes and subcategories of familial/genetic and non-familial/non-genetic disease. In this position statement, we propose a framework for the clinical approach to diagnosis in cardiomyopathies based on the recognition of diagnostic 'red flags' that can be used to guide rational selection of specialized tests including genetic analysis. The basic premise is that the adoption of a cardiomyopathy-specific mindset which combines conventional cardiological assessment with non-cardiac and molecular parameters increases diagnostic accuracy and thus improves advice and treatment for patients and families.

Published
2013

21. Proposal for a Revised Definition of Dilated Cardiomyopathy and its Implications for Clinical Practice: A Position Statement of the ESC Working Group on Myocardial and Pericardial Diseases

Author

Pinto, Ym, Elliott, Pm, Arbustini, E, Adler, Y, Anastasakis, A, Böhm, M, Duboc, D, Gimeno, J, de Groote, P, Imazio, M, Heymans, S, Klingel, K, Komajda, M, Limongelli, G, Linhart, A, Mogensen, J, Moon, J, Pieper, Pg, Seferovic, Pm, Schueler, S, Zamorano, Jl, Caforio, A, and Charron, P.

Published
2016

23. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

Author

Caforio, ALIDA LINDA PATRIZIA, Pankuweit, S, Arbustini, E, Basso, Cristina, Gimeno Blanes, J, Felix, Sb, Fu, M, Heliö, T, Heymans, S, Jahns, R, Klingel, K, Linhart, A, Maisch, B, Mckenna, W, Mogensen, J, Pinto, Ym, Ristic, A, Schultheiss, Hp, Seggewiss, H, Tavazzi, L, Thiene, Gaetano, Yilmaz, A, Charron, P, Elliott, Pm, European Society of Cardiology Working Group on Myocardial, Pericardial, Diseases, Cardiologie, RS: CARIM School for Cardiovascular Diseases, ACS - Amsterdam Cardiovascular Sciences, and Cardiology

Subjects
Position statement, Diagnostic Imaging, medicine.medical_specialty, Viral Myocarditis, Myocarditis, Cardiomyopathy, Biopsy, Internal medicine, Idiopathic dilated cardiomyopathy, Diagnosis, Medicine, Humans, Referral and Consultation, business.industry, medicine.disease, Long-Term Care, Pericardial diseases, Diagnosis management, Etiology, Cardiology, Therapy, Cardiology and Cardiovascular Medicine, business, Biomarkers, Immunosuppressive Agents
Abstract

In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease. ispartof: European Heart Journal vol:34 issue:33 pages:2636- ispartof: location:England status: published

Published
2013

24. OXYGEN CONSUMPTION DIFFERENTIATES PHYSIOLOGICAL LEFT VENTRICULAR HYPERTROPHY IN JUNIOR ATHLETES FROM PATHOLOGICAL HYPERTROPHY IN ADOLESCENTS WITH HYPERTROPHIC CARDIOMYOPATHY

Author

Firoozi, S, Sharma, S, Mist, B, Elliott, PM, Whyte, G, and McKenna, W J.

Subjects
Cardiomyopathy, Hypertrophic -- Physiological aspects, Oxygen consumption -- Physiological aspects, Athletes -- Physiological aspects, Health, Physiological aspects
Abstract

Background: Hypertrophic cardiomyopathy (HCM) is the commonest cause of sudden cardiac death in adolescent (14-18 year old) athletes. A large study of junior elite athletes showed 5% to have substantially [...]

Published
2001

25. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008

Author

Dickstein, K, Cohen-Solal, A, Filippatos, G, Mcmurray, Jj, Ponikowski, P, Poole-Wilson, Pa, Stromberg, A, van Veldhuisen DJ, Atar, D, Hoes, Aw, Keren, A, Mebazaa, A, Nieminen, M, Priori, Sg, Swedberg, K, Vahanian, A, Camm, J, De Caterina, R, Dean, V, Funck-Brentano, C, Hellemans, I, Kristensen, Sd, Mcgregor, K, Sechtem, U, Silber, S, Tendera, M, Widimsky, P, Zamorano, Jl, Auricchio, A, Bax, J, Bohm, M, Corra, U, Della Bella, P, Elliott, Pm, Follath, F, Gheorghiade, M, Hasin, Y, Hernborg, A, Jaarsma, T, Komajda, M, Kornowski, R, Piepoli, M, Prendergast, B, Tavazzi, L, Vachiery, Jl, Verheugt, Fw, and Zannad, F

Published
2008

27. Subclinical skeletal muscle abnormalities in patients with hypertrophic cardiomyopathy and their relation to clinical characteristics

Author

Anastasakis, A Karandreas, N Stathis, P Rigopoulos, A and Theopistou, A Sepp, R Elliott, PM Panagiotakos, DB and Stefanadis, C Toutouzas, P

Abstract

Background: Some mutations of cardiac sarcomeric proteins causing hypertrophic cardiomyopathy (beta-myosin heavy chain) are associated with skeletal muscle fiber dysfunction, while subclinical skeletal myopathy can be diagnosed by electromyography (EMG) in a substantial proportion of hypertrophic cardiomyopathy patients. Methods: In 49 consecutive, unrelated patients with hypertrophic cardiomyopathy, conventional EMG of deltoid, vastus lateralis, tibialis anterior and soleus muscles was performed. No patient had clinically detectable muscle weakness. We compared the clinical and echocardiographic characteristics between patients with normal and patients with myopathic EMG. Results: Myopathic EMG findings were demonstrated in 13 patients (26.5%), 26 patients (53.1%) had normal findings and 10 patients (20.4%) had indeterminate recordings. There was no significant difference in mean age, maximum wall thickness, left ventricular fraction shortening, NYHA class, the existence of left ventricular outflow tract obstruction, syncope, or the occurrence of nonsustained ventricular tachycardia in the Holler recording among the three groups. Comparison between the myopathic and the normal group revealed that nine patients from the latter (34.6%) had a positive history of sudden death in the family, whereas no patient had such a history in the former group (P=0.015). Conclusion: The higher prevalence of a family history of sudden death in patients with normal EMG, although not thoroughly explained by our data, may reflect differences in the genetic substrate produced by the higher prevalence of high-risk mutations that are not expressed in skeletal muscle (e.g. troponin T). Further evaluation in genotyped patients is warranted. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

Published
2003

29. Restrictive transmitral filling patterns predict improvements in left ventricular function after biventricular pacing

Author

Thaman, R, Murphy, RT, Firoozi, S, Hamid, SM, Gimeno, JR, Sachdev, B, Paul, V, Rowland, E, Frenneaux, MP, and Elliott, PM

Subjects
Heart function tests -- Evaluation -- Physiological aspects, Congestive heart failure -- Physiological aspects, Heart ventricle, Left -- Physiological aspects, Cardiac patients -- Evaluation -- Physiological aspects, Health, Evaluation, Physiological aspects
Abstract

Numerous studies have shown that biventricular pacing (BVP) improves symptoms and exercise capacity in patients with congestive cardiac failure (CCF) and left bundle branch block (LBBB). The mechanism of symptomatic [...]

Published
2003

43. ST segment "hump" during exercise testing and the risk of sudden cardiac death in patients with hypertrophic cardiomyopathy.

Author

Michaelides AP, Stamatopoulos I, Antoniades C, Anastasakis A, Kotsiopoulou C, Theopistou A, Misailidou M, Fourlas C, Elliott PM, Stefanadis C, Michaelides, Andreas P, Stamatopoulos, Ilias, Antoniades, Charalambos, Anastasakis, Aris, Kotsiopoulou, Christina, Theopistou, Artemisia, Misailidou, Maria, Fourlas, Christos, Elliott, Perry M, and Stefanadis, Christodoulos

Abstract

Background: The appearance of a discrete upward deflection of the ST segment termed "the ST hump sign" (STHS) during exercise testing has been associated with resting hypertension and exaggerated blood pressure response to exercise.Objective: We investigated the prevalence and clinical significance of this sign in a population of patients with hypertrophic cardiomyopathy.Methods: Eighty-one patients with hypertrophic cardiomyopathy (HCM) who underwent cardiopulmonary exercise testing were followed in a retrospective cohort study for a mean period of 5.3 years.Results: The appearance of the STHS at the peak of exercise testing was observed in 42 patients (52%), particularly in the inferior and the lateral leads. Patients with the STHS had higher fractional shortening and maximum left ventricular wall thickness and exhibited more frequently outflow tract gradient >30 mmHg at rest. Furthermore, the presence of STHS was a strong independent predictor of the risk of sudden cardiac death (SCD), as the latter occurred in eight of the patients with this sign (8/42, 19%) and in none of the patients without it (0/39, 0%) (P < 0.001).Conclusion: The appearance of a "hump" at the ST segment during exercise testing appears to be a risk factor for SCD in patients with HCM. However, further studies are necessary to validate this finding in larger populations and to elucidate the mechanism of the appearance of the "hump." [ABSTRACT FROM AUTHOR]

Published
2009
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44. B-type natriuretic peptide predicts disease severity in children with hypertrophic cardiomyopathy.

Author

Kaski JP, Tomé-Esteban MT, Mead-Regan S, Pantazis A, Marek J, Deanfield JE, McKenna WJ, and Elliott PM

Abstract

BACKGROUND: In adults with hypertrophic cardiomyopathy (HCM), plasma B-type natriuretic peptide (BNP) levels correlate with dyspnoea class and other markers of disease severity. In children with HCM, symptoms are a poor guide to disease severity and no studies have evaluated the clinical utility of BNP testing. OBJECTIVE: To assess the relation of BNP levels to symptoms and markers of disease severity in children with HCM. METHODS: Forty-four consecutive patients with HCM (27 male, age 10 (area under the receiver operator characteristic curve = 0.875 (p<0.001)). CONCLUSIONS: BNP levels correlate with non-invasive parameters of disease severity in children with HCM, including measures of raised LV filling pressures. For patients in whom evaluation of symptoms is difficult, BNP may be a useful additional tool in the assessment of disease severity. [ABSTRACT FROM AUTHOR]

Published
2008

45. Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy.

Author

Shah JS, Esteban MTT, Thaman R, Sharma R, Mist B, Pantazis A, Ward D, Kohli SK, Page SP, Demetrescu C, Sevdalis E, Keren A, Pellerin D, McKenna WJ, and Elliott PM

Abstract

BACKGROUND: Resting left ventricular outflow tract obstruction (LVOTO) occurs in 25% of patients with hypertrophic cardiomyopathy (HCM) and is an important cause of symptoms and disease progression. The prevalence and clinical significance of exercise induced LVOTO in patients with symptomatic non-obstructive HCM is uncertain. METHODS AND RESULTS: 87 symptomatic patients (43.3 (13.7) years, 67.8% males) with HCM and no previously documented LVOTO (defined as a gradient >/=30 mm Hg) underwent echocardiography during upright cardiopulmonary exercise testing: 54 patients (62.1%; 95% CI 51.5 to 71.6) developed LVOTO during exercise (latent LVOTO); 33 (37.9%; 95% CI 28.4 to 48.5) had neither resting nor exercise LVOTO (non-obstructive). Patients with latent LVOTO were more likely to have systolic anterior motion of the mitral valve (SAM) at rest (relative risk 2.1, 95% CI 1.2 to 3.8; p = 0.01), and higher peak oxygen consumption (mean difference: 10.3%, 95% CI 2.1 to 18.5; p = 0.02) than patients with non-obstructive HCM. The only independent predictors of [delta] gradient during exercise were a history of presyncope/syncope, incomplete/complete SAM at rest and Wigle score (all p<0.05). Subsequent invasive reduction of LVOTO in 10 patients with latent obstruction and drug refractory symptoms resulted in improved functional class and less syncope/presyncope (all p<0.05). CONCLUSIONS: Approximately two-thirds of patients with symptomatic non-obstructive HCM have latent LVOTO. This study suggests that all patients with symptomatic non-obstructive HCM should have exercise stress echocardiography. [ABSTRACT FROM AUTHOR]

Published
2008

46. Episodic syncope in hypertrophic cardiomyopathy: evidence for inappropriate vasodilation.

Author

Prasad K, Williams L, Campbell R, Elliott PM, McKenna WJ, and Frenneaux M

Abstract

Symptoms of impaired consciousness (syncope and pre-syncope) occur in 15-25% of patients with hypertrophic cardiomyopathy (HCM). In young patients a history of recurrent syncope is associated with an increased risk of sudden death. Syncope usually occurs without warning or symptoms suggestive of the cause. Detailed investigations identify a probable mechanism in a minority, usually paroxysmal atrial fibrillation or ventricular tachycardia. In the majority however no likely mechanism is found despite repeated 24-hour ambulatory echocardiography (ECG) or patient-activated monitoring, exercise testing and invasive electrophysiological studies. Empirical treatment with amiodarone, a pacemaker or an implantable cardioverter-defibrillator is commonly employed, but is often unsuccessful in relieving the symptoms. We have previously observed that approximately 30% of patients with HCM have abnormal blood pressure response during maximal upright exercise. This was due in the majority of patients to an exaggerated fall in systemic vascular resistance, possibly arising from abnormal activation of stretch-sensitive left ventricular mechanoreceptors, by a mechanism similar to that described in aortic stenosis. However, in some patients an inadequate cardiac output response to exercise may be responsible. We hypothesised that abnormal vasodepressor-mediated hypotension may also occur during daily life in patients with HCM, and that this may be an important mechanism of syncope when conventional investigations fail to reveal a cause. [ABSTRACT FROM AUTHOR]

Published
2008

47. Role of beta adrenergic receptor polymorphisms in heart failure: systematic review and meta-analysis.

Author

Muthumala A, Drenos F, Elliott PM, Humphries SE, Muthumala, Amal, Drenos, Fotios, Elliott, Perry M, and Humphries, Steve E

Abstract

Heart Failure (HF) is a common disorder associated with substantial morbidity and mortality. beta adrenergic receptors (betaAR) are the primary pathway through which cardiac function is influenced. Chronic beta(1)AR activation is implicated in the pathogenesis of HF and betaAR blockade improves survival in left ventricular systolic dysfunction. Common functional polymorphisms in beta adrenergic receptor genes (ADRB) have been associated with HF phenotypes, and with pharmacogenetic interaction with beta adrenergic receptor blockers (beta blockers). However, these associations have not been consistently replicated. The evidence for ADRB variant involvement in pathogenesis, progression and response to beta blockers in HF is reviewed. In addition, a meta-analysis of three studies analysing the effect of ADRB1 Arg389Gly polymorphism on left ventricular remodelling with the use of beta blockers, demonstrating a 5% improvement in left ventricular ejection fraction in Arg389 homozygotes, is presented. There is now accumulating molecular evidence for a different functional response to beta blockers associated with this polymorphism. In the future, confirmed genotypic associations may enable patients to be identified who are either at greater risk of developing HF, whose HF may rapidly progress, or who are unlikely to benefit from beta blockers, and such patients may benefit from targeted aggressive therapy. [ABSTRACT FROM AUTHOR]

Published
2008
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50. Historical trends in reported survival rates in patients with hypertrophic cardiomyopathy.

Author

Elliott PM, Gimeno JR, Thaman R, Shah J, Ward D, Dickie S, Tome Esteban MT, and McKenna WJ

Abstract

OBJECTIVE: To determine the range of survival rates of patients with hypertrophic cardiomyopathy (HCM) by comparing and contrasting the natural history of a cohort of patients seen between 1988 and 2002 with that of other published series. METHODS: 956 adult (> or = 16 years old) patients with HCM (572 men, mean (SD) age 42 (15) years, range 16-88) were evaluated by ECG, Holter, exercise testing, and echocardiography. Patient characteristics and survival data were compared with those in natural history studies from referral and non-referral centres published between 1960 and January 2003. RESULTS: The duration of follow up was 69 (45) months. 120 (12.6%) patients died or underwent cardiac transplantation. Sudden cardiac death (n = 48) was the most common mode of death. The annual rate of sudden death or implantable cardioverter-defibrillator discharge was 1.02 (95% confidence interval (CI) 0.76 to 1.26). Annual rates for heart failure death or transplantation and stroke related death were 0.55% (95% CI 0.37% to 0.78%) and 0.07% (95% CI 0.02% to 0.19%), respectively. When studies published within the last 10 years of the study period were compared with earlier reports, the size of individual study cohorts was larger (309 (240.6) v 136.5 (98.8), p = 0.058) and the proportion with severe functional limitation NYHA class III/IV lower (12.4% v 24.8%, p < 0.0001), and fewer patients underwent septal myotomy-myectomy (5.2% v 18.7%, p < 0.0001). Published sudden death rates over the last 10 years were lower than previously published figures (median 1.0% (range 0.1-1.7) v 2.0% (0-3.5)). CONCLUSION: Published survival rates in HCM cohorts have improved progressively over the past 40 years. In the modern era the prevalence of disease related complications is similar in all reporting centres. [ABSTRACT FROM AUTHOR]

Published
2006

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