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1. Validity of device-measured activity in patients with an implantable cardioverter-defibrillator

Author

Kolk, M Z H, Frodi, D M, Langford, J, Price, E, Andersen, T O, Niels Risum, N, Jacobsen, P K, Tan, H L, Svendsen, J H, Knops, R E, Diederichsen, S Z, Tjong, F V Y, Kolk, M Z H, Frodi, D M, Langford, J, Price, E, Andersen, T O, Niels Risum, N, Jacobsen, P K, Tan, H L, Svendsen, J H, Knops, R E, Diederichsen, S Z, and Tjong, F V Y

Abstract

Introduction There is a growing interest in the use of accelerometers and sensors embedded in implantable cardioverter-defibrillators (ICDs) for monitoring patient activity. Despite evidence regarding the potential clinical value of device-measured activity (D-PA), the validity of these measurements has not yet been established. Objective To assess the validity of device-measured activity against a research-grade, widely validated wearable accelerometer. Methods This is a subanalysis of the ongoing multicenter, prospective SafeHeart study. Raw accelerometry data was continuously sampled at 50Hz from a wrist-worn accelerometer (GENEActiv) during 12 months. Days with at least 22 hours of wear time were used to create summary measures of time in activity, daily active volume and total slow walking steps. These measures were compared to D-PA harmonised as percentage of active time per day, from four different ICD vendors’ remote transmission data, using linear mixed effect models. Results Wearable and device-measured activity data in 51 ICD patients rendered 1228 days (mean 24 days ±19) with both wearable and device-measured activity data. There were significant differences between wearable and device-measured accelerometery in the average time active per day (Table 1). For two vendors significant associations between D-PA, daily active volume, and total slow walking steps were observed. Also, associations between D-PA and daily active time and moderate vigorous physical activity were found in a third vendor. For the fourth vendor no association between any wearable activity metric and D-PA was found. Inter-patient differences accounted for 73.1% of the total variance in D-PA. Conclusion Results demonstrate substantial differences in device-measured activity measurements compared to research-grade activity data. This has implications for the utility and generalizability of D-PA as clinical parameter.

Published
2023

2. Validity of device-measured activity in patients with an implantable cardioverter-defibrillator

Author

Kolk, M Z H, Frodi, D M, Langford, J, Price, E, Andersen, T O, Niels Risum, N, Jacobsen, P K, Tan, H L, Svendsen, J H, Knops, R E, Diederichsen, S Z, Tjong, F V Y, Kolk, M Z H, Frodi, D M, Langford, J, Price, E, Andersen, T O, Niels Risum, N, Jacobsen, P K, Tan, H L, Svendsen, J H, Knops, R E, Diederichsen, S Z, and Tjong, F V Y

Abstract

Introduction There is a growing interest in the use of accelerometers and sensors embedded in implantable cardioverter-defibrillators (ICDs) for monitoring patient activity. Despite evidence regarding the potential clinical value of device-measured activity (D-PA), the validity of these measurements has not yet been established. Objective To assess the validity of device-measured activity against a research-grade, widely validated wearable accelerometer. Methods This is a subanalysis of the ongoing multicenter, prospective SafeHeart study. Raw accelerometry data was continuously sampled at 50Hz from a wrist-worn accelerometer (GENEActiv) during 12 months. Days with at least 22 hours of wear time were used to create summary measures of time in activity, daily active volume and total slow walking steps. These measures were compared to D-PA harmonised as percentage of active time per day, from four different ICD vendors’ remote transmission data, using linear mixed effect models. Results Wearable and device-measured activity data in 51 ICD patients rendered 1228 days (mean 24 days ±19) with both wearable and device-measured activity data. There were significant differences between wearable and device-measured accelerometery in the average time active per day (Table 1). For two vendors significant associations between D-PA, daily active volume, and total slow walking steps were observed. Also, associations between D-PA and daily active time and moderate vigorous physical activity were found in a third vendor. For the fourth vendor no association between any wearable activity metric and D-PA was found. Inter-patient differences accounted for 73.1% of the total variance in D-PA. Conclusion Results demonstrate substantial differences in device-measured activity measurements compared to research-grade activity data. This has implications for the utility and generalizability of D-PA as clinical parameter.

Published
2023

3. Clinical presentation, disease course, and outcome of COVID-19 in hospitalized patients with and without pre-existing cardiac disease: a cohort study across 18 countries

Author

Linschoten, M., Uijl, A., Schut, A., Jakob, C. E. M., Romao, L. R., Bell, R. M., McFarlane, E., Stecher, M., Zondag, A. G. M., van Iperen, E. P. A., Hermans-van Ast, J. F., Lea, N. C., Schaap, J., Jewbali, L. S., Smits, P. C., Patel, R. S., Aujayeb, A., van Smeden, M., Siebelink, H. J., Williams, S., Pilgram, L., Tieleman, R. G., Williams, B., Asselbergs, F. W., Al-Ali, A. K., Al-Muhanna, F. A., Al-Rubaish, A. M., Al-Windy, N. Y. Y., Alkhalil, M., Almubarak, Y. A., Al Nafie, A. N., Al Shahrani, M., Al Shehri, A. M., Anning, C., Anthonio, R. L., Badings, E. A., Ball, C., Van Beek, E. A., Ten Berg, J. M., Von Bergwelt-Baildon, M., Bianco, M., Blagova, O., V, Bleijendaal, H., Bor, W. L., Borgmann, S., van Boxem, A. J. M., van den Brink, F. S., Bucciarelli-Ducci, C., Van Bussel, B. C. T., Byrom-Goulthorp, R., Captur, G., Caputo, M., Charlotte, N., vom Dahl, J., Dark, P., De Sutter, J., Degenhardt, C., Delsing, C. E., Dolff, S., Dorman, H. G. R., Drost, J. T., Eberwein, L., Emans, M. E., Er, A. G., Ferreira, J. B., Forner, M. J., Friedrichs, A., Gabriel, L., Groenemeijer, B. E., Groenendijk, A. L., Gruener, B., Guggemos, W., Haerkens-Arends, H. E., Hanses, F., Hedayat, B., Heigener, D., van der Heijden, D. J., Hellou, E., Hellwig, K., Henkens, M. T. H. M., Hermanides, R. S., Hermans, W. R. M., van Hessen, M. W. J., Heymans, S. R. B., Hilt, A. D., van der Horst, I. C. C., Hower, M., van Ierssel, S. H., Isberner, N., Jensen, B., Kearney, M. T., Kielstein, J. T., Kietselaer, B. L. J. H., Kochanek, M., Kolk, M. Z. H., Koning, A. M. H., Kopylov, P. Y., Kuijper, A. F. M., Kwakkel-van, E. R. P. J. M., Lanznaster, J., van der Linden, M. M. J. M., van der Lingen, A. C. J., Linssen, G. C. M., Lomas, D., Maarse, M., Magdelijns, F. J. H., Magro, M., Markart, P., Martens, F. M. A. C., Mazzilli, S. G., McCann, G. P., van der Meer, P., Meijs, M. F. L., Merle, U., Messiaen, P., Milovanovic, M., Monraats, P. S., Montagna, L., Moriarty, A., Moss, A. J., Mosterd, A., Nadalin, S., Nattermann, J., Neufang, M., Nierop, P. R., Offerhaus, J. A., Van Ofwegen-Hanekamp, C. E. E., Parker, E., Persoon, A. M., Piepel, C., Pinto, Y. M., Poorhosseini, H., Prasad, S., Raafs, A. G., Raichle, C., Rauschning, D., Redon, J., Reidinga, A. C., Ribeiro, M. I. A., Riedel, C., Rieg, S., Ripley, D. P., Rommele, C., Rothfuss, K., Ruddel, J., Ruthrich, M. M., Salah, R., Saneei, E., Saxena, M., Schellings, D. A. A. M., Scholte, N. T. B., Schubert, J., Seelig, J., Shafiee, A., Shore, A. C., Spinner, C., Stieglitz, S., Strauss, R., Sturkenboom, N. H., Tessitore, E., Thomson, R. J., Timmermans, P. J. R., Tio, R. A., Tjong, F. V. Y., Tometten, L., Trauth, J., Van Craenenbroeck, E. M., van Veen, H. P. A. A., den Uil, C. A., Vehreschild, M. J. G. T., Veldhuis, L., I, Veneman, T., Verschure, D. O., Voigt, I, Walter, L., vande Watering, D. J., de Vries, J. K., vande Wal, R. M. A., Westendorp, I. C. D., Westendorp, P. H. M., Westhoff, T., Weytjens, C., Wierda, E., Wille, K., de With, K., Worm, M., Woudstra, P., Wu, K. W., Zaal, R., Zaman, A. G., van der Zee, P. M., Zijlstra, L. E., Alling, T. E., Ahmed, R., Bayraktar-Verver, E. C. E., van Aken, K., Jimenes, Bermudez F. J., Biole, C. A., Den Boer-Penning, P., Bontje, M., Bos, M., Bosch, L., Broekman, M., Broeyer, F. J. F., de Bruijn, E. A. W., Bruinsma, S., Cardoso, N. M., Cosyns, B., Len, van Da D. H., Dekimpe, E., Domange, J., van Doorn, J. L., van DOorn, P., Dormal, F., Drost, I. M. J., Dunnink, A., van Eck, J. W. M., Elshinawy, K., Gevers, R. M. M., Gognieva, D. G., van der Graaf, M., Grangeon, S., Guclu, A., Habib, A., Haenen, N. A., Hamilton, K., Handgraaf, S., Heidbuchel, H., Hendriks-van Woerden, M., Hessels-Linnemeijer, B. M., Hosseini, K., Huisman, J., Jacobs, T. C., Jansen, S. E., Janssen, A., Jourdan, K., ten Kate, G. L., van Kempen, M. J., Kievit, C. M., Kleikers, P., Knufman, N., van der Kooi, S. E., Koole, B. A. S., Koole, M. A. C., Kui, K. K., Kuipers-Elferink, L., Lemoine, I, Lensink, E., van Marrewijk, V, Meijer, E. J., Melein, A. J., Mesitskaya, D. F., van Nes, C. P. M., Paris, F. M. A., Perrelli, M. G., Pieterse-Rots, A., Pisters, R., Polkerman, B. C., van Poppel, A., Reinders, S., Reitsma, M. J., Ruiter, A. H., Selder, J. L., van der Sluis, A., Sousa, A. I. C., Tajdini, M., Sanchez, Tercedor L., Van de Heyning, C. M., Vial, H., Vlieghe, E., Vonkeman, H. E., Vreugdenhil, P., de Vries, T. A. C., Willems, A. M., Wils, A. M., Zoet-Nugteren, S. K., Linschoten, M., Uijl, A., Schut, A., Jakob, C. E. M., Romao, L. R., Bell, R. M., McFarlane, E., Stecher, M., Zondag, A. G. M., van Iperen, E. P. A., Hermans-van Ast, J. F., Lea, N. C., Schaap, J., Jewbali, L. S., Smits, P. C., Patel, R. S., Aujayeb, A., van Smeden, M., Siebelink, H. J., Williams, S., Pilgram, L., Tieleman, R. G., Williams, B., Asselbergs, F. W., Al-Ali, A. K., Al-Muhanna, F. A., Al-Rubaish, A. M., Al-Windy, N. Y. Y., Alkhalil, M., Almubarak, Y. A., Al Nafie, A. N., Al Shahrani, M., Al Shehri, A. M., Anning, C., Anthonio, R. L., Badings, E. A., Ball, C., Van Beek, E. A., Ten Berg, J. M., Von Bergwelt-Baildon, M., Bianco, M., Blagova, O., V, Bleijendaal, H., Bor, W. L., Borgmann, S., van Boxem, A. J. M., van den Brink, F. S., Bucciarelli-Ducci, C., Van Bussel, B. C. T., Byrom-Goulthorp, R., Captur, G., Caputo, M., Charlotte, N., vom Dahl, J., Dark, P., De Sutter, J., Degenhardt, C., Delsing, C. E., Dolff, S., Dorman, H. G. R., Drost, J. T., Eberwein, L., Emans, M. E., Er, A. G., Ferreira, J. B., Forner, M. J., Friedrichs, A., Gabriel, L., Groenemeijer, B. E., Groenendijk, A. L., Gruener, B., Guggemos, W., Haerkens-Arends, H. E., Hanses, F., Hedayat, B., Heigener, D., van der Heijden, D. J., Hellou, E., Hellwig, K., Henkens, M. T. H. M., Hermanides, R. S., Hermans, W. R. M., van Hessen, M. W. J., Heymans, S. R. B., Hilt, A. D., van der Horst, I. C. C., Hower, M., van Ierssel, S. H., Isberner, N., Jensen, B., Kearney, M. T., Kielstein, J. T., Kietselaer, B. L. J. H., Kochanek, M., Kolk, M. Z. H., Koning, A. M. H., Kopylov, P. Y., Kuijper, A. F. M., Kwakkel-van, E. R. P. J. M., Lanznaster, J., van der Linden, M. M. J. M., van der Lingen, A. C. J., Linssen, G. C. M., Lomas, D., Maarse, M., Magdelijns, F. J. H., Magro, M., Markart, P., Martens, F. M. A. C., Mazzilli, S. G., McCann, G. P., van der Meer, P., Meijs, M. F. L., Merle, U., Messiaen, P., Milovanovic, M., Monraats, P. S., Montagna, L., Moriarty, A., Moss, A. J., Mosterd, A., Nadalin, S., Nattermann, J., Neufang, M., Nierop, P. R., Offerhaus, J. A., Van Ofwegen-Hanekamp, C. E. E., Parker, E., Persoon, A. M., Piepel, C., Pinto, Y. M., Poorhosseini, H., Prasad, S., Raafs, A. G., Raichle, C., Rauschning, D., Redon, J., Reidinga, A. C., Ribeiro, M. I. A., Riedel, C., Rieg, S., Ripley, D. P., Rommele, C., Rothfuss, K., Ruddel, J., Ruthrich, M. M., Salah, R., Saneei, E., Saxena, M., Schellings, D. A. A. M., Scholte, N. T. B., Schubert, J., Seelig, J., Shafiee, A., Shore, A. C., Spinner, C., Stieglitz, S., Strauss, R., Sturkenboom, N. H., Tessitore, E., Thomson, R. J., Timmermans, P. J. R., Tio, R. A., Tjong, F. V. Y., Tometten, L., Trauth, J., Van Craenenbroeck, E. M., van Veen, H. P. A. A., den Uil, C. A., Vehreschild, M. J. G. T., Veldhuis, L., I, Veneman, T., Verschure, D. O., Voigt, I, Walter, L., vande Watering, D. J., de Vries, J. K., vande Wal, R. M. A., Westendorp, I. C. D., Westendorp, P. H. M., Westhoff, T., Weytjens, C., Wierda, E., Wille, K., de With, K., Worm, M., Woudstra, P., Wu, K. W., Zaal, R., Zaman, A. G., van der Zee, P. M., Zijlstra, L. E., Alling, T. E., Ahmed, R., Bayraktar-Verver, E. C. E., van Aken, K., Jimenes, Bermudez F. J., Biole, C. A., Den Boer-Penning, P., Bontje, M., Bos, M., Bosch, L., Broekman, M., Broeyer, F. J. F., de Bruijn, E. A. W., Bruinsma, S., Cardoso, N. M., Cosyns, B., Len, van Da D. H., Dekimpe, E., Domange, J., van Doorn, J. L., van DOorn, P., Dormal, F., Drost, I. M. J., Dunnink, A., van Eck, J. W. M., Elshinawy, K., Gevers, R. M. M., Gognieva, D. G., van der Graaf, M., Grangeon, S., Guclu, A., Habib, A., Haenen, N. A., Hamilton, K., Handgraaf, S., Heidbuchel, H., Hendriks-van Woerden, M., Hessels-Linnemeijer, B. M., Hosseini, K., Huisman, J., Jacobs, T. C., Jansen, S. E., Janssen, A., Jourdan, K., ten Kate, G. L., van Kempen, M. J., Kievit, C. M., Kleikers, P., Knufman, N., van der Kooi, S. E., Koole, B. A. S., Koole, M. A. C., Kui, K. K., Kuipers-Elferink, L., Lemoine, I, Lensink, E., van Marrewijk, V, Meijer, E. J., Melein, A. J., Mesitskaya, D. F., van Nes, C. P. M., Paris, F. M. A., Perrelli, M. G., Pieterse-Rots, A., Pisters, R., Polkerman, B. C., van Poppel, A., Reinders, S., Reitsma, M. J., Ruiter, A. H., Selder, J. L., van der Sluis, A., Sousa, A. I. C., Tajdini, M., Sanchez, Tercedor L., Van de Heyning, C. M., Vial, H., Vlieghe, E., Vonkeman, H. E., Vreugdenhil, P., de Vries, T. A. C., Willems, A. M., Wils, A. M., and Zoet-Nugteren, S. K.

Abstract

Aims Patients with cardiac disease are considered high risk for poor outcomes following hospitalization with COVID-19. The primary aim of this study was to evaluate heterogeneity in associations between various heart disease subtypes and in-hospital mortality. Methods and results We used data from the CAPACITY-COVID registry and LEOSS study. Multivariable Poisson regression models were fitted to assess the association between different types of pre-existing heart disease and in-hospital mortality. A total of 16 511 patients with COVID-19 were included (21.1% aged 66-75 years; 40.2% female) and 31.5% had a history of heart disease. Patients with heart disease were older, predominantly male, and often had other comorbid conditions when compared with those without. Mortality was higher in patients with cardiac disease (29.7%; n= 1545 vs. 15.9%; n= 1797). However, following multivariable adjustment, this difference was not significant [adjusted risk ratio (aRR) 1.08, 95% confidence interval (CI) 1.02-1.15; P = 0.12 (corrected for multiple testing)]. Associations with in-hospital mortality by heart disease subtypes differed considerably, with the strongest association for heart failure (aRR 1.19, 95% CI 1.10-1.30; P <0.018) particularly for severe (New York Heart Association class III/IV) heart failure (aRR 1.41, 95% CI 1.20-1.64; P < 0.018). None of the other heart disease subtypes, including ischaemic heart disease, remained significant after multivariable adjustment. Serious cardiac complications were diagnosed in <1% of patients. Conclusion Considerable heterogeneity exists in the strength of association between heart disease subtypes and in-hospital mortality. Of all patients with heart disease, those with heart failure are at greatest risk of death when hospitalized with COVID-19. Serious cardiac complications are rare during hospitalization. [GRAPHICS] .

Published
2022

4. Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome

Author

Krane, M, Dressen, M, Santamaria, G, My, I, Schneider, C, Dorn, T, Laue, S, Mastantuono, E, Berutti, R, Rawat, H, Gilsbach, R, Schneider, P, Lahm, H, Schwarz, S, Doppler, S, Paige, S, Puluca, N, Doll, S, Neb, I, Brade, T, Zhang, Z, Abou-Ajram, C, Northoff, B, Holdt, L, Sudhop, S, Sahara, M, Goedel, A, Dendorfer, A, Tjong, F, Rijlaarsdam, M, Cleuziou, J, Lang, N, Kupatt, C, Bezzina, C, Lange, R, Bowles, N, Mann, M, Gelb, B, Crotti, L, Hein, L, Meitinger, T, Wu, S, Sinnecker, D, Gruber, P, Laugwitz, K, Moretti, A, Krane M., Dressen M., Santamaria G., My I., Schneider C. M., Dorn T., Laue S., Mastantuono E., Berutti R., Rawat H., Gilsbach R., Schneider P., Lahm H., Schwarz S., Doppler S. A., Paige S., Puluca N., Doll S., Neb I., Brade T., Zhang Z., Abou-Ajram C., Northoff B., Holdt L. M., Sudhop S., Sahara M., Goedel A., Dendorfer A., Tjong F. V. Y., Rijlaarsdam M. E., Cleuziou J., Lang N., Kupatt C., Bezzina C., Lange R., Bowles N. E., Mann M., Gelb B. D., Crotti L., Hein L., Meitinger T., Wu S., Sinnecker D., Gruber P. J., Laugwitz K. -L., Moretti A., Krane, M, Dressen, M, Santamaria, G, My, I, Schneider, C, Dorn, T, Laue, S, Mastantuono, E, Berutti, R, Rawat, H, Gilsbach, R, Schneider, P, Lahm, H, Schwarz, S, Doppler, S, Paige, S, Puluca, N, Doll, S, Neb, I, Brade, T, Zhang, Z, Abou-Ajram, C, Northoff, B, Holdt, L, Sudhop, S, Sahara, M, Goedel, A, Dendorfer, A, Tjong, F, Rijlaarsdam, M, Cleuziou, J, Lang, N, Kupatt, C, Bezzina, C, Lange, R, Bowles, N, Mann, M, Gelb, B, Crotti, L, Hein, L, Meitinger, T, Wu, S, Sinnecker, D, Gruber, P, Laugwitz, K, Moretti, A, Krane M., Dressen M., Santamaria G., My I., Schneider C. M., Dorn T., Laue S., Mastantuono E., Berutti R., Rawat H., Gilsbach R., Schneider P., Lahm H., Schwarz S., Doppler S. A., Paige S., Puluca N., Doll S., Neb I., Brade T., Zhang Z., Abou-Ajram C., Northoff B., Holdt L. M., Sudhop S., Sahara M., Goedel A., Dendorfer A., Tjong F. V. Y., Rijlaarsdam M. E., Cleuziou J., Lang N., Kupatt C., Bezzina C., Lange R., Bowles N. E., Mann M., Gelb B. D., Crotti L., Hein L., Meitinger T., Wu S., Sinnecker D., Gruber P. J., Laugwitz K. -L., and Moretti A.

Abstract

BACKGROUND: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. METHODS: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. RESULTS: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/ maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. CONCLUSIONS: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting n

Published
2021

5. Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome

Author

Krane, M, Dressen, M, Santamaria, G, My, I, Schneider, C, Dorn, T, Laue, S, Mastantuono, E, Berutti, R, Rawat, H, Gilsbach, R, Schneider, P, Lahm, H, Schwarz, S, Doppler, S, Paige, S, Puluca, N, Doll, S, Neb, I, Brade, T, Zhang, Z, Abou-Ajram, C, Northoff, B, Holdt, L, Sudhop, S, Sahara, M, Goedel, A, Dendorfer, A, Tjong, F, Rijlaarsdam, M, Cleuziou, J, Lang, N, Kupatt, C, Bezzina, C, Lange, R, Bowles, N, Mann, M, Gelb, B, Crotti, L, Hein, L, Meitinger, T, Wu, S, Sinnecker, D, Gruber, P, Laugwitz, K, Moretti, A, Krane M., Dressen M., Santamaria G., My I., Schneider C. M., Dorn T., Laue S., Mastantuono E., Berutti R., Rawat H., Gilsbach R., Schneider P., Lahm H., Schwarz S., Doppler S. A., Paige S., Puluca N., Doll S., Neb I., Brade T., Zhang Z., Abou-Ajram C., Northoff B., Holdt L. M., Sudhop S., Sahara M., Goedel A., Dendorfer A., Tjong F. V. Y., Rijlaarsdam M. E., Cleuziou J., Lang N., Kupatt C., Bezzina C., Lange R., Bowles N. E., Mann M., Gelb B. D., Crotti L., Hein L., Meitinger T., Wu S., Sinnecker D., Gruber P. J., Laugwitz K. -L., Moretti A., Krane, M, Dressen, M, Santamaria, G, My, I, Schneider, C, Dorn, T, Laue, S, Mastantuono, E, Berutti, R, Rawat, H, Gilsbach, R, Schneider, P, Lahm, H, Schwarz, S, Doppler, S, Paige, S, Puluca, N, Doll, S, Neb, I, Brade, T, Zhang, Z, Abou-Ajram, C, Northoff, B, Holdt, L, Sudhop, S, Sahara, M, Goedel, A, Dendorfer, A, Tjong, F, Rijlaarsdam, M, Cleuziou, J, Lang, N, Kupatt, C, Bezzina, C, Lange, R, Bowles, N, Mann, M, Gelb, B, Crotti, L, Hein, L, Meitinger, T, Wu, S, Sinnecker, D, Gruber, P, Laugwitz, K, Moretti, A, Krane M., Dressen M., Santamaria G., My I., Schneider C. M., Dorn T., Laue S., Mastantuono E., Berutti R., Rawat H., Gilsbach R., Schneider P., Lahm H., Schwarz S., Doppler S. A., Paige S., Puluca N., Doll S., Neb I., Brade T., Zhang Z., Abou-Ajram C., Northoff B., Holdt L. M., Sudhop S., Sahara M., Goedel A., Dendorfer A., Tjong F. V. Y., Rijlaarsdam M. E., Cleuziou J., Lang N., Kupatt C., Bezzina C., Lange R., Bowles N. E., Mann M., Gelb B. D., Crotti L., Hein L., Meitinger T., Wu S., Sinnecker D., Gruber P. J., Laugwitz K. -L., and Moretti A.

Abstract

BACKGROUND: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. METHODS: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. RESULTS: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/ maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. CONCLUSIONS: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting n

Published
2021

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