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1. Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Author

Zheng, Sean L., Henry, Albert, Cannie, Douglas, Lee, Michael, Miller, David, McGurk, Kathryn A., Bond, Isabelle, Xu, Xiao, Issa, Hanane, Francis, Catherine, De Marvao, Antonio, Theotokis, Pantazis I., Buchan, Rachel J., Speed, Doug, Abner, Erik, Adams, Lance, Aragam, Krishna G., Ärnlöv, Johan, Raja, Anna Axelsson, Backman, Joshua D., Baksi, John, Barton, Paul J. R., Biddinger, Kiran J., Boersma, Eric, Brandimarto, Jeffrey, Brunak, Søren, Bundgaard, Henning, Carey, David J., Charron, Philippe, Cook, James P., Cook, Stuart A., Denaxas, Spiros, Deleuze, Jean-François, Doney, Alexander S., Elliott, Perry, Erikstrup, Christian, Esko, Tõnu, Farber-Eger, Eric H., Finan, Chris, Garnier, Sophie, Ghouse, Jonas, Giedraitis, Vilmantas, Guðbjartsson, Daniel F., Haggerty, Christopher M., Halliday, Brian P., Helgadottir, Anna, Hemingway, Harry, Hillege, Hans L., Kardys, Isabella, Lind, Lars, Lindgren, Cecilia M., Lowery, Brandon D., Manisty, Charlotte, Margulies, Kenneth B., Moon, James C., Mordi, Ify R., Morley, Michael P., Morris, Andrew D., Morris, Andrew P., Morton, Lori, Noursadeghi, Mahdad, Ostrowski, Sisse R., Owens, Anjali T., Palmer, Colin N. A., Pantazis, Antonis, Pedersen, Ole B. V., Prasad, Sanjay K., Shekhar, Akshay, Smelser, Diane T., Srinivasan, Sundararajan, Stefansson, Kari, Sveinbjörnsson, Garðar, Syrris, Petros, Tammesoo, Mari-Liis, Tayal, Upasana, Teder-Laving, Maris, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Tragante, Vinicius, Trégouët, David-Alexandre, Treibel, Thomas A., Ullum, Henrik, Valdes, Ana M., van Setten, Jessica, van Vugt, Marion, Veluchamy, Abirami, Verschuren, W. M. Monique, Villard, Eric, Yang, Yifan, Asselbergs, Folkert W., Cappola, Thomas P., Dube, Marie-Pierre, Dunn, Michael E., Ellinor, Patrick T., Hingorani, Aroon D., Lang, Chim C., Samani, Nilesh J., Shah, Svati H., Smith, J. Gustav, Vasan, Ramachandran S., O’Regan, Declan P., Holm, Hilma, Noseda, Michela, Wells, Quinn, Ware, James S., and Lumbers, R. Thomas

Published
2024
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2. Protocol for a type 3 hybrid implementation cluster randomized clinical trial to evaluate the effect of patient and clinician nudges to advance the use of genomic medicine across a diverse health system

Author

Raper, Anna C., Weathers, Benita L., Drivas, Theodore G., Ellis, Colin A., Kripke, Colleen Morse, Oyer, Randall A., Owens, Anjali T., Verma, Anurag, Wileyto, Paul E., Wollack, Colin C., Zhou, Wenting, Ritchie, Marylyn D., Schnoll, Robert A., and Nathanson, Katherine L.

Published
2024
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3. Mavacamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Design, Rationale, and Baseline Characteristics of ODYSSEY-HCM

Author

Desai, Milind Y., Nissen, Steve E., Abraham, Theodore, Olivotto, Iacopo, Garcia-Pavia, Pablo, Lopes, Renato D., Verheyen, Nicolas, Wever-Pinzon, Omar, Wolski, Kathy, Jaber, Wael, Mitchell, Lisa, Davey, Deborah, Myers, Jonathan, Rano, Thomas, Bhatia, Vandana, Zhong, Yue, Carter-Bonanza, Suzanne, Florea, Victoria, Aronson, Ron, and Owens, Anjali T.

Published
2025
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4. The Clinical Trajectory of NYHA Functional Class I Patients With Obstructive Hypertrophic Cardiomyopathy

Author

Ahluwalia, Monica, Liu, Jiankang, Olivotto, Iacopo, Parikh, Victoria, Ashley, Euan A., Michels, Michelle, Ingles, Jodie, Lampert, Rachel, Stendahl, John C., Colan, Steven D., Abrams, Dominic, Pereira, Alexandre C., Rossano, Joseph W., Ryan, Thomas D., Owens, Anjali T., Ware, James S., Saberi, Sara, Helms, Adam S., Day, Sharlene, Claggett, Brian, Ho, Carolyn Y., and Lakdawala, Neal K.

Published
2025
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6. Impact of Aficamten on Disease and Symptom Burden in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM

Author

Maron, Martin S., Masri, Ahmad, Nassif, Michael E., Barriales-Villa, Roberto, Abraham, Theodore P., Arad, Michael, Cardim, Nuno, Choudhury, Lubna, Claggett, Brian, Coats, Caroline J., Düngen, Hans-Dirk, Garcia-Pavia, Pablo, Hagège, Albert A., Januzzi, James L., Kulac, Ian, Lee, Matthew M.Y., Lewis, Gregory D., Ma, Chang-Sheng, Michels, Michelle, Oreziak, Artur, Owens, Anjali T., Spertus, John A., Solomon, Scott D., Tfelt-Hansen, Jacob, van Sinttruije, Marion, Veselka, Josef, Watkins, Hugh C., Jacoby, Daniel L., Heitner, Stephen B., Kupfer, Stuart, Malik, Fady I., Meng, Lisa, Wohltman, Amy, and Olivotto, Iacopo

Published
2024
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7. Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4

Author

MASRI, AHMAD, SHERRID, MARK V., ABRAHAM, THEODORE P., CHOUDHURY, LUBNA, GARCIA-PAVIA, PABLO, KRAMER, CHRISTOPHER M., BARRIALES-VILLA, ROBERTO, OWENS, ANJALI T., RADER, FLORIAN, NAGUEH, SHERIF F., OLIVOTTO, IACOPO, SABERI, SARA, TOWER-RADER, ALBREE, WONG, TIMOTHY C., COATS, CAROLINE J., WATKINS, HUGH, FIFER, MICHAEL A., SOLOMON, SCOTT D., HEITNER, STEPHEN B., JACOBY, DANIEL L., KUPFER, STUART, MALIK, FADY I., MENG, LISA, SOHN, REGINA L., WOHLTMAN, AMY, and MARON, MARTIN S.

Published
2024
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8. Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes

Author

Shah, Parisha P, Lv, Wenjian, Rhoades, Joshua H, Poleshko, Andrey, Abbey, Deepti, Caporizzo, Matthew A, Linares-Saldana, Ricardo, Heffler, Julie G, Sayed, Nazish, Thomas, Dilip, Wang, Qiaohong, Stanton, Liam J, Bedi, Kenneth, Morley, Michael P, Cappola, Thomas P, Owens, Anjali T, Margulies, Kenneth B, Frank, David B, Wu, Joseph C, Rader, Daniel J, Yang, Wenli, Prosser, Benjamin L, Musunuru, Kiran, and Jain, Rajan

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Induced Pluripotent Stem Cell, Heart Disease, Cardiovascular, Rare Diseases, Stem Cell Research, 2.1 Biological and endogenous factors, Cardiomyopathy, Dilated, Chromatin, Humans, Induced Pluripotent Stem Cells, Lamin Type A, Mutation, Myocytes, Cardiac, genome organization, hiPSC, laminopathy, peripheral heterochromatin, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Pathogenic mutations in LAMIN A/C (LMNA) cause abnormal nuclear structure and laminopathies. These diseases have myriad tissue-specific phenotypes, including dilated cardiomyopathy (DCM), but how LMNA mutations result in tissue-restricted disease phenotypes remains unclear. We introduced LMNA mutations from individuals with DCM into human induced pluripotent stem cells (hiPSCs) and found that hiPSC-derived cardiomyocytes, in contrast to hepatocytes or adipocytes, exhibit aberrant nuclear morphology and specific disruptions in peripheral chromatin. Disrupted regions were enriched for transcriptionally active genes and regions with lower LAMIN B1 contact frequency. The lamina-chromatin interactions disrupted in mutant cardiomyocytes were enriched for genes associated with non-myocyte lineages and correlated with higher expression of those genes. Myocardium from individuals with LMNA variants similarly showed aberrant expression of non-myocyte pathways. We propose that the lamina network safeguards cellular identity and that pathogenic LMNA variants disrupt peripheral chromatin with specific epigenetic and molecular characteristics, causing misexpression of genes normally expressed in other cell types.

Published
2021

11. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, and Stott, David J

Subjects
Regeneron Genetics Center, Humans, Atrial Fibrillation, Cardiomyopathies, Microfilament Proteins, Adaptor Proteins, Signal Transducing, Carrier Proteins, Muscle Proteins, Risk Factors, Case-Control Studies, Ventricular Function, Left, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Coronary Artery Disease, Heart Failure, Genome-Wide Association Study, Mendelian Randomization Analysis, Adaptor Proteins, Signal Transducing, Ventricular Function, Left
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Published
2020

12. Abstract 17216: Limited Concordance of Core Lab Left Ventricular Ejection Fraction With Automated Assessments: A Sub-Study From VALOR-HCM

Author

Parizher, Gary, Jaber, Wael A, Owens, Anjali T, Wolski, Kathy E, Geske, Jeffrey B, Saberi, Sara, Wang, Andrew, Sherrid, Mark, Lakdawala, Neal K, Fifer, Michael A, Fermin, David R, Naidu, Srihari S, Smedira, Nicholas G, Schaff, Hartzell, McErlean, Ellen, Sewell, Christina M, Lampl, Kathy L, Sehnert, Amy J, Nissen, Steven E, Desai, Milind Y, and Cremer, Paul C

Published
2023
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13. Abstract 16660: Precision Diagnosis of Hypertrophic Cardiomyopathy: A New Definition of Inappropriate Hypertrophy

Author

Shiwani, Hunain, Davies, Rhodri, Topriceanu, Constantin-Cristian, Owens, Anjali T, Raman, Betty, Ditaranto, Raffaello, Augusto, Joao, Torlasco, Camilla, Webber, Matthew, Dowsing, Benjamin, Hughes, Rebecca, Miranda, Inês, Witschey, Walter, Thompson, Elizabeth, Castelletti, Silvia, Crotti, Lia, Lovato, Luigi, Ponziani, Alberto, Moschonas, Konstantinos, Joy, George, Pierce, Iain, Kellman, Peter, Hughes, Alun, Biagini, Elena, Mohiddin, Saidi, Lopes, Luis, Ferrari, Victor, Litt, Harold, Captur, Gabriella, and Moon, James

Published
2023
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14. Abstract 15706: Common- and Rare-Variant Genetic Architecture of Heart Failure Across the Allele Frequency Spectrum

Author

Lee, David S, Depaolo, John, Aragam, Krishna, Biddinger, Kiran, Conery, Mitchell, Dikilitas, Ozan, Khan, Atlas, Puckelwartz, Megan, Reza, Nosheen, Satterfield, Benjamin A, Arany, Zoltan, Cappola, Thomas P, Day, Sharlene, Joseph, Jacob, McNally, Elizabeth M, Owens, Anjali T, Voight, Benjamin F, Levin, Michael, and Damrauer, Scott M

Published
2023
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15. Abstract 14249: Sex and Gene Based Differences in Age Related Penetrance of Dilated and Arrhythmogenic Cardiomyopathy

Author

Bart, Nicole K, Stroeks, Sophie, Khan, Sadiya S, Reza, Nosheen, Olivotto, Iacopo, Vissing, Christoffer, Sinnette, Corine, Owens, Anjali T, Fornaro, Alessandra, Mestroni, Luisa, Taylor, Matthew, Helms, Adam S, Prasad, Sanjay K, Saberi, Sara, Shore, Supriya, Verdonschot, Job, sinagra, Gianfranco, Merlo, Marco, Gigli, Marta, Wilsbacher, Lisa D, Heymans, Stephane, Wheeler, Matthew, Ashley, Euan A, Dal Ferro, Matteo, Paldino, Alessia, Day, Sharlene, de Feria, Alejandro, Stevenson, Lynne W, Ho, Carolyn, Claggett, Brian, Ware, James S, Parikh, Victoria N, Tayal, Upasana, and Lakdawala, Neal K

Published
2023
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18. Abstract 12135: Quality of Life in Early-Stage Hypertrophic Cardiomyopathy: A Secondary Analysis of the VANISH Trial

Author

Ireland, Catherine G, Day, Sharlene, Axelsson, Anna, Russell, Mark W, Zahka, Kenneth G, Pereira, Alexandre, Canter, Charles E, Bach, Richard G, Wheeler, Matthew T, Rossano, Joseph W, Owens, Anjali T, Bundgaard, Henning, Mestroni, Luisa, Taylor, Matthew R, Amit, Patel R, Wilmot, Ivan, Soslow, Jonathan H, Becker, Jason R, Orav, Endel J, and Ho, Carolyn Y

Published
2023
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20. TTR variants in patients with dilated cardiomyopathy: An investigation of the DCM Precision Medicine Study

Author

Hershberger, Ray E., Kinnamon, Daniel D., Jordan, Elizabeth, Haas, Garrie, Huggins, Gordon S., Fishbein, Daniel, Gottlieb, Stephen S., Wheeler, Matthew T., Hofmeyer, Mark, Tang, W. H. Wilson, Owens, Anjali T., Moore, Charles K., Carcamo, Javier Jimenez, Trachtenberg, Barry, Sweitzer, Nancy K., Shah, Palak, Lowes, Brian, Stoller, Douglas, Smart, Frank, Morris, Alanna A., Wilcox, Jane, Katz, Stuart, Ewald, Gregory A., Aaronson, Keith D., Wang, Jessica J., Pamboukian, Salpy, Judge, Daniel P., Kransdorf, Evan P., Garg, Sonia, Desvigne-Nickens, Patrice, Troendle, James, Fu, Yi-Ping, Hindorff, Lucia, Trachtenberg, Barry H., Jimenez, Javier, Kransdorf, Evan, Owens, Anjali, Fishbein, Daniel P., and Mead, Jonathan O.

Published
2022
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21. Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry

Author

Abou Alaiwi, Sarah, Roston, Thomas M., Marstrand, Peter, Claggett, Brian Lee, Parikh, Victoria N., Helms, Adam S., Ingles, Jodie, Lampert, Rachel, Lakdawala, Neal K., Michels, Michelle, Owens, Anjali T., Rossano, Joseph W., Saberi, Sara, Abrams, Dominic J., Ashley, Euan A., Semsarian, Christopher, Stendahl, John C., Ware, James S., Miller, Erin, Ryan, Thomas D., Russell, Mark W., Day, Sharlene M., Olivotto, Iacopo, Vissing, Christoffer R., and Ho, Carolyn Y.

Published
2023
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24. Coronavirus disease 2019 in heart transplant recipients: Risk factors, immunosuppression, and outcomes

Author

Genuardi, Michael V., Moss, Noah, Najjar, Samer S., Houston, Brian A., Shore, Supriya, Vorovich, Esther, Atluri, Pavan, Molina, Maria, Chambers, Susan, Sharkoski, Tiffany, Hsich, Eileen, Estep, Jerry D., Owens, Anjali T., Alexander, Kevin M., Chaudhry, Sunit-Preet, Garcia-Cortes, Rafael, Molina, Ezequiel, Rodrigo, Maria, Wald, MDc Joyce, Margulies, Kenneth B., Hanff, Thomas C., Zimmer, Ross, Kilic, Arman, Mclean, Rhondalyn, Vidula, Himabindu, Dodd, Katherine, Blumberg, Emily A., Mazurek, Jeremy A., Goldberg, Lee R., Alvarez-Garcia, Jesus, Mancini, Donna, Teuteberg, Jeffrey J., Tedford, Ryan J., and Birati, Edo Y.

Published
2021
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25. Long-term effect of mavacamten in obstructive hypertrophic cardiomyopathy.

Author

Garcia-Pavia, Pablo, Oręziak, Artur, Masri, Ahmad, Barriales-Villa, Roberto, Abraham, Theodore P, Owens, Anjali T, Jensen, Morten K, Wojakowski, Wojciech, Seidler, Tim, Hagege, Albert, Lakdawala, Neal K, Wang, Andrew, Wheeler, Matthew T, Choudhury, Lubna, Balaratnam, Ganesh, Shah, Ashish, Fox, Shawna, Hegde, Sheila M, and Olivotto, Iacopo

Subjects
HYPERTROPHIC cardiomyopathy, VENTRICULAR ejection fraction, PEPTIDES, STANDARD deviations, SYMPTOMS
Abstract

Background and Aims Long-term safety and efficacy of mavacamten in patients with obstructive hypertrophic cardiomyopathy (HCM) are unknown. MAVA-LTE (NCT03723655) is an ongoing, 5-year, open-label extension study designed to evaluate the long-term effects of mavacamten. Methods Participants from EXPLORER-HCM (NCT03470545) could enrol in MAVA-LTE upon study completion. Results At the latest data cut-off, 211 (91.3%) of the 231 patients originally enrolled in MAVA-LTE still received mavacamten. Median (range) time on study was 166.1 (6.0–228.1) weeks; 185 (80.1%) and 99 (42.9%) patients had completed the Week 156 and 180 visits, respectively. Sustained reductions from baseline to Week 180 occurred in left ventricular outflow tract gradients [mean (standard deviation): resting, −40.3 (32.7) mmHg; Valsalva, −55.3 (33.7) mmHg], N-terminal pro B-type natriuretic peptide [median (interquartile range): −562 (−1162.5, −209) ng/L], and EQ-5D-5L score [mean (standard deviation): 0.09 (0.17)]. Mean left ventricular ejection fraction (LVEF) decreased from 73.9% (baseline) to 66.6% (Week 24) and 63.9% (Week 180). At Week 180, 74 (77.9%) of the 95 patients improved by at least one New York Heart Association class from baseline. Over 739 patient-years exposure, 20 patients (8.7%; exposure-adjusted incidence: 2.77/100 patient-years) experienced 22 transient reductions in LVEF to <50% resulting in temporary treatment interruption (all recovered LVEF of ≥50%). Five (2.2%) patients died (all considered unrelated to mavacamten). Conclusions Long-term mavacamten treatment resulted in sustained improvements in cardiac function and symptoms in patients with obstructive HCM, with no new safety concerns identified. Transient, reversible reductions in LVEF were observed in a small proportion of patients during long-term follow-up. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial.

Author

Coats, Caroline J, Masri, Ahmad, Barriales-Villa, Roberto, Abraham, Theodore P, Brinkley, Douglas Marshall, Claggett, Brian L, Hagege, Albert, Hegde, Sheila M, Ho, Carolyn Y, Kulac, Ian J, Lee, Matthew M Y, Maron, Martin S, Olivotto, Iacopo, Owens, Anjali T, Solomon, Scott D, Tfelt-Hansen, Jacob, Watkins, Hugh, Jacoby, Daniel L, Heitner, Stephen B, and Kupfer, Stuart

Subjects
BRAIN natriuretic factor, TROPONIN I, HYPERTROPHIC cardiomyopathy, NATRIURETIC peptides, TREATMENT effectiveness
Abstract

Background and Aims The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate the effect of treatment with aficamten on biomarker concentrations. Methods Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and evaluated whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. Results Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% confidence interval 76%–83%, P <.001) and hs-cTnI by 41% (95% confidence interval 32%–49%, P <.001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. N-Terminal pro-B-type natriuretic peptide reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints. Conclusions N-Terminal pro-B-type natriuretic peptide and hs-cTnI concentrations are associated with key variables in obstructive hypertrophic cardiomyopathy. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Promise and Peril of a Genotype-First Approach to Mendelian Cardiovascular Disease.

Author

Asatryan, Babken, Murray, Brittney, Tadros, Rafik, Rieder, Marina, Shah, Ravi A., Dabbagh, Ghaith Sharaf, Landstrom, Andrew P., Dobner, Stephan, Munroe, Patricia B., Haggerty, Christopher M., Medeiros-Domingo, Argelia, Owens, Anjali T., Kullo, Iftikhar J., Semsarian, Christopher, Reichlin, Tobias, Barth, Andreas S., Roden, Dan M., James, Cynthia A., Ware, James S., and Chahal, C. Anwar A.

Published
2024
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29. Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial.

Author

Lee, Matthew M. Y., Masri, Ahmad, Nassif, Michael E., Barriales-Villa, Roberto, Abraham, Theodore P., Claggett, Brian L., Coats, Caroline J., Gimeno, Juan Ramón, Kulac, Ian J., Landsteiner, Isabela, Ma, Changsheng, Maron, Martin S., Olivotto, Iacopo, Owens, Anjali T., Solomon, Scott D., Veselka, Josef, Jacoby, Daniel L., Heitner, Stephen B., Kupfer, Stuart, and Malik, Fady I.

Published
2024
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30. Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy–Associated Putative Pathogenic Gene Variants in UK Biobank Participants

Author

Shah, Ravi A., Asatryan, Babken, Dabbagh, Ghaith Sharaf, Aung, Nay, Khanji, Mohammed Y., Lopes, Luis R., van Duijvenboden, Stefan, Holmes, Anthony, Muser, Daniele, Landstrom, Andrew P., Lee, Aaron Mark, Arora, Pankaj, Semsarian, Christopher, Somers, Virend K., Owens, Anjali T., Munroe, Patricia B., Petersen, Steffen E., and Chahal, C. Anwar A.

Published
2022
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32. Abstract 12598: Effect of Mavacamten on Systolic Anterior Motion of the Mitral Valve and Mitral Regurgitation in Patients With Obstructive Hypertrophic Cardiomyopathy: Insights From the VALOR-HCM Study

Author

Cremer, Paul C, Geske, Jeffrey B, Owens, Anjali T, Jaber, Wael A, Harb, Serge C, Saberi, Sara, Wang, Andrew, Naidu, Srihari S, Schaff, Hartzell V, Smedira, Nicholas G, Wang, Quing, Lampl, Kathy, Sehnert, Amy J, Nissen, Steven E, and Desai, Milind Y

Published
2022
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36. Abstract 12104: Pediatric Hypertrophic Cardiomyopathy With Left Ventricular Systolic Dysfunction: Insights From the Sarcomeric Human Cardiomyopathy Registry (SHaRe)

Author

Abou Alaiwi, Sarah, Roston, Thomas M, Vissing, Christoffer, Marstrand, Peter, Claggett, Brian, Nauffal, Victor, Parikh, Victoria N, Helms, Adam S, Ingles, Jodie, Jacoby, Daniel L, Lakdawala, Neal K, Michels, Michelle, Owens, Anjali T, Ashley, Euan A, Pereira, Alexandre, Rossano, Joseph, Saberi, Sara, Semsarian, Christopher, Ware, James S, Miller, Erin, Wittekind, Samuel, Russell, Mark W, Day, Sharlene, olivotto, iacopo, and Ho, Carolyn

Published
2022
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38. Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy

Author

Maron, Martin S., primary, Masri, Ahmad, additional, Nassif, Michael E., additional, Barriales-Villa, Roberto, additional, Arad, Michael, additional, Cardim, Nuno, additional, Choudhury, Lubna, additional, Claggett, Brian, additional, Coats, Caroline J., additional, Düngen, Hans-Dirk, additional, Garcia-Pavia, Pablo, additional, Hagège, Albert A., additional, Januzzi, James L., additional, Lee, Matthew M.Y., additional, Lewis, Gregory D., additional, Ma, Chang-Sheng, additional, Michels, Michelle, additional, Olivotto, Iacopo, additional, Oreziak, Artur, additional, Owens, Anjali T., additional, Spertus, John A., additional, Solomon, Scott D., additional, Tfelt-Hansen, Jacob, additional, van Sinttruije, Marion, additional, Veselka, Josef, additional, Watkins, Hugh, additional, Jacoby, Daniel L., additional, Heitner, Stephen B., additional, Kupfer, Stuart, additional, Malik, Fady I., additional, Meng, Lisa, additional, Wohltman, Amy, additional, and Abraham, Theodore P., additional

Published
2024
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41. Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Author

Zheng, Sean L, Henry, Albert, Cannie, Douglas, Lee, Michael, Miller, David, McGurk, Kathryn A, Bond, Isabelle, Xu, Xiao, Issa, Hanane, Francis, Catherine, De Marvao, Antonio, Theotokis, Pantazis I, Buchan, Rachel J, Speed, Doug, Abner, Erik, Adams, Lance, Aragam, Krishna G, Ärnlöv, Johan, Raja, Anna Axelsson, Backman, Joshua D, Baksi, John, Barton, Paul J R, Biddinger, Kiran J, Boersma, Eric, Brandimarto, Jeffrey, Brunak, Søren, Bundgaard, Henning, Carey, David J, Charron, Philippe, Cook, James P, Cook, Stuart A, Denaxas, Spiros, Deleuze, Jean-François, Doney, Alexander S, Elliott, Perry, Erikstrup, Christian, Esko, Tõnu, Farber-Eger, Eric H, Finan, Chris, Garnier, Sophie, Ghouse, Jonas, Giedraitis, Vilmantas, Guðbjartsson, Daniel F, Haggerty, Christopher M, Halliday, Brian P, Helgadottir, Anna, Hemingway, Harry, Hillege, Hans L, Kardys, Isabella, Lind, Lars, Lindgren, Cecilia M, Lowery, Brandon D, Manisty, Charlotte, Margulies, Kenneth B, Moon, James C, Mordi, Ify R, Morley, Michael P, Morris, Andrew D, Morris, Andrew P, Morton, Lori, Noursadeghi, Mahdad, Ostrowski, Sisse R, Owens, Anjali T, Palmer, Colin N A, Pantazis, Antonis, Pedersen, Ole B V, Prasad, Sanjay K, Shekhar, Akshay, Smelser, Diane T, Srinivasan, Sundararajan, Stefansson, Kari, Sveinbjörnsson, Garðar, Syrris, Petros, Tammesoo, Mari-Liis, Tayal, Upasana, Teder-Laving, Maris, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Tragante, Vinicius, Trégouët, David-Alexandre, Treibel, Thomas A, Ullum, Henrik, Valdes, Ana M, van Setten, Jessica, van Vugt, Marion, Veluchamy, Abirami, Verschuren, W M Monique, Villard, Eric, Yang, Yifan, Asselbergs, Folkert W, Cappola, Thomas P, Dube, Marie-Pierre, Dunn, Michael E, Ellinor, Patrick T, Hingorani, Aroon D, Lang, Chim C, Samani, Nilesh J, Shah, Svati H, Smith, J Gustav, Vasan, Ramachandran S, O'Regan, Declan P, Holm, Hilma, Noseda, Michela, Wells, Quinn, Ware, James S, Lumbers, R Thomas, Zheng, Sean L, Henry, Albert, Cannie, Douglas, Lee, Michael, Miller, David, McGurk, Kathryn A, Bond, Isabelle, Xu, Xiao, Issa, Hanane, Francis, Catherine, De Marvao, Antonio, Theotokis, Pantazis I, Buchan, Rachel J, Speed, Doug, Abner, Erik, Adams, Lance, Aragam, Krishna G, Ärnlöv, Johan, Raja, Anna Axelsson, Backman, Joshua D, Baksi, John, Barton, Paul J R, Biddinger, Kiran J, Boersma, Eric, Brandimarto, Jeffrey, Brunak, Søren, Bundgaard, Henning, Carey, David J, Charron, Philippe, Cook, James P, Cook, Stuart A, Denaxas, Spiros, Deleuze, Jean-François, Doney, Alexander S, Elliott, Perry, Erikstrup, Christian, Esko, Tõnu, Farber-Eger, Eric H, Finan, Chris, Garnier, Sophie, Ghouse, Jonas, Giedraitis, Vilmantas, Guðbjartsson, Daniel F, Haggerty, Christopher M, Halliday, Brian P, Helgadottir, Anna, Hemingway, Harry, Hillege, Hans L, Kardys, Isabella, Lind, Lars, Lindgren, Cecilia M, Lowery, Brandon D, Manisty, Charlotte, Margulies, Kenneth B, Moon, James C, Mordi, Ify R, Morley, Michael P, Morris, Andrew D, Morris, Andrew P, Morton, Lori, Noursadeghi, Mahdad, Ostrowski, Sisse R, Owens, Anjali T, Palmer, Colin N A, Pantazis, Antonis, Pedersen, Ole B V, Prasad, Sanjay K, Shekhar, Akshay, Smelser, Diane T, Srinivasan, Sundararajan, Stefansson, Kari, Sveinbjörnsson, Garðar, Syrris, Petros, Tammesoo, Mari-Liis, Tayal, Upasana, Teder-Laving, Maris, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Tragante, Vinicius, Trégouët, David-Alexandre, Treibel, Thomas A, Ullum, Henrik, Valdes, Ana M, van Setten, Jessica, van Vugt, Marion, Veluchamy, Abirami, Verschuren, W M Monique, Villard, Eric, Yang, Yifan, Asselbergs, Folkert W, Cappola, Thomas P, Dube, Marie-Pierre, Dunn, Michael E, Ellinor, Patrick T, Hingorani, Aroon D, Lang, Chim C, Samani, Nilesh J, Shah, Svati H, Smith, J Gustav, Vasan, Ramachandran S, O'Regan, Declan P, Holm, Hilma, Noseda, Michela, Wells, Quinn, Ware, James S, and Lumbers, R Thomas

Abstract

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation. We report a genome-wide association study and multi-trait analysis of DCM (14,256 cases) and three left ventricular traits (36,203 UK Biobank participants). We identified 80 genomic risk loci and prioritized 62 putative effector genes, including several with rare variant DCM associations (MAP3K7, NEDD4L and SSPN). Using single-nucleus transcriptomics, we identify cellular states, biological pathways, and intracellular communications that drive pathogenesis. We demonstrate that polygenic scores predict DCM in the general population and modify penetrance in carriers of rare DCM variants. Our findings may inform the design of genetic testing strategies that incorporate polygenic background. They also provide insights into the molecular etiology of DCM that may facilitate the development of targeted therapeutics.

Published
2024
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42. Impact of Aficamten on Disease and Symptom Burden in Obstructive Hypertrophic Cardiomyopathy:Results From SEQUOIA-HCM

Author

Maron, Martin S., Masri, Ahmad, Nassif, Michael E., Barriales-Villa, Roberto, Abraham, Theodore P., Arad, Michael, Cardim, Nuno, Choudhury, Lubna, Claggett, Brian, Coats, Caroline J., Düngen, Hans Dirk, Garcia-Pavia, Pablo, Hagège, Albert A., Januzzi, James L., Kulac, Ian, Lee, Matthew M.Y., Lewis, Gregory D., Ma, Chang Sheng, Michels, Michelle, Oreziak, Artur, Owens, Anjali T., Spertus, John A., Solomon, Scott D., Tfelt-Hansen, Jacob, van Sinttruije, Marion, Veselka, Josef, Watkins, Hugh C., Jacoby, Daniel L., Heitner, Stephen B., Kupfer, Stuart, Malik, Fady I., Meng, Lisa, Wohltman, Amy, Olivotto, Iacopo, Maron, Martin S., Masri, Ahmad, Nassif, Michael E., Barriales-Villa, Roberto, Abraham, Theodore P., Arad, Michael, Cardim, Nuno, Choudhury, Lubna, Claggett, Brian, Coats, Caroline J., Düngen, Hans Dirk, Garcia-Pavia, Pablo, Hagège, Albert A., Januzzi, James L., Kulac, Ian, Lee, Matthew M.Y., Lewis, Gregory D., Ma, Chang Sheng, Michels, Michelle, Oreziak, Artur, Owens, Anjali T., Spertus, John A., Solomon, Scott D., Tfelt-Hansen, Jacob, van Sinttruije, Marion, Veselka, Josef, Watkins, Hugh C., Jacoby, Daniel L., Heitner, Stephen B., Kupfer, Stuart, Malik, Fady I., Meng, Lisa, Wohltman, Amy, and Olivotto, Iacopo

Abstract

Background: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined. Objectives: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten. Methods: Patients who were symptomatic of oHCM were randomized to aficamten (n = 142) or placebo (n = 140) daily for 24 weeks. Outcomes assessed included the proportion of patients with complete hemodynamic response (rest and Valsalva gradient <30 mm Hg and <50 mm Hg, respectively), relief in limiting symptoms (≥1 improvement in NYHA functional class and/or ≥10-point change in Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score), enhanced exercise capacity (≥1.5 mL/kg/min change in peak oxygen uptake), and ≥50% reduction in N-terminal pro–B-type natriuretic peptide. Eligibility for septal reduction therapy was also evaluated. Results: At 24 weeks, patients treated with aficamten vs placebo showed significant improvement in limiting symptoms (71% vs 42%), were more likely to have complete hemodynamic response (68% vs 7%), demonstrated enhanced exercise capacity (47% vs 24%), and showed a decrease ≥50% in N-terminal pro–B-type natriuretic peptide (84% vs 8%) (P ≤ 0.002 for all). An improvement in ≥1 of these outcome measures was achieved in 97% of patients treated with aficamten (vs 59% placebo), including 23% on aficamten who achieved all 4 outcomes compared with none in placebo. Among 32 patients receiving aficamten and 29 patients receiving placebo who were eligible for septal reduction therapy, 28 (88%) from the aficamten group were no longer eligible at 24 weeks compared with 15 (52%) from the placebo group (P =

Published
2024

43. Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy:Results From SEQUOIA-HCM

Author

Coats, Caroline J., Masri, Ahmad, Nassif, Michael E., Barriales-Villa, Roberto, Arad, Michael, Cardim, Nuno, Choudhury, Lubna, Claggett, Brian, Düngen, Hans Dirk, Garcia-Pavia, Pablo, Hagège, Albert A., Januzzi, James L., Lee, Matthew M.Y., Lewis, Gregory D., Ma, Chang Sheng, Maron, Martin S., Miao, Zi Michael, Michels, Michelle, Olivotto, Iacopo, Oreziak, Artur, Owens, Anjali T., Spertus, John A., Solomon, Scott D., Tfelt-Hansen, Jacob, van Sinttruije, Marion, Veselka, Josef, Watkins, Hugh, Jacoby, Daniel L., German, Polina, Heitner, Stephen B., Kupfer, Stuart, Lutz, Justin D., Malik, Fady I., Meng, Lisa, Wohltman, Amy, Abraham, Theodore P., Coats, Caroline J., Masri, Ahmad, Nassif, Michael E., Barriales-Villa, Roberto, Arad, Michael, Cardim, Nuno, Choudhury, Lubna, Claggett, Brian, Düngen, Hans Dirk, Garcia-Pavia, Pablo, Hagège, Albert A., Januzzi, James L., Lee, Matthew M.Y., Lewis, Gregory D., Ma, Chang Sheng, Maron, Martin S., Miao, Zi Michael, Michels, Michelle, Olivotto, Iacopo, Oreziak, Artur, Owens, Anjali T., Spertus, John A., Solomon, Scott D., Tfelt-Hansen, Jacob, van Sinttruije, Marion, Veselka, Josef, Watkins, Hugh, Jacoby, Daniel L., German, Polina, Heitner, Stephen B., Kupfer, Stuart, Lutz, Justin D., Malik, Fady I., Meng, Lisa, Wohltman, Amy, and Abraham, Theodore P.

Abstract

BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation.CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throug

Published
2024

44. Exercise Capacity in Patients With Obstructive Hypertrophic Cardiomyopathy:SEQUOIA-HCM Baseline Characteristics and Study Design

Author

Coats, Caroline J., Maron, Martin S., Abraham, Theodore P., Olivotto, Iacopo, Lee, Matthew M.Y., Arad, Michael, Cardim, Nuno, Ma, Chang Sheng, Choudhury, Lubna, Düngen, Hans Dirk, Garcia-Pavia, Pablo, Hagège, Albert A., Lewis, Gregory D., Michels, Michelle, Oreziak, Artur, Owens, Anjali T., Tfelt-Hansen, Jacob, Veselka, Josef, Watkins, Hugh C., Heitner, Stephen B., Jacoby, Daniel L., Kupfer, Stuart, Malik, Fady I., Meng, Lisa, Wohltman, Amy, Masri, Ahmad, Coats, Caroline J., Maron, Martin S., Abraham, Theodore P., Olivotto, Iacopo, Lee, Matthew M.Y., Arad, Michael, Cardim, Nuno, Ma, Chang Sheng, Choudhury, Lubna, Düngen, Hans Dirk, Garcia-Pavia, Pablo, Hagège, Albert A., Lewis, Gregory D., Michels, Michelle, Oreziak, Artur, Owens, Anjali T., Tfelt-Hansen, Jacob, Veselka, Josef, Watkins, Hugh C., Heitner, Stephen B., Jacoby, Daniel L., Kupfer, Stuart, Malik, Fady I., Meng, Lisa, Wohltman, Amy, and Masri, Ahmad

Abstract

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). This large, phase 3 trial is now fully enrolled (N = 282). Baseline characteristics reflect an ethnically diverse population with characteristics typical of patients encountered clinically with substantial functional and symptom burden. The study will assess the effect of aficamten vs placebo, in addition to standard-of-care medications, on functional capacity and symptoms over 24 weeks. Future clinical trials could model the approach in SEQUOIA-HCM to evaluate the effect of potential therapies on the burden of oHCM. (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM [SEQUOIA-HCM]; NCT05186818).

Published
2024

45. Emergency Department Use and Hospital Mortality Among Heart Transplant Recipients in the United States

Author

Holzhauser, Luise, primary, Reza, Nosheen, additional, Edwards, Jonathan J., additional, Birati, Edo Y., additional, Owens, Anjali T., additional, McLean, Rhondalyn, additional, Maeda, Katsuhide, additional, O'Connor, Matthew J., additional, Rossano, Joseph W., additional, Mondal, Antara, additional, Katcoff, Hannah, additional, and Edelson, Jonathan B., additional

Published
2024
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46. Baseline Characteristics of Patients in SEQUOIA-HCM: A Phase 3 Trial of Aficamten in Obstructive Hypertrophic Cardiomyopathy

Author

Maron, Martin S., primary, Abraham, Theodore P., additional, Coats, Caroline J., additional, Olivotto, Iacopo, additional, Lee, Matthew M.Y., additional, Arad, Michael, additional, Cardim, Nuno, additional, Ma, Chang-Sheng, additional, Choudhury, Lubna, additional, Düngen, Hans-Dirk, additional, Garcia-Pavia, Pablo, additional, Hagege, Albert, additional, Lewis, Gregory D., additional, Michels, Michelle, additional, Oreziak, Artur, additional, Owens, Anjali T., additional, Tfelt-Hansen, Jacob, additional, Veselka, Josef, additional, Watkins, Hugh C., additional, Heitner, Stephen B., additional, Jacoby, Daniel L., additional, Kupfer, Stuart, additional, Malik, Fady I., additional, Meng, Lisa, additional, Wohltman, Amy, additional, and Masri, Ahmad, additional

Published
2024
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47. Serial Changes in Ventricular Strain in Symptomatic Obstructive Hypertrophic Cardiomyopathy Treated With Mavacamten: Insights From the VALOR-HCM Trial.

Author

Desai, Milind Y., Yuichiro Okushi, Gaballa, Andrew, Qiuqing Wang, Geske, Jeffrey B., Owens, Anjali T., Saberi, Sara, Wang, Andrew, Cremer, Paul C., Sherrid, Mark, Lakdawala, Neal K., Tower-Rader, Albree, Fermin, David, Naidu, Srihari S., Lampl, Kathy L., Sehnert, Amy J., Nissen, Steven E., and Popovic, Zoran B.

Abstract

BACKGROUND: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy, VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) demonstrated that mavacamten reduces the need for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function. In VALOR-HCM, we assessed serial changes in LV and right ventricular (RV) strain. METHODS: VALOR-HCM included 112 patients with symptomatic obstructive hypertrophic cardiomyopathy (mean, 60 years; 51% male; LV ejection fraction, 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo (n=52) transitioned to mavacamten from weeks 16 to 56 (40-week exposure). LV-GLS and RV-GLS assessment was performed using a vendor-neutral software. Non-foreshortened apical (4-, 3-, and 2-chamber) views were used to obtain peak LV-GLS. RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. RESULTS: At baseline, the mean LV-GLS, RV 4-chamber, and free wall strain values were -14.7%, -22.2%, and -16.8%, respectively (all worse than reported normal means). In the total study sample, LV-GLS significantly improved from baseline to week 56 (P=0.02). Twelve patients had transient reduction in LV ejection fraction (<50%) requiring temporary drug interruption (including 3 permanent discontinuations). The LV-GLS in this subgroup was worse at baseline versus total study population (-11.4%), with no significant worsening from baseline through week 56 (P=0.64). Both free wall and 4-chamber RV-GLS remained unchanged from baseline to week 56 (P=0.62 and P=0.56, respectively). CONCLUSIONS: In VALOR-HCM, treatment with mavacamten improved LV-GLS from baseline through week 56 (with no significant worsening of LV-GLS in patients with a reduction in LV ejection fraction ≤50%), suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no detrimental impact on RV systolic function. [ABSTRACT FROM AUTHOR]

Published
2024
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49. Safety and efficacy of aficamten in patients with non‐obstructive hypertrophic cardiomyopathy: A 36‐week analysis from FOREST‐HCM.

Author

Masri, Ahmad, Barriales‐Villa, Roberto, Elliott, Perry, Nassif, Michael E., Oreziak, Artur, Owens, Anjali T., Tower‐Rader, Albree, Heitner, Stephen B., Kupfer, Stuart, Malik, Fady I., Melloni, Chiara, Meng, Lisa, Wei, Jenny, and Saberi, Sara

Subjects
HYPERTROPHIC cardiomyopathy, VENTRICULAR ejection fraction, TROPONIN I, PULMONARY veins, ATRIAL fibrillation
Abstract

Aims: The aim of this study was to report safety and efficacy of aficamten in patients with non‐obstructive hypertrophic cardiomyopathy (nHCM) over 36 weeks in the ongoing FOREST‐HCM trial. Methods and results: Patients were started on aficamten 5 mg daily, with doses adjusted in 5‐mg increments (5–20 mg) at ≥2‐week intervals according to site‐read left ventricular ejection fraction (LVEF). Aficamten dose was increased if LVEF ≥55%, maintained if LVEF 50–54%, decreased if LVEF 40–<50%, and temporarily interrupted if LVEF <40%. Safety and efficacy were assessed over 36 weeks. Overall, 34 patients were enrolled (mean age 57.2 ± 15.3 years, 62% female, 41% in New York Heart Association [NYHA] class III). Over 36 weeks, 82.3% achieved 15–20 mg daily dose and there was a modest reduction in LVEF by −4.3% ± 5.2 from 70% ± 6.1 (p < 0.0001). At Week 36, NYHA class improved by ≥1 class in 27 (79.4%) patients. Mean Kansas City Cardiomyopathy Questionnaire clinical summary score improved by 13.8 ± 12.5 points relative to baseline. Median (interquartile range) levels of N‐terminal pro‐B‐type natriuretic peptide were significantly improved from baseline (−665.5 pg/ml [−1244.0, −232.0]; p < 0.0001), while high‐sensitivity cardiac troponin I was unchanged (−2.7 ng/L [−11.3, 1.6]; p = 0.25). There were no drug discontinuations due to adverse events. LVEF <50% occurred in 2 (5.9%) patients, one following pulmonary vein isolation and one associated with atrial fibrillation. Conclusions: Over 36 weeks, aficamten appeared safe and effective in the studied patients with nHCM. [ABSTRACT FROM AUTHOR]

Published
2024
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50. Quality of Life and Exercise Capacity in Early Stage and Subclinical Hypertrophic Cardiomyopathy: A Secondary Analysis of the VANISH Trial.

Author

Ireland, Catherine G., Burstein, Danielle S., Day, Sharlene M., Raja, Anna Axelsson, Russell, Mark W., Zahka, Kenneth G., Pereira, Alexandre, Canter, Charles E., Bach, Richard G., Wheeler, Matthew T., Rossano, Joseph W., Owens, Anjali T., Bundgaard, Henning, Mestroni, Luisa, Taylor, Matthew R. G., Patel, Amit R., Wilmot, Ivan, Soslow, Jonathan H., Becker, Jason R., and Giverts, Ilya

Abstract

BACKGROUND: The health-related quality of life (HRQOL) and cardiopulmonary exercise testing (CPET) performance of individuals with subclinical and early stage hypertrophic cardiomyopathy (HCM) have not been systematically studied. Improved understanding will inform the natural history of HCM and factors influencing well-being. METHODS: VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric HCM) participants with early stage sarcomeric HCM (primary analysis cohort) and subclinical HCM (sarcomere variant without left ventricular hypertrophy comprising the exploratory cohort) who completed baseline and year 2 HRQOL assessment via the pediatric quality of life inventory and CPET were studied. Metrics correlating with baseline HRQOL and CPET performance were identified. The impact of valsartan treatment on these measures was analyzed in the early stage cohort. RESULTS: Two hundred participants were included: 166 with early stage HCM (mean age, 23±10 years; 40% female; 97% White; and 92% New York Heart Association class I) and 34 subclinical sarcomere variant carriers (mean age, 16±5 years; 50% female; and 100% White). Baseline HRQOL was good in both cohorts, although slightly better in subclinical HCM (composite pediatric quality of life score 84.6±10.6 versus 90.2±9.8; P=0.005). Both cohorts demonstrated mildly reduced functional status (mean percent predicted peak oxygen uptake 73±16 versus 78±12 mL/kg per minute; P=0.18). Percent predicted peak oxygen uptake and peak oxygen pulse correlated with HRQOL. Valsartan improved physical HRQOL in early stage HCM (adjusted mean change in pediatric quality of life score +4.1 versus placebo; P=0.01) but did not significantly impact CPET performance. CONCLUSIONS: Functional capacity can be impaired in young, healthy people with early stage HCM, despite New York Heart Association class I status and good HRQOL. Peak oxygen uptake was similarly decreased in subclinical HCM despite normal left ventricular wall thickness and excellent HRQOL. Valsartan improved physical pediatric quality of life scores but did not significantly impact CPET performance. Further studies are needed for validation and to understand how to improve patient experience. [ABSTRACT FROM AUTHOR]

Published
2024
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