Victoria Parikh

All Publications

• One-year real-world experience with mavacamten and its physiologic effects on obstructive hypertrophic cardiomyopathy FRONTIERS IN CARDIOVASCULAR MEDICINE Kim, D., Chu, E. L., Keamy-Minor, E. E., Paranjpe, I., Tang, W. L., O'Sullivan, J. W., Desai, Y. B., Liu, M. B., Munsey, E., Hecker, K., Cuenco, I., Kao, B., Bacolor, E., Bonnett, C., Linder, A., Lacar, K., Robles, N., Lamendola, C., Smith, A., Knowles, J. W., Perez, M. V., Kawana, M., Sallam, K. I., Weldy, C. S., Wheeler, M. T., Parikh, V. N., Salisbury, H., Ashley, E. A., Stanford Ctr Inherited Cardiovasc Dis 2024; 11

  View details for DOI 10.3389/fcvm.2024.1429230

  View details for Web of Science ID 001312496500001

• Toward Precision Medicine in the Treatment of Arrhythmogenic Cardiomyopathy CURRENT TREATMENT OPTIONS IN CARDIOVASCULAR MEDICINE Liu, M. B., Parikh, V. N. 2024

  View details for DOI 10.1007/s11936-024-01052-4

  View details for Web of Science ID 001290049800001

• Minimum information and guidelines for reporting a multiplexed assay of variant effect. Genome biology Claussnitzer, M., Parikh, V. N., Wagner, A. H., Arbesfeld, J. A., Bult, C. J., Firth, H. V., Muffley, L. A., Nguyen Ba, A. N., Riehle, K., Roth, F. P., Tabet, D., Bolognesi, B., Glazer, A. M., Rubin, A. F. 2024; 25 (1): 100

  Abstract

  Multiplexed assays of variant effect (MAVEs) have emerged as a powerful approach for interrogating thousands of genetic variants in a single experiment. The flexibility and widespread adoption of these techniques across diverse disciplines have led to a heterogeneous mix of data formats and descriptions, which complicates the downstream use of the resulting datasets. To address these issues and promote reproducibility and reuse of MAVE data, we define a set of minimum information standards for MAVE data and metadata and outline a controlled vocabulary aligned with established biomedical ontologies for describing these experimental designs.

  View details for DOI 10.1186/s13059-024-03223-9

  View details for PubMedID 38641812

  View details for PubMedCentralID PMC11027375

• Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy. Circulation. Genomic and precision medicine Krysov, V. A., Wilson, R. H., Ten, N. S., Youlton, N., De Jong, H. N., Sutton, S., Huang, Y., Reuter, C. M., Grove, M. E., Wheeler, M. T., Ashley, E. A., Parikh, V. N. 2024: e004370

  Abstract

  To realize the potential of genome engineering therapeutics, tractable strategies must be identified that balance personalized therapy with the need for off-the-shelf availability. We hypothesized that regional clustering of pathogenic variants can inform the design of rational prime editing therapeutics to treat the majority of genetic cardiovascular diseases with a limited number of reagents.We collated 2435 high-confidence pathogenic/likely pathogenic (P/LP) variants in 82 cardiovascular disease genes from ClinVar. We assessed the regional density of these variants by defining a regional clustering index. We then combined a highly active base editor with prime editing to demonstrate the feasibility of a P/LP hotspot-directed genome engineering therapeutic strategy in vitro.P/LP variants in cardiovascular disease genes display higher regional density than rare variants found in the general population. P/LP missense variants displayed higher average regional density than P/LP truncating variants. Following hypermutagenesis at a pathogenic hotspot, mean prime editing efficiency across introduced variants was 57±27%.Designing therapeutics that target pathogenic hotspots will not only address known missense P/LP variants but also novel P/LP variants identified in these hotspots as well. Moreover, the clustering of P/LP missense rather than truncating variants in these hotspots suggests that prime editing technology is particularly valuable for dominant negative disease. Although prime editing technology in relation to cardiac health continues to improve, this study presents an approach to targeting the most impactful regions of the genome for inherited cardiovascular disease.

  View details for DOI 10.1161/CIRCGEN.123.004370

  View details for PubMedID 38506054

• Genetic Risk Stratification in Arrhythmogenic Left Ventricular Cardiomyopathy. Cardiac electrophysiology clinics Desai, Y. B., Parikh, V. N. 2023; 15 (3): 391-399

  Abstract

  Arrhythmogenic left ventricular cardiomyopathy is characterized by early malignant ventricular arrhythmia associated with varying degrees and times of onset of left ventricular dysfunction. Variants in numerous genes have been associated with this phenotype. Here, the authors review the literature on recent cohort studies of patients with variants in desmoplakin, lamin A/C, filamin-C, phospholamban, RBM20, TMEM43, and selected channelopathy genes also associated with structural disease. Unlike traditional sudden cardiac death risk assessment in nonischemic cardiomyopathy, left ventricular systolic function is an insensitive predictor of risk in patients with these genetic diagnoses.

  View details for DOI 10.1016/j.ccep.2023.04.005

  View details for PubMedID 37558308

• A Precision Approach to Family Screening in ARVC. Journal of the American College of Cardiology Heidenreich, P. A., Haddad, F., Parikh, V. N. 2023; 82 (3): 226-227

  View details for DOI 10.1016/j.jacc.2023.05.020

  View details for PubMedID 37438008

• Proactive Variant Effect Mapping Aids Diagnosis in Pediatric Cardiac Arrest. Circulation. Genomic and precision medicine Floyd, B. J., Weile, J., Kannankeril, P. J., Glazer, A. M., Reuter, C. M., MacRae, C. A., Ashley, E. A., Roden, D. M., Roth, F. P., Parikh, V. N. 2023

  View details for DOI 10.1161/CIRCGEN.122.003792

  View details for PubMedID 36716194

• Intrinsic Atrial Myopathy Precedes Left Ventricular Dysfunction and Predicts Atrial Fibrillation in Lamin A/C Cardiomyopathy. Circulation. Genomic and precision medicine Tremblay-Gravel, M., Ichimura, K., Picard, K., Kawano, Y., Dries, A. M., Haddad, F., Lakdawala, N. K., Wheeler, M. T., Parikh, V. N. 2022: e003480

  Abstract

  BACKGROUND: In Lamin A/C (LMNA) cardiomyopathy, atrial fibrillation (AF) commonly occurs before dilated cardiomyopathy, and the ability to predict its incidence is limited. We hypothesized that left atrial (LA) echocardiographic phenotyping can identify atrial myopathy and harbingers of AF.METHODS: Echocardiograms from patients with pathogenic or likely pathogenic variants in LMNA (n=77) with and without reduced left ventricular ejection fraction (LVEF, <50%) were compared to healthy individuals (n=70) and patients with Titin truncating variant cardiomyopathy (n=35) with similar LVEF, sex, and age distributions. Echocardiographic analysis, blinded to genotype, included strain and volumetric measures of left ventricular and atrial function. The primary outcome was incident AF.RESULTS: At baseline, 43% of the patients with pathogenic or likely pathogenic LMNA variants had a history of AF, including 26% of those with LVEF ≥50%. Compared with healthy subjects, the patients with pathogenic or likely pathogenic LMNA variants and LVEF ≥50% had reduced LA contractile strain (LMNA, 11.8±6.1% versus control, 15.0±4.2%; P=0.003). Compared to LVEF-matched Titin truncating variant cardiomyopathy patients, the patients with pathogenic or likely pathogenic LMNA variants and LVEF <50% displayed no difference in LA size, but a worse LA contractile dysfunction (6.4±4.7% versus 12.6±9.6%; P=0.02). Over a median follow-up of 2.8 (1.2-5.7) years, LA contractile strain was the only significant predictor of AF in multivariable Cox regression (hazard ratio, 4.0 [95% CI, 1.04-15.2]).CONCLUSIONS: LMNA cardiomyopathy is associated with early intrinsic atrial myopathy reflected by high AF prevalence and reduced LA contractile strain, even in the absence of LV dysfunction and LA dilation. Whether LA strain can be used as a monitoring strategy to detect and mitigate AF complications requires validation.

  View details for DOI 10.1161/CIRCGEN.121.003480

  View details for PubMedID 36548481

• Deconvoluting complex correlates of COVID-19 severity with a multi-omic pandemic tracking strategy. Nature communications Parikh, V. N., Ioannidis, A. G., Jimenez-Morales, D., Gorzynski, J. E., De Jong, H. N., Liu, X., Roque, J., Cepeda-Espinoza, V. P., Osoegawa, K., Hughes, C., Sutton, S. C., Youlton, N., Joshi, R., Amar, D., Tanigawa, Y., Russo, D., Wong, J., Lauzon, J. T., Edelson, J., Mas Montserrat, D., Kwon, Y., Rubinacci, S., Delaneau, O., Cappello, L., Kim, J., Shoura, M. J., Raja, A. N., Watson, N., Hammond, N., Spiteri, E., Mallempati, K. C., Montero-Martín, G., Christle, J., Kim, J., Kirillova, A., Seo, K., Huang, Y., Zhao, C., Moreno-Grau, S., Hershman, S. G., Dalton, K. P., Zhen, J., Kamm, J., Bhatt, K. D., Isakova, A., Morri, M., Ranganath, T., Blish, C. A., Rogers, A. J., Nadeau, K., Yang, S., Blomkalns, A., O'Hara, R., Neff, N. F., DeBoever, C., Szalma, S., Wheeler, M. T., Gates, C. M., Farh, K., Schroth, G. P., Febbo, P., deSouza, F., Cornejo, O. E., Fernandez-Vina, M., Kistler, A., Palacios, J. A., Pinsky, B. A., Bustamante, C. D., Rivas, M. A., Ashley, E. A. 2022; 13 (1): 5107

  Abstract

  The SARS-CoV-2 pandemic has differentially impacted populations across race and ethnicity. A multi-omic approach represents a powerful tool to examine risk across multi-ancestry genomes. We leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from nasopharyngeal swabs of 1049 individuals (736 SARS-CoV-2 positive and 313 SARS-CoV-2 negative) and integrate them with digital phenotypes from electronic health records from a diverse catchment area in Northern California. Genome-wide association disaggregated by admixture mapping reveals novel COVID-19-severity-associated regions containing previously reported markers of neurologic, pulmonary and viral disease susceptibility. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. Summary data from multiomic investigation reveals metagenomic and HLA associations with severe COVID-19. The wealth of data available from residual nasopharyngeal swabs in combination with clinical data abstracted automatically at scale highlights a powerful strategy for pandemic tracking, and reveals distinct epidemiologic, genetic, and biological associations for those at the highest risk.

  View details for DOI 10.1038/s41467-022-32397-8

  View details for PubMedID 36042219

• The genetic architecture of Plakophilin 2 cardiomyopathy. Genetics in medicine : official journal of the American College of Medical Genetics Dries, A. M., Kirillova, A., Reuter, C. M., Garcia, J., Zouk, H., Hawley, M., Murray, B., Tichnell, C., Pilichou, K., Protonotarios, A., Medeiros-Domingo, A., Kelly, M. A., Baras, A., Ingles, J., Semsarian, C., Bauce, B., Celeghin, R., Basso, C., Jongbloed, J. D., Nussbaum, R. L., Funke, B., Cerrone, M., Mestroni, L., Taylor, M. R., Sinagra, G., Merlo, M., Saguner, A. M., Elliott, P. M., Syrris, P., van Tintelen, J. P., Regeneron Genetics Center, James, C. A., Haggerty, C. M., Parikh, V. N. 2021

  Abstract

  PURPOSE: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function.METHODS: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort.RESULTS: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p<2*10-16), increases for ARVC specifically (EF=0.96 [0.94,0.97], p<2*10-16), and is highest in definite ARVC versus non-ACM individuals (EF=1.00 [1.00,1.00], p<2*10-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants.CONCLUSION: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position.

  View details for DOI 10.1038/s41436-021-01233-7

  View details for PubMedID 34120153

• Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy. Circulation. Heart failure Parikh, V. N., Caleshu, C., Reuter, C., Lazzeroni, L. C., Ingles, J., Garcia, J., McCaleb, K., Adesiyun, T., Sedaghat-Hamedani, F., Kumar, S., Graw, S., Gigli, M., Stolfo, D., Dal Ferro, M., Ing, A. Y., Nussbaum, R., Funke, B., Wheeler, M. T., Hershberger, R. E., Cook, S., Steinmetz, L. M., Lakdawala, N. K., Taylor, M. R., Mestroni, L., Merlo, M., Sinagra, G., Semsarian, C., Meder, B., Judge, D. P., Ashley, E. 2019; 12 (3): e005371

  Abstract

  Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.

  View details for PubMedID 30871351

• Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy. Circulation Meisner, J. K., Renberg, A., Smith, E. D., Tsan, Y., Elder, B., Bullard, A., Merritt, O., Zheng, S. L., Lakdawala, N., Owens, A., Ryan, T. D., Miller, E. M., Rossano, J., Lin, K. Y., Claggett, B., Ashley, E., Michels, M., Lampert, R., Stendahl, J. C., Abrahams, D., Semsarian, C., Parikh, V. N., Wheeler, M., Ingles, J., Day, S. M., Saberi, S., Russell, M. W., Previs, M., Ho, C., Ware, J. S., Helms, A. S. 2024

  Abstract

  BACKGROUND: Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity.METHODS: Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5*10-5 in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2*) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data.RESULTS: Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; P<0.001). An intermediate functional impact was validated for 2 specific LowSVs-MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM.CONCLUSIONS: This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.

  View details for DOI 10.1161/CIRCULATIONAHA.124.069398

  View details for PubMedID 39633578

• The Clinical Trajectory of NYHA Functional Class I Patients With Obstructive Hypertrophic Cardiomyopathy. JACC. Heart failure Ahluwalia, M., Liu, J., Olivotto, I., Parikh, V., Ashley, E. A., Michels, M., Ingles, J., Lampert, R., Stendahl, J. C., Colan, S. D., Abrams, D., Pereira, A. C., Rossano, J. W., Ryan, T. D., Owens, A. T., Ware, J. S., Saberi, S., Helms, A. S., Day, S., Claggett, B., Ho, C. Y., Lakdawala, N. K. 2024

  Abstract

  BACKGROUND: An improved understanding of the natural history in NYHA functional class I patients with obstructive hypertrophic cardiomyopathy (oHCM) is needed.OBJECTIVES: Using a multicenter registry (SHaRe [Sarcomeric Human Cardiomyopathy Registry]), this study described the natural history in patients with oHCM who were classified as NYHA functional class I at the initial visit compared with patients classified as NYHA functional class II and reported baseline characteristics associated with incident clinical events.METHODS: Incident events assessed included a composite of NYHA functional class III to IV symptoms, left ventricular ejection fraction<50%, atrial fibrillation, stroke, ventricular arrhythmias, septal reduction therapy, ventricular assist device or transplantation, or death. Factors associated with incident events were determined using Kaplan-Meier, Cox proportional hazards, and restricted cubic spline models.RESULTS: Of 7,964 patients with HCM in SHaRe, 1,239 patients with oHCM met inclusion criteria; 598 were in NYHA functional class I at the initial visit (age 48 ± 17 years; 31.1% female; peak gradient, 75 ± 40mmHg). At 5-year follow-up, the composite event rate of NYHA functional class I patients was 28% compared with 44% (P< 0.001) in 641 NYHA functional class II patients with oHCM (age 54 ± 16 years; 46.5% female; peak gradient, 83 ± 39mmHg). Left atrial (LA) diameter≥45mm (HR: 1.56 [95%CI: 1.14-2.12]; P = 0.005), female sex (HR: 1.61 [95%CI: 1.16-2.24]; P = 0.003), and older age (HR: 1.21 per 10 years [95%CI: 1.09-1.34]; P< 0.001), but not the magnitude of left ventricular outflow tract obstruction, were associated with a higher risk of the composite outcome in NYHA functional class I patients.CONCLUSIONS: Although NYHA functional class I patients with oHCM fared better than NYHA functional class II patients, more than one-fourth experienced adverse events over 5-year follow-up, especially if they were older, female, and/or had LA enlargement. Strategies to reduce the rate of clinical outcomes in NYHA functional class I patients warrant further study.

  View details for DOI 10.1016/j.jchf.2024.09.008

  View details for PubMedID 39520446

• Long-Term Outcomes After Septal Reduction Therapies in Obstructive Hypertrophic Cardiomyopathy: Insights From the SHARE Registry. Circulation Maurizi, N., Anthiochos, P., Owens, A., Lakdwala, N., Saberi, S., Russell, M. W., Fumagalli, C., Skalidis, I., Lin, K. Y., Nathan, A. S., De Feria Alsina, A., Reza, N., Stendahl, J. C., Abrams, D., Scemsarian, C., Clagget, B., Lampert, R., Wheeler, M., Parikh, V. N., Ashley, E., Michels, M., Rossano, J., Ryan, T. D., Ingles, J., Ware, J., Ho, C. Y., Helms, A. S., Day, S. M., Olivotto, I. 2024

  Abstract

  BACKGROUND: Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined.METHODS: Data from 13 high clinical volume HCM centers from the international SHARE (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Patients were followed from the time of SRT until last follow-up or occurrence of heart failure (HF) composite outcome (cardiac transplantation, implantation of a left ventricular assist device, left ventricular ejection fraction <35%, development of New York Heart Association class III or IV symptoms), ventricular arrhythmias composite outcome (sudden cardiac death, resuscitated cardiac arrest, or appropriate implantable cardioverter defibrillator therapy), or HCM-related death. Cox proportional hazards models were used to identify predictors of outcome.RESULTS: Of the 10 225 patients in SHARE, 1832 (18%; 968 [53%] male) underwent SRT, including 455 (25%) with alcohol septal ablation and 1377 (75%) with septal myectomy. The periprocedural 30-day mortality rate was 0.4% (8 of 1832) and 1499 of 1565 (92%) had a maximal left ventricular outflow tract gradient <50 mm Hg at 1 year. After 6.8 years (range, 3.4-9.8 years; 12 565 person-years) from SRT, 77 (4%) experienced HCM-related death (0.6% per year), 236 (13%) a composite HF outcome (1.9% per year), and 87 (5%) a composite ventricular arrhythmia outcome (0.7% per year). Among adults, older age at SRT was associated with a higher incidence of HCM death (hazard ratio, 1.22 [95 CI, 1.1-1.3]; P<0.01) and the HF composite (hazard ratio, 1.14 [95 CI, 1.1-1.2] per 5-year increase; P<0.01) in a multivariable model. Female patients also had a higher risk of the HF composite after SRT (hazard ratio, 1.4 [95 CI, 1.1-1.8]; P<0.01). De novo atrial fibrillation occurred after SRT in 387 patients (21%). Among pediatric patients followed for a median of 13 years after SRT, 26 of 343 (16%) developed the HF composite outcome, despite 96% being free of recurrent left ventricular outflow tract obstruction.CONCLUSIONS: Successful short- and long-term relief of outflow tract obstruction was observed in experienced multidisciplinary HCM centers. A subset of patients progressed to develop HF, but event-free survival at 10 years was 83% and ventricular arrhythmias were rare. Older age, female sex, and SRT during childhood were associated with a greater risk of developing HF.

  View details for DOI 10.1161/CIRCULATIONAHA.124.069378

  View details for PubMedID 39355918

• Clinical features and outcomes in carriers of pathogenic desmoplakin variants. European heart journal Gasperetti, A., Carrick, R. T., Protonotarios, A., Murray, B., Laredo, M., van der Schaaf, I., Lekanne, R. H., Syrris, P., Cannie, D., Tichnell, C., Cappelletto, C., Gigli, M., Medo, K., Saguner, A. M., Duru, F., Gilotra, N. A., Zimmerman, S., Hylind, R., Abrams, D. J., Lakdawala, N. K., Cadrin-Tourigny, J., Targetti, M., Olivotto, I., Graziosi, M., Cox, M., Biagini, E., Charron, P., Casella, M., Tondo, C., Yazdani, M., Ware, J. S., Prasad, S. K., Calò, L., Smith, E. D., Helms, A. S., Hespe, S., Ingles, J., Tandri, H., Ader, F., Peretto, G., Peters, S., Horton, A., Yao, J., Dittmann, S., Schulze-Bahr, E., Qureshi, M., Young, K., Carruth, E. D., Haggerty, C., Parikh, V. N., Taylor, M., Mestroni, L., Wilde, A., Sinagra, G., Merlo, M., Gandjbakhch, E., van Tintelen, J. P., Te Riele, A. S., Elliott, P. M., Calkins, H., James, C. A. 2024

  Abstract

  Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown.All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine-Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes.Eight hundred patients [40.3 ± 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 ± 13.9%] were included. Over 3.7 [1.4-7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤ 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤ 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively).Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤ 50%, and myocardial injury events.

  View details for DOI 10.1093/eurheartj/ehae571

  View details for PubMedID 39288222

• ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy. medRxiv : the preprint server for health sciences Hespe, S., Waddell, A., Asatryan, B., Owens, E., Thaxton, C., Adduru, M. L., Anderson, K., Brown, E. E., Hoffman-Andrews, L., Jordan, E., Josephs, K., Mayers, M., Peters, S., Stafford, F., Bagnall, R. D., Bronicki, L., Callewaert, B., Chahal, C. A., James, C. A., Jarinova, O., Landstrom, A. P., McNally, E. M., Murray, B., Muiño-Mosquera, L., Parikh, V., Reuter, C., Walsh, R., Wayburn, B., Ware, J. S., Ingles, J. 2024

  Abstract

  Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Here we report work by the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes.The ClinGen systematic gene curation framework was used to re-classify the gene-disease relationships for HCM and related syndromic entities involving left ventricular hypertrophy. Genes previously curated were included if their classification was not definitive, and if the time since curation was >2-3 years. New genes with literature assertions for HCM were included for initial evaluation. Existing genes were curated for new inheritance patterns where evidence existed. Curations were presented on twice monthly calls, with the HCVD-GCEP composed of 29 individuals from 21 institutions across 6 countries.Thirty-one genes were re-curated and an additional 5 new potential HCM-associated genes were curated. Among the re-curated genes, 17 (55%) genes changed classification: 1 limited and 4 disputed (from no known disease relationship), 9 disputed (from limited), and 3 definitive (from moderate). Among these, 3 (10%) genes had a clinically relevant upgrade, including TNNC1, a 9th sarcomere gene with definitive HCM association. With new evidence, two genes were curated for multiple inheritance patterns (TRIM63, disputed for autosomal dominant but moderate for autosomal recessive; ALPK3, strong for autosomal dominant and definitive for recessive). CSRP3 was curated for a semi-dominant mode of inheritance (definitive). Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes. Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive).We report 29 genes with definitive, strong or moderate evidence of causation for HCM or isolated LVH, including sarcomere, sarcomere-associated and syndromic conditions.

  View details for DOI 10.1101/2024.07.29.24311195

  View details for PubMedID 39132495

  View details for PubMedCentralID PMC11312670

• A novel tool for arrhythmic risk stratification in desmoplakin gene variant carriers. European heart journal Carrick, R. T., Gasperetti, A., Protonotarios, A., Murray, B., Laredo, M., van der Schaaf, I., Dooijes, D., Syrris, P., Cannie, D., Tichnell, C., Gilotra, N. A., Cappelletto, C., Medo, K., Saguner, A. M., Duru, F., Hylind, R. J., Abrams, D. J., Lakdawala, N. K., Cadrin-Tourigny, J., Targetti, M., Olivotto, I., Graziosi, M., Cox, M., Biagini, E., Charron, P., Compagnucci, P., Casella, M., Conte, G., Tondo, C., Yazdani, M., Ware, J. S., Prasad, S. K., Calò, L., Smith, E. D., Helms, A. S., Hespe, S., Ingles, J., Tandri, H., Ader, F., Peretto, G., Peters, S., Horton, A., Yao, J., Schulze-Bahr, E., Dittman, S., Carruth, E. D., Young, K., Qureshi, M., Haggerty, C., Parikh, V. N., Taylor, M., Mestroni, L., Wilde, A., Sinagra, G., Merlo, M., Gandjbakhch, E., van Tintelen, J. P., Te Riele, A. S., Elliot, P., Calkins, H., Wu, K. C., James, C. A. 2024

  Abstract

  Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population.Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86).In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%.The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach.

  View details for DOI 10.1093/eurheartj/ehae409

  View details for PubMedID 39011630

• Multisite Validation of a Functional Assay to AdjudicateSCN5ABrugada Syndrome-Associated Variants. Circulation. Genomic and precision medicine Ma, J. G., O'Neill, M. J., Richardson, E., Thomson, K. L., Ingles, J., Muhammad, A., Solus, J. F., Davogustto, G., Anderson, K. C., Shoemaker, M. B., Stergachis, A. B., Floyd, B. J., Dunn, K., Parikh, V. N., ChubbW, H., Perrin, M. J., Roden, D. M., Vandenberg, J. I., Ng, C., Glazer, A. M. 2024: e004569

  Abstract

  BACKGROUND: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A. Interpreting the pathogenicity of SCN5A missense variants is challenging, and 79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification.METHODS: An in vitro SCN5A-Brugada syndrome automated patch clamp assay was generated and independently studied at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function.RESULTS: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak INa density (R2=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values yielded 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic.CONCLUSIONS: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A-Brugada syndrome variants of uncertain significance.

  View details for DOI 10.1161/CIRCGEN.124.004569

  View details for PubMedID 38953211

• Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension. Science translational medicine Tai, Y. Y., Yu, Q., Tang, Y., Sun, W., Kelly, N. J., Okawa, S., Zhao, J., Schwantes-An, T. H., Lacoux, C., Torrino, S., Al Aaraj, Y., El Khoury, W., Negi, V., Liu, M., Corey, C. G., Belmonte, F., Vargas, S. O., Schwartz, B., Bhat, B., Chau, B. N., Karnes, J. H., Satoh, T., Barndt, R. J., Wu, H., Parikh, V. N., Wang, J., Zhang, Y., McNamara, D., Li, G., Speyer, G., Wang, B., Shiva, S., Kaufman, B., Kim, S., Gomez, D., Mari, B., Cho, M. H., Boueiz, A., Pauciulo, M. W., Southgate, L., Trembath, R. C., Sitbon, O., Humbert, M., Graf, S., Morrell, N. W., Rhodes, C. J., Wilkins, M. R., Nouraie, M., Nichols, W. C., Desai, A. A., Bertero, T., Chan, S. Y. 2024; 16 (729): eadd2029

  Abstract

  Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)-dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N-methyltransferase 2E-antisense 1 (KMT2E-AS1) and histone lysine N-methyltransferase 2E (KMT2E). KMT2E-AS1 stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α-dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a KMT2E intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)-specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, KMT2E-AS1 deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the KMT2E-AS1/KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension.

  View details for DOI 10.1126/scitranslmed.add2029

  View details for PubMedID 38198571

• Genetic architecture of cardiac dynamic flow volumes. Nature genetics Gomes, B., Singh, A., O'Sullivan, J. W., Schnurr, T. M., Goddard, P. C., Loong, S., Amar, D., Hughes, J. W., Kostur, M., Haddad, F., Salerno, M., Foo, R., Montgomery, S. B., Parikh, V. N., Meder, B., Ashley, E. A. 2023

  Abstract

  Cardiac blood flow is a critical determinant of human health. However, the definition of its genetic architecture is limited by the technical challenge of capturing dynamic flow volumes from cardiac imaging at scale. We present DeepFlow, a deep-learning system to extract cardiac flow and volumes from phase-contrast cardiac magnetic resonance imaging. A mixed-linear model applied to 37,653 individuals from the UK Biobank reveals genome-wide significant associations across cardiac dynamic flow volumes spanning from aortic forward velocity to aortic regurgitation fraction. Mendelian randomization reveals a causal role for aortic root size in aortic valve regurgitation. Among the most significant contributing variants, localizing genes (near ELN, PRDM6 and ADAMTS7) are implicated in connective tissue and blood pressure pathways. Here we show that DeepFlow cardiac flow phenotyping at scale, combined with genotyping data, reinforces the contribution of connective tissue genes, blood pressure and root size to aortic valve function.

  View details for DOI 10.1038/s41588-023-01587-5

  View details for PubMedID 38082205

  View details for PubMedCentralID 7612636

• Epistasis regulates genetic control of cardiac hypertrophy. medRxiv : the preprint server for health sciences Wang, Q., Tang, T. M., Youlton, N., Weldy, C. S., Kenney, A. M., Ronen, O., Hughes, J. W., Chin, E. T., Sutton, S. C., Agarwal, A., Li, X., Behr, M., Kumbier, K., Moravec, C. S., Tang, W. H., Margulies, K. B., Cappola, T. P., Butte, A. J., Arnaout, R., Brown, J. B., Priest, J. R., Parikh, V. N., Yu, B., Ashley, E. A. 2023

  Abstract

  The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close to CCDC141, IGF1R, TTN, and TNKS. Several loci not prioritized by univariate genome-wide association analysis are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we show that these interactions are preserved at the level of the cardiac transcriptome. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions between CCDC141 and both TTN and IGF1R. Our results expand the scope of genetic regulation of cardiac structure to epistasis.

  View details for DOI 10.1101/2023.11.06.23297858

  View details for PubMedID 37987017

  View details for PubMedCentralID PMC10659487

• Improved Cardiac Performance and Decreased Arrhythmia in Hypertrophic Cardiomyopathy With Non-β-Blocking R-Enantiomer Carvedilol. Circulation Seo, K., Yamamoto, Y., Kirillova, A., Kawana, M., Yadav, S., Huang, Y., Wang, Q., Lane, K. V., Pruitt, B. L., Perez, M. V., Bernstein, D., Wu, J. C., Wheeler, M. T., Parikh, V. N., Ashley, E. A. 2023

  Abstract

  Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown.We screened 21 β-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM (Myh6R403Q/+ [myosin heavy chain 6]) and iPSC cardiomyocytes derived from patients with HCM (MYH7R403Q/+) [myosin heavy chain 7]).We identified that carvedilol, a β-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a β1-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α1-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of β-blocking effect, retains the ability to inhibit both α1-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In Myh6R403Q/+ mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in MYH7R403Q/+ induced pluripotent stem cell cardiomyocytes.R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α1-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.

  View details for DOI 10.1161/CIRCULATIONAHA.123.065017

  View details for PubMedID 37850394

• Emery-Dreifuss Muscular Dystrophy 1 is associated with high risk of malignant ventricular arrhythmias and end-stage heart failure. European heart journal Cannie, D. E., Syrris, P., Protonotarios, A., Bakalakos, A., Pruny, J. F., Ditaranto, R., Martinez-Veira, C., Larrañaga-Moreira, J. M., Medo, K., Bermúdez-Jiménez, F. J., Ben Yaou, R., Leturq, F., Mezcua, A. R., Marini-Bettolo, C., Cabrera, E., Reuter, C., Limeres Freire, J., Rodríguez-Palomares, J. F., Mestroni, L., Taylor, M. R., Parikh, V. N., Ashley, E. A., Barriales-Villa, R., Jiménez-Jáimez, J., Garcia-Pavia, P., Charron, P., Biagini, E., García Pinilla, J. M., Bourke, J., Savvatis, K., Wahbi, K., Elliott, P. M. 2023

  Abstract

  Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterise the cardiac complications of EMD variants.Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidence in male and female variant-carriers was determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared to consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC).Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers (mean [SD] ages 33.4 [13.3] and 43.3 [16.8] years, respectively). Nine (23.6%) males developed MVA and five (13.2%) developed ESHF during a median [IQR] follow-up of 65.0 [24.3, 109.5] months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median [IQR] age of 58.6 [53.2, 60.4] years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank p = 0.49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank p = 0.09).Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.

  View details for DOI 10.1093/eurheartj/ehad561

  View details for PubMedID 37639473

• Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3. Nature communications Kornienko, J., Rodríguez-Martínez, M., Fenzl, K., Hinze, F., Schraivogel, D., Grosch, M., Tunaj, B., Lindenhofer, D., Schraft, L., Kueblbeck, M., Smith, E., Mao, C., Brown, E., Owens, A., Saguner, A. M., Meder, B., Parikh, V., Gotthardt, M., Steinmetz, L. M. 2023; 14 (1): 4312

  Abstract

  Severe forms of dilated cardiomyopathy (DCM) are associated with point mutations in the alternative splicing regulator RBM20 that are frequently located in the arginine/serine-rich domain (RS-domain). Such mutations can cause defective splicing and cytoplasmic mislocalization, which leads to the formation of detrimental cytoplasmic granules. Successful development of personalized therapies requires identifying the direct mechanisms of pathogenic RBM20 variants. Here, we decipher the molecular mechanism of RBM20 mislocalization and its specific role in DCM pathogenesis. We demonstrate that mislocalized RBM20 RS-domain variants retain their splice regulatory activity, which reveals that aberrant cellular localization is the main driver of their pathological phenotype. A genome-wide CRISPR knockout screen combined with image-enabled cell sorting identified Transportin-3 (TNPO3) as the main nuclear importer of RBM20. We show that the direct RBM20-TNPO3 interaction involves the RS-domain, and is disrupted by pathogenic variants. Relocalization of pathogenic RBM20 variants to the nucleus restores alternative splicing and dissolves cytoplasmic granules in cell culture and animal models. These findings provide proof-of-principle for developing therapeutic strategies to restore RBM20's nuclear localization in RBM20-DCM patients.

  View details for DOI 10.1038/s41467-023-39965-6

  View details for PubMedID 37463913

  View details for PubMedCentralID PMC10353998

• An Atlas of Variant Effects to understand the genome at nucleotide resolution. Genome biology Fowler, D. M., Adams, D. J., Gloyn, A. L., Hahn, W. C., Marks, D. S., Muffley, L. A., Neal, J. T., Roth, F. P., Rubin, A. F., Starita, L. M., Hurles, M. E. 2023; 24 (1): 147

  Abstract

  Sequencing has revealed hundreds of millions of human genetic variants, and continued efforts will only add to this variant avalanche. Insufficient information exists to interpret the effects of most variants, limiting opportunities for precision medicine and comprehension of genome function. A solution lies in experimental assessment of the functional effect of variants, which can reveal their biological and clinical impact. However, variant effect assays have generally been undertaken reactively for individual variants only after and, in most cases long after, their first observation. Now, multiplexed assays of variant effect can characterise massive numbers of variants simultaneously, yielding variant effect maps that reveal the function of every possible single nucleotide change in a gene or regulatory element. Generating maps for every protein encoding gene and regulatory element in the human genome would create an 'Atlas' of variant effect maps and transform our understanding of genetics and usher in a new era of nucleotide-resolution functional knowledge of the genome. An Atlas would reveal the fundamental biology of the human genome, inform human evolution, empower the development and use of therapeutics and maximize the utility of genomics for diagnosing and treating disease. The Atlas of Variant Effects Alliance is an international collaborative group comprising hundreds of researchers, technologists and clinicians dedicated to realising an Atlas of Variant Effects to help deliver on the promise of genomics.

  View details for DOI 10.1186/s13059-023-02986-x

  View details for PubMedID 37394429

  View details for PubMedCentralID PMC10316620

• Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry (Sarcomeric Human Cardiomyopathy). Circulation Alaiwi, S. A., Roston, T. M., Marstrand, P., Claggett, B. L., Parikh, V. N., Helms, A. S., Ingles, J., Lampert, R., Lakdawala, N. K., Michels, M., Owens, A. T., Rossano, J. W., Saberi, S., Abrams, D. J., Ashley, E. A., Semsarian, C., Stendahl, J. C., Ware, J. S., Miller, E., Ryan, T. D., Russell, M. W., Day, S. M., Olivotto, I., Vissing, C. R., Ho, C. Y. 2023

  Abstract

  The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children.Data from patients with HCM in the international, multicenter SHaRe Registry (Sarcomeric Human Cardiomyopathy) were analyzed. LVSD was defined as left ventricular ejection fraction <50% on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models.We studied 1010 patients diagnosed with HCM during childhood (<18 years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0-15.3), and 393 (36%) patients were female. At initial SHaRe Registry site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3-41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3-66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age <12 years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13-2.62), male sex (HR, 3.1 [CI, 1.88-5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08-4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42-3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38-1.69] per 5% decrease). Forty percent of patients with LVSD and HCM diagnosed during childhood met the composite outcome, with higher rates in female participants (HR, 2.60 [CI, 1.41-4.78]) and patients with a left ventricular ejection fraction <35% (HR, 3.76 [2.16-6.52]).Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care.

  View details for DOI 10.1161/CIRCULATIONAHA.122.062517

  View details for PubMedID 37226762

• Cardiac splicing as a diagnostic and therapeutic target. Nature reviews. Cardiology Gotthardt, M., Badillo-Lisakowski, V., Parikh, V. N., Ashley, E., Furtado, M., Carmo-Fonseca, M., Schudy, S., Meder, B., Grosch, M., Steinmetz, L., Crocini, C., Leinwand, L. 2023

  Abstract

  Despite advances in therapeutics for heart failure and arrhythmias, a substantial proportion of patients with cardiomyopathy do not respond to interventions, indicating a need to identify novel modifiable myocardial pathobiology. Human genetic variation associated with severe forms of cardiomyopathy and arrhythmias has highlighted the crucial role of alternative splicing in myocardial health and disease, given that it determines which mature RNA transcripts drive the mechanical, structural, signalling and metabolic properties of the heart. In this Review, we discuss how the analysis of cardiac isoform expression has been facilitated by technical advances in multiomics and long-read and single-cell sequencing technologies. The resulting insights into the regulation of alternative splicing - including theidentification of cardiac splice regulators as therapeutic targets and the development of a translational pipeline to evaluate splice modulators in human engineered heart tissue, animal models and clinical trials - provide a basis for improved diagnosis and therapy. Finally, we consider how the medical and scientific communities can benefit from facilitated acquisition and interpretation of splicing data towards improved clinical decision-making and patient care.

  View details for DOI 10.1038/s41569-022-00828-0

  View details for PubMedID 36653465

• Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant. Circulation. Genomic and precision medicine Hoorntje, E. T., Burns, C., Marsili, L., Corden, B., Parikh, V. N., Te Meerman, G. J., Gray, B., Adiyaman, A., Bagnall, R. D., Barge-Schaapveld, D. Q., van den Berg, M. P., Bootsma, M., Bosman, L. P., Correnti, G., Duflou, J., Eppinga, R. N., Fatkin, D., Fietz, M., Haan, E., Jongbloed, J. D., Hauer, A. D., Lam, L., van Lint, F. H., Lota, A., Marcelis, C., McCarthy, H. J., van Mil, A. M., Oldenburg, R. A., Pachter, N., Planken, R. N., Reuter, C., Semsarian, C., van der Smagt, J. J., Thompson, T., Vohra, J., Volders, P. G., van Waning, J. I., Whiffin, N., van den Wijngaard, A., Amin, A. S., Wilde, A. A., van Woerden, G., Yeates, L., Zentner, D., Ashley, E. A., Wheeler, M. T., Ware, J. S., van Tintelen, J. P., Ingles, J. 2022: e003672

  Abstract

  Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy.Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed.There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions, resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 gnomAD control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001).In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

  View details for DOI 10.1161/CIRCGEN.121.003672

  View details for PubMedID 36580316

• Generation of two induced pluripotent stem cell lines from dilated cardiomyopathy patients carrying TTN mutations. Stem cell research Zhang, T. T., Zhao, S. R., Alamana, C., Shen, M., Parikh, V., Wheeler, M. T., Wu, J. C. 2022; 65: 102941

  Abstract

  Dilated cardiomyopathy (DCM) is a common heart disease that can lead to heart failure and sudden cardiac death. Mutations in the TTN gene are the most frequent cause of DCM. Here, we generated two human induced pluripotent stem cell (iPSC) lines from the peripheral blood mononuclear cells (PBMCs) of two DCM patients carrying c.94816C>T and c.104188A>G mutations in TTN, respectively. The two lines exhibited a normal morphology, full expression of pluripotency markers, a normal karyotype and the ability of trilineage differentiation. The two lines can serve as useful tools for drug screening and mechanism studies on DCM.

  View details for DOI 10.1016/j.scr.2022.102941

  View details for PubMedID 36270069

• Scalable Functional Assays for the Interpretation of Human Genetic Variation. Annual review of genetics Tabet, D., Parikh, V., Mali, P., Roth, F. P., Claussnitzer, M. 2022

  Abstract

  Scalable sequence-function studies have enabled the systematic study and cataloging of hundreds of thousands of coding and noncoding genetic variants in the human genome. This has improved clinical variant interpretation and provided insights into the molecular, biophysical, and cellular effects of genetic variants at an astonishing scale and resolution across the spectrum of allele frequencies. In this review, we explore current applications and prospects for the field, and outline the principles underlying scalable functional assay design, with a focus on the study of single-nucleotide coding and noncoding variants. Expected final online publication date for the Annual Review of Genetics, Volume 56 is November 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for DOI 10.1146/annurev-genet-072920-032107

  View details for PubMedID 36055970

• Impact of SARS-Cov-2 infection in patients with hypertrophic cardiomyopathy: results of an international multicentre registry. ESC heart failure Gimeno, J. R., Olivotto, I., Rodríguez, A. I., Ho, C. Y., Fernández, A., Quiroga, A., Espinosa, M. A., Gómez-González, C., Robledo, M., Tojal-Sierra, L., Day, S. M., Owens, A., Barriales-Villa, R., Larrañaga, J. M., Rodríguez-Palomares, J., González-Del-Hoyo, M., Piqueras-Flores, J., Reza, N., Chumakova, O., Ashley, E. A., Parikh, V., Wheeler, M., Jacoby, D., Pereira, A. C., Saberi, S., Helms, A. S., Villacorta, E., Gallego-Delgado, M., de Castro, D., Domínguez, F., Ripoll-Vera, T., Zorio-Grima, E., Sánchez-Martínez, J. C., García-Álvarez, A., Arbelo, E., Mogollón, M. V., Fuentes-Cañamero, M. E., Grande, E., Peña, C., Monserrat, L., Lakdawala, N. K. 2022; 9 (4): 2189-2198

  Abstract

  To describe the natural history of SARS-CoV-2 infection in patients with hypertrophic cardiomyopathy (HCM) compared with a control group and to identify predictors of adverse events.Three hundred and five patients [age 56.6 ± 16.9 years old, 191 (62.6%) male patients] with HCM and SARS-Cov-2 infection were enrolled. The control group consisted of 91 131 infected individuals. Endpoints were (i) SARS-CoV-2 related mortality and (ii) severe clinical course [death or intensive care unit (ICU) admission]. New onset of atrial fibrillation, ventricular arrhythmias, shock, stroke, and cardiac arrest were also recorded. Sixty-nine (22.9%) HCM patients were hospitalized for non-ICU level care, and 21 (7.0%) required ICU care. Seventeen (5.6%) died: eight (2.6%) of respiratory failure, four (1.3%) of heart failure, two (0.7%) suddenly, and three (1.0%) due to other SARS-CoV-2-related complications. Covariates associated with mortality in the multivariable were age {odds ratio (OR) per 10 year increase 2.25 [95% confidence interval (CI): 1.12-4.51], P = 0.0229}, baseline New York Heart Association class [OR per one-unit increase 4.01 (95%CI: 1.75-9.20), P = 0.0011], presence of left ventricular outflow tract obstruction [OR 5.59 (95%CI: 1.16-26.92), P = 0.0317], and left ventricular systolic impairment [OR 7.72 (95%CI: 1.20-49.79), P = 0.0316]. Controlling for age and sex and comparing HCM patients with a community-based SARS-CoV-2 cohort, the presence of HCM was associated with a borderline significant increased risk of mortality OR 1.70 (95%CI: 0.98-2.91, P = 0.0600).Over one-fourth of HCM patients infected with SARS-Cov-2 required hospitalization, including 6% in an ICU setting. Age and cardiac features related to HCM, including baseline functional class, left ventricular outflow tract obstruction, and systolic impairment, conveyed increased risk of mortality.

  View details for DOI 10.1002/ehf2.13964

  View details for PubMedID 36255281

• Emerging Genotype-Phenotype Associations in Dilated Cardiomyopathy. Current cardiology reports Njoroge, J. N., Mangena, J. C., Aribeana, C., Parikh, V. N. 2022

  Abstract

  The disease burden of inherited dilated cardiomyopathy (DCM) is large and likely underestimated. This population stands to benefit immensely from therapeutic approaches tailored to the underlying genetic causes. Here, we review recent advances in understanding novel genotype-phenotype relationships and how these can improve the care of patients with inherited DCM.In the last several years, discovery of novel DCM-associated genes, gene-specific DCM outcomes, and nuanced information about variant-environment interactions have advanced our understanding of inherited DCM. Specifically, novel associations of genes with specific clinical phenotypes can help to assess sudden cardiac death risk and guide counseling around behavioral and environmental exposures that may worsen disease. Important expansions of the current genotype-phenotype profiling include the newly DCM-associated FLNC variant, prognostically significant LMNA, DSP inflammatory cardiomyopathy, and the highly penetrant features of RBM20 variants as well as the role of TTN variants in compounding the effects of environmental factors on toxin-mediated DCM. Future directions to improve diagnostic accuracy and prognostic improvement in DCM will center not just on identification of new genes, but also on understanding the interaction of known and novel variants in known DCM genes with patient genetic background and environment.

  View details for DOI 10.1007/s11886-022-01727-z

  View details for PubMedID 35900642

• Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy. Circulation. Genomic and precision medicine De Jong, H. N., Dewey, F. E., Cordero, P., Victorio, R. A., Kirillova, A., Huang, Y., Madhvani, R., Seo, K., Werdich, A. A., Lan, F., Orcholski, M., Robert Liu, W., Erbilgin, A., Wheeler, M. T., Chen, R., Pan, S., Kim, Y. M., Bommakanti, K., Marcou, C. A., Martijn Bos, J., Haddad, F., Ackerman, M., Vasan, R. S., MacRae, C., Wu, J. C., de Jesus Perez, V., Snyder, M., Parikh, V. N., Ashley, E. A. 2022: 101161CIRCGEN121003563

  Abstract

  BACKGROUND: The study of hypertrophic cardiomyopathy (HCM)-a severe Mendelian disease-can yield insight into the mechanisms underlying the complex trait of cardiac hypertrophy. To date, most genetic variants associated with HCM have been found in sarcomeric genes. Here, we describe a novel HCM-associated variant in the noncanonical Wnt signaling interactor WTIP (Wilms tumor interacting protein) and provide evidence of a role for WTIP in complex disease.METHODS: In a family affected by HCM, we used exome sequencing and identity-by-descent analysis to identify a novel variant in WTIP (p.Y233F). We knocked down WTIP in isolated neonatal rat ventricular myocytes with lentivirally delivered shRNAs and in Danio rerio via morpholino injection. We performed weighted gene coexpression network analysis for WTIP in human cardiac tissue, as well as association analysis for WTIP variation and left ventricular hypertrophy. Finally, we generated induced pluripotent stem cell-derived cardiomyocytes from patient tissue, characterized size and calcium cycling, and determined the effect of verapamil treatment on calcium dynamics.RESULTS: WTIP knockdown caused hypertrophy in neonatal rat ventricular myocytes and increased cardiac hypertrophy, peak calcium, and resting calcium in D rerio. Network analysis of human cardiac tissue indicated WTIP as a central coordinator of prohypertrophic networks, while common variation at the WTIP locus was associated with human left ventricular hypertrophy. Patient-derived WTIP p.Y233F-induced pluripotent stem cell-derived cardiomyocytes recapitulated cellular hypertrophy and increased resting calcium, which was ameliorated by verapamil.CONCLUSIONS: We demonstrate that a novel genetic variant found in a family with HCM disrupts binding to a known Wnt signaling protein, misregulating cardiomyocyte calcium dynamics. Further, in orthogonal model systems, we show that expression of the gene WTIP is important in complex cardiac hypertrophy phenotypes. These findings, derived from the observation of a rare Mendelian disease variant, uncover a novel disease mechanism with implications across diverse forms of cardiac hypertrophy.

  View details for DOI 10.1161/CIRCGEN.121.003563

  View details for PubMedID 35671065

• The Response to Cardiac Resynchronization Therapy in LMNA cardiomyopathy. European journal of heart failure Sidhu, K., Castrini, A. I., Parikh, V., Reza, N., Owens, A., Tremblay-Gravel, M., Wheeler, M. T., Mestroni, L., Taylor, M., Graw, S., Gigli, M., Merlo, M., Paldino, A., Sinagra, G., Judge, D. P., Ramos, H., Mesubi, O., Brown, E., Turnbull, S., Kumar, S., Roy, D., Tedrow, U. B., Ngo, L., Haugaa, K., Lakdawala, N. K. 2022

  Abstract

  AIMS: Cardiac implantable electronic device (CIED) therapy is fundamental to the management of LMNA-cardiomyopathy due to the high frequency of atrioventricular block and ventricular tachyarrhythmias. We aim to define the role of cardiac resynchronization therapy (CRT) in impacting heart failure in LMNA-cardiomyopathy.METHODS AND RESULTS: From 9 referral centers, LMNA-cardiomyopathy patients who underwent CRT with available pre- and post- echocardiograms were identified retrospectively. Factors associated with CRT response were identified [defined as improvement in left ventricular ejection fraction (LVEF) ≥5% 6-months post-implant] and the associated impact on the primary outcome of death, implantation of a left ventricular assist device or cardiac transplantation was assessed. We identified 105 patients (51±10years) undergoing CRT, including 70 (67%) who underwent CRT as a CIED upgrade. The mean change in LVEF ~6 months post CRT was +4±9%. A CRT response occurred in 40 (38%) patients and was associated with lower baseline LVEF or a high percentage of right ventricular pacing prior to CRT in patients with pre-existing CIED. In patients with an ESC Class I guideline indication for CRT, response rates were 61%. A CRT response was evident at thresholds of LVEF ≤45% or percent pacing ≥50%. There was a 1.3 year estimated median difference in event-free survival in those who responded to CRT (p=0.04).CONCLUSION: Systolic function improves in patients with LMNA-cardiomyopathy who undergo CRT, especially with strong guideline indications for implantation. Post CRT improvements in LVEF are associated with survival benefits in this population with otherwise limited options.

  View details for DOI 10.1002/ejhf.2463

  View details for PubMedID 35229420

• Association of Titin Variations With Late-Onset Dilated Cardiomyopathy. JAMA cardiology Cannata, A., Merlo, M., Dal Ferro, M., Barbati, G., Manca, P., Paldino, A., Graw, S., Gigli, M., Stolfo, D., Johnson, R., Roy, D., Tharratt, K., Bromage, D. I., Jirikowic, J., Abbate, A., Goodwin, A., Rao, K., Marawan, A., Carr-White, G., Robert, L., Parikh, V., Ashley, E., McDonagh, T., Lakdawala, N. K., Fatkin, D., Taylor, M. R., Mestroni, L., Sinagra, G. 2022

  Abstract

  Importance: Dilated cardiomyopathy (DCM) is frequently caused by genetic factors. Studies identifying deleterious rare variants have predominantly focused on early-onset cases, and little is known about the genetic underpinnings of the growing numbers of patients with DCM who are diagnosed when they are older than 60 years (ie, late-onset DCM).Objective: To investigate the prevalence, type, and prognostic impact of disease-associated rare variants in patients with late-onset DCM.Design, Setting, and Participants: A population of patients with late-onset DCM who had undergone genetic testing in 7 international tertiary referral centers worldwide were enrolled from March 1990 to August 2020. A positive genotype was defined as the presence of pathogenic or likely pathogenic (P/LP) variants.Main Outcomes and Measures: The study outcome was all-cause mortality.Results: A total of 184 patients older than 60 years (103 female [56%]; mean [SD] age, 67[6] years; mean [SD] left ventricular ejection fraction, 32%[10%]) were studied. Sixty-six patients (36%) were carriers of a P/LP variant. Titin-truncating variants were the most prevalent (present in 46 [25%] of the total population and accounting for 46 [69%] of all genotype-positive patients). During a median (interquartile range) follow-up of 42 (10-115) months, 23 patients (13%) died; 17 (25%) of these were carriers of P/LP variants, while 6 patients (5.1%) were genotype-negative.Conclusions and Relevance: Late-onset DCM might represent a distinct subgroup characterized by and a high genetic variation burden, largely due to titin-truncating variants. Patients with a positive genetic test had higher mortality than genotype-negative patients. These findings support the extended use of genetic testing also in older patients.

  View details for DOI 10.1001/jamacardio.2021.5890

  View details for PubMedID 35138330

• Worldwide differences in primary prevention implantable cardioverter defibrillator utilization and outcomes in hypertrophic cardiomyopathy. European heart journal Nauffal, V., Marstrand, P., Han, L., Parikh, V. N., Helms, A. S., Ingles, J., Jacoby, D., Lakdawala, N. K., Kapur, S., Michels, M., Owens, A. T., Ashley, E. A., Pereira, A. C., Rossano, J. W., Saberi, S., Semsarian, C., Ware, J. S., Wittekind, S. G., Day, S., Olivotto, I., Ho, C. Y. 2021; 42 (38): 3932-3944

  Abstract

  Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry.We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89-2.74]), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76-6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28-0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74-1.97]).Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM.

  View details for DOI 10.1093/eurheartj/ehab598

  View details for PubMedID 36282238

• Phenotypic Expression, Natural History and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants. Circulation Gigli, M., Stolfo, D., Graw, S., Merlo, M., Gregorio, C., Chen, S. N., Dal Ferro, M., Paldino, A., De Angelis, G., Brun, F., Jirikowic, J., Salcedo, E. E., Turja, S., Fatkin, D., Johnson, R., van Tintelen, J. P., Te Riele, A. S., Wilde, A., Lakdawala, N. K., Picard, K., Miani, D., Muser, D., Severini, G. M., Calkins, H., James, C. A., Murray, B., Tichnell, C., Parikh, V. N., Ashley, E. A., Reuter, C., Song, J., Judge, D., McKenna, W. J., Taylor, M. R., Sinagra, G., Mestroni, L. 2021

  Abstract

  Background: Filamin C truncating variants (FLNCtv) cause a form of arrhythmogenic cardiomyopathy (ACM): the mode of presentation, natural history and risk stratification of FLNCtv remain incompletely explored. We sought to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers. Methods: FLNCtv carriers were identified from ten tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), non-arrhythmic death/HT/LVAD and SCD/major ventricular arrhythmias (SCD/MVA). Previously established cohorts of 46 patients with LMNA and 60 with DSP-related ACM were used for prognostic comparison. Results: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% males, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction (LVEF) was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/ right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) non-arrhythmic death/HT/LVAD and 23 (27%) SCD/MVA. The SCD/MVA incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, LVEF was associated with the risk of D/HT/LVAD and non-arrhythmic death/HT/LVAD. CConclusions: Among patients referred to tertiary referral centers, FLNCtv ACM is phenotypically heterogeneous and characterized by high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of LV dysfunction.

  View details for DOI 10.1161/CIRCULATIONAHA.121.053521

  View details for PubMedID 34587765

• Worldwide differences in primary prevention implantable cardioverter defibrillator utilization and outcomes in hypertrophic cardiomyopathy. European heart journal Nauffal, V., Marstrand, P., Han, L., Parikh, V. N., Helms, A. S., Ingles, J., Jacoby, D., Lakdawala, N. K., Kapur, S., Michels, M., Owens, A. T., Ashley, E. A., Pereira, A. C., Rossano, J. W., Saberi, S., Semsarian, C., Ware, J. S., Wittekind, S. G., Day, S., Olivotto, I., Ho, C. Y. 2021

  Abstract

  AIMS: Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry.METHODS AND RESULTS: We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89-2.74]), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76-6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28-0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74-1.97]).CONCLUSION: Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM.

  View details for DOI 10.1093/eurheartj/ehab598

  View details for PubMedID 34491319

• Mapping the human genetic architecture of COVID-19. Nature COVID-19 Host Genetics Initiative 2021

  Abstract

  The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity1,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprised of up to 49,562 COVID-19 patients from 46 studies across 19 countries. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian Randomization analyses support a causal role for smoking and body mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was made possible by the community of human genetic researchers coming together to prioritize sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

  View details for DOI 10.1038/s41586-021-03767-x

  View details for PubMedID 34237774

• Iron Deficiency as a Potential Modulator of Subclinical Deficiencies in Cardiac Performance and Exercise Capacity. Journal of cardiac failure Elezaby, A., Parikh, V. N., Nayor, M. 2021; 27 (7): 822-824

  View details for DOI 10.1016/j.cardfail.2021.04.018

  View details for PubMedID 34246431

• Arrhythmogenic Cardiomyopathy: Mechanisms, Genetics, and Their Clinical Implications CURRENT CARDIOVASCULAR RISK REPORTS Reuter, C. M., Dries, A. M., Parikh, V. N. 2021; 15 (5)

  View details for DOI 10.1007/s12170-021-00669-5

  View details for Web of Science ID 000633384600001

• Promise and Peril of Population Genomics for the Development of Genome-First Approaches in Mendelian Cardiovascular Disease. Circulation. Genomic and precision medicine Parikh, V. N. 2021: CIRCGEN120002964

  Abstract

  The rich tradition of cardiovascular genomics has placed the field in prime position to extend our knowledge toward a genome-first approach to diagnosis and therapy. Population-scale genomic data has enabled exponential improvements in our ability to adjudicate variant pathogenicity based on allele rarity, and there has been a significant effort to employ these sizeable data in the investigation of rare disease. Certainly, population genomics data has great potential to aid the development of a genome-first approach to Mendelian cardiovascular disease, but its use in the clinical and investigative decision making is limited by the characteristics of the populations studied, and the evolutionary constraints on human Mendelian variation. To truly empower clinicians and patients, the successful implementation of a genome-first approach to rare cardiovascular disease will require the nuanced incorporation of population-based discovery with detailed investigation of rare disease cohorts and prospective variant evaluation.

  View details for DOI 10.1161/CIRCGEN.120.002964

  View details for PubMedID 33517676

• Patient-Specific Induced Pluripotent Stem Cells Implicate Intrinsic Impaired Contractility in Hypoplastic Left Heart Syndrome. Circulation Paige, S. L., Galdos, F. X., Lee, S., Chin, E. T., Ranjbarvaziri, S., Feyen, D. A., Darsha, A. K., Xu, S., Ryan, J. A., Beck, A. L., Qureshi, M. Y., Miao, Y., Gu, M., Bernstein, D., Nelson, T. J., Mercola, M., Rabinovitch, M., Ashley, E. A., Parikh, V. N., Wu, S. M. 2020; 142 (16): 1605–8

  View details for DOI 10.1161/CIRCULATIONAHA.119.045317

  View details for PubMedID 33074758

• Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association CIRCULATION-GENOMIC AND PRECISION MEDICINE Musunuru, K., Hershberger, R. E., Day, S. M., Klinedinst, N., Landstrom, A. P., Parikh, V. N., Prakash, S., Semsarian, C., Sturm, A. C., Amer Heart Assoc Council, Council Arteriosclerosis Thromb, Council Cardiovasc & S 2020; 13 (4): e000067

  Abstract

  Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all cardiovascular practitioners are fully aware of the utility and potential pitfalls of incorporating genetic test results into the care of patients and their families. This statement summarizes current best practices with respect to genetic testing and its implications for the management of inherited cardiovascular diseases.

  View details for DOI 10.1161/HCG.0000000000000067

  View details for Web of Science ID 000576935900002

  View details for PubMedID 32698598

• Circulating microRNAs as Biomarkers for Sudden Cardiac Death: Truth in the Serum? JACC. Clinical electrophysiology Parikh, V. N. 2020; 6 (1): 80–82

  View details for DOI 10.1016/j.jacep.2019.09.008

  View details for PubMedID 31971909

• Stretch-Induced Biased Signaling in Angiotensin II Type 1 and Apelin Receptors for the Mediation of Cardiac Contractility and Hypertrophy. Frontiers in physiology Seo, K., Parikh, V. N., Ashley, E. A. 2020; 11: 181

  Abstract

  The myocardium has an intrinsic ability to sense and respond to mechanical load in order to adapt to physiological demands. Primary examples are the augmentation of myocardial contractility in response to increased ventricular filling caused by either increased venous return (Frank-Starling law) or aortic resistance to ejection (the Anrep effect). Sustained mechanical overload, however, can induce pathological hypertrophy and dysfunction, resulting in heart failure and arrhythmias. It has been proposed that angiotensin II type 1 receptor (AT1R) and apelin receptor (APJ) are primary upstream actors in this acute myocardial autoregulation as well as the chronic maladaptive signaling program. These receptors are thought to have mechanosensing capacity through activation of intracellular signaling via G proteins and/or the multifunctional transducer protein, beta-arrestin. Importantly, ligand and mechanical stimuli can selectively activate different downstream signaling pathways to promote inotropic, cardioprotective or cardiotoxic signaling. Studies to understand how AT1R and APJ integrate ligand and mechanical stimuli to bias downstream signaling are an important and novel area for the discovery of new therapeutics for heart failure. In this review, we provide an up-to-date understanding of AT1R and APJ signaling pathways activated by ligand versus mechanical stimuli, and their effects on inotropy and adaptive/maladaptive hypertrophy. We also discuss the possibility of targeting these signaling pathways for the development of novel heart failure therapeutics.

  View details for DOI 10.3389/fphys.2020.00181

  View details for PubMedID 32231588

• Pathological overlap of Arrhythmogenic Right Ventricular Cardiomyopathy and Cardiac Sarcoidosis. Circulation. Genomic and precision medicine Kerkar, A., Hazard, F., Caleshu, C. A., Shah, R. L., Reuter, C., Ashley, E. A., Parikh, V. N. 2019

  Abstract

  A previously healthy 50-year-old female long-distance runner initially presented to the emergency room with sustained palpitations and was found to be in a hemodynamically stable wide complex tachycardia at 220 bpm. Initial electrocardiogram (ECG) demonstrated monomorphic tachycardia with a right inferoapical ventricular origin (Figure 1A). Echocardiogram revealed normal left ventricular (LV) size and moderately reduced function, but severe right ventricular (RV) enlargement and systolic dysfunction in the absence of elevated pulmonary pressures (Figure 1B). Her ECG in normal sinus rhythm showed T wave inversions in V1-V4 (Figure 1C) and her signal averaged ECG was abnormal with a filtered QRS duration of 150 msec, root mean square amplitude of the last 40 msec of late potentials (RMS40) of 2.16 mV and duration of low amplitude signal (LAS) of 92.5msec. Electrophysiology study confirmed inducible ventricular arrhythmias from the RV, and internal cardiac defibrillator (ICD) was placed.

  View details for DOI 10.1161/CIRCGEN.119.002638

  View details for PubMedID 31542937

• Allele-Specific Silencing Ameliorates Restrictive Cardiomyopathy Due to a Human Myosin Regulatory Light Chain Mutation. Circulation Zaleta-Rivera, K., Dainis, A., Ribeiro, A. J., Sanchez Cordero, P., Rubio, G., Shang, C., Liu, J., Finsterbach, T., Parikh, V. N., Sutton, S., Seo, K., Sinha, N., Jain, N., Huang, Y., Hajjar, R. J., Kay, M. A., Szczesna-Cordary, D., Pruitt, B. L., Wheeler, M. T., Ashley, E. A. 2019

  Abstract

  BACKGROUND: Restrictive cardiomyopathy (RCM) is a rare heart disease associated with mutations in sarcomeric genes and with phenotypic overlap with hypertrophic cardiomyopathy. There is no approved therapy. Here, we explore the potential of an interfering RNA (RNAi) therapeutic for a human sarcomeric mutation in MYL2 causative of restrictive cardiomyopathy in a mouse model.METHODS: AAV9-M7.8L shRNA was selected from a pool of RNAi oligonucleotides containing the SNV in different positions to specifically target the mutated allele causative of RCM by FACS screening. Two groups of RLC-N47K transgenic mice were injected with a single dose of AAV9-M7.8L shRNA at 3 days of age and at 60 days of age. Mice were subjected to treadmill exercise and echocardiography after treatment to determine VO2max and left ventricular mass. At the end of treatment, heart, lung, liver and kidney tissue was harvested to determine viral tropism and for transcriptome and proteomic analysis. Cardiomyocytes were isolated for single cell studies.RESULTS: One time injection of AAV9-M7.8L RNAi in 3-day-old humanized RLC mutant transgenic mice silenced the mutated allele (RLC-47K) with minimal effects on the normal allele (RLC-47N) assayed 16 weeks post-injection. AAV9-M7.8L RNAi suppressed the expression of hypertrophic biomarkers, reduced heart weight and attenuated a pathological increase in left ventricular mass (LVM). Single adult cardiac myocytes from mice treated with AAV9-M7.8L showed partial restoration of the maximal contraction velocity with marked reduction in hypercontractility as well as relaxation kinetics and improved time to maximal calcium reuptake velocity. In addition, cardiac stress protein biomarkers, such as calmodulin-dependent protein kinase II (CAMKII) and the transcription activator Brg1 were reduced suggesting recovery towards a healthy myocardium. Transcriptome analyses further revealed no significant changes of argonaute (AGO1, AGO2) and endoribonuclease dicer (DICER1) transcripts while endogenous microRNAs were preserved suggesting the RNAi pathway was not saturated.CONCLUSIONS: Our results show the feasibility, efficacy, and safety of RNAi therapeutics directed at human restrictive cardiomyopathy. This is a promising step towards targeted therapy for a prevalent human disease.

  View details for DOI 10.1161/CIRCULATIONAHA.118.036965

  View details for PubMedID 31315475

• Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure. Nature communications Cordero, P., Parikh, V. N., Chin, E. T., Erbilgin, A., Gloudemans, M. J., Shang, C., Huang, Y., Chang, A. C., Smith, K. S., Dewey, F., Zaleta, K., Morley, M., Brandimarto, J., Glazer, N., Waggott, D., Pavlovic, A., Zhao, M., Moravec, C. S., Tang, W. H., Skreen, J., Malloy, C., Hannenhalli, S., Li, H., Ritter, S., Li, M., Bernstein, D., Connolly, A., Hakonarson, H., Lusis, A. J., Margulies, K. B., Depaoli-Roach, A. A., Montgomery, S. B., Wheeler, M. T., Cappola, T., Ashley, E. A. 2019; 10 (1): 2760

  Abstract

  Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.

  View details for DOI 10.1038/s41467-019-10591-5

  View details for PubMedID 31235787

• Apelin and APJ orchestrate complex tissue-specific control of cardiomyocyte hypertrophy and contractility in the hypertrophy-heart failure transition. American journal of physiology. Heart and circulatory physiology Parikh, V. N., Liu, J., Shang, C., Woods, C., Chang, A. C., Zhao, M., Charo, D. N., Grunwald, Z., Huang, Y., Seo, K., Tsao, P. S., Bernstein, D., Ruiz-Lozano, P., Quertermous, T., Ashley, E. A. 2018

  Abstract

  The G protein coupled receptor APJ is a promising therapeutic target for heart failure. Constitutive deletion of APJ in the mouse is protective against the hypertrophy-heart failure transition via elimination of ligand-independent, beta-arrestin dependent stretch transduction. However, the cellular origin of this stretch transduction and the details of its interaction with apelin signaling remain unknown. We generated mice with conditional elimination of APJ in the endothelium (APJendo-/-) and myocardium (APJmyo-/-). No baseline difference was observed in LV function in APJendo-/-, APJmyo-/- or controls (APJendo+/+, APJmyo+/+). After exposure to transaortic constriction (TAC), APJendo-/- animals developed left ventricular failure while APJmyo-/- were protected. At the cellular level, carbon fiber stretch of freshly isolated single cardiomyocytes demonstrated decreased contractile response to stretch in APJ-/- cardiomyocytes compared to APJ+/+ cardiomyocytes. Calcium transient did not change with stretch in either APJ-/- or APJ+/+ cardiomyocytes. Application of apelin to APJ+/+ cardiomyocytes resulted in decreased calcium transient. Further, hearts of mice treated with apelin exhibited decreased phosphorylation at Troponin I (cTnI) N-terminal residues (Ser 22,23), consistent with increased calcium sensitivity. These data establish that APJ stretch transduction is mediated specifically by myocardial APJ, that APJ is necessary for stretch-induced increases in contractility, and that apelin opposes APJ's stretch-mediated hypertrophy signaling by lowering calcium transient while maintaining contractility through myofilament calcium sensitization. These findings underscore apelin's unique potential as a therapeutic agent that can simultaneously support cardiac function and protect against the hypertrophy-heart failure transition.

  View details for PubMedID 29775410

• Mind the Gap: Current Challenges and Future State of Heart Failure Care CANADIAN JOURNAL OF CARDIOLOGY McDonald, M. A., Ashley, E. A., Fedak, P. M., Hawkins, N., Januzzi, J. L., McMurray, J. V., Parikh, V. N., Rao, V., Svystonyuk, D., Teerlink, J. R., Virani, S. 2017; 33 (11): 1434–49

  Abstract

  The past decade has seen many advances in the management of heart failure (HF) that have improved survival and quality of life for patients living with this condition. A number of gaps remain in our understanding of the pathophysiology of HF, and the application of emerging treatment strategies is an exciting but daunting challenge. It is possible that advances in genetic evaluation of cardiomyopathy will provide a more refined approach to characterizing HF syndromes, whereas large-scale clinical trials on the horizon should further clarify the role of novel pharmacologic agents and invasive therapies. Cardiac repair and regeneration hold great promise, but a number of pragmatic issues will limit clinical application in the near term. Replacing cardiac function with ventricular assist devices represents significant progress in the management of advanced disease; however, unacceptable rates of complications and costs need to be addressed before broader use in the general HF population is feasible. The ability to personalize care is limited, and the optimal model of disease management in the Canadian context remains uncertain. The emergence of biomarker-guided management and remote monitoring technologies might facilitate a more personalized approach to care in an effort to maintain health and stability and to prevent worsening HF. Ultimately, a greater understanding of how and when to intervene in the setting of acute HF should translate into improved outcomes for the highest-risk subgroup of patients. This review highlights key challenges in the management of HF and highlights the progress toward an ideal future state.

  View details for PubMedID 29111107

• Delivering Clinical Grade Sequencing and Genetic Test Interpretation for Cardiovascular Medicine. Circulation. Cardiovascular genetics Harper, A. R., Parikh, V. N., Goldfeder, R. L., Caleshu, C., Ashley, E. A. 2017; 10 (2)

  View details for DOI 10.1161/CIRCGENETICS.116.001221

  View details for PubMedID 28411191

• Next-Generation Sequencing in Cardiovascular Disease Present Clinical Applications and the Horizon of Precision Medicine CIRCULATION Parikh, V. N., Ashley, E. A. 2017; 135 (5): 406–9

  View details for PubMedID 28137961

  View details for PubMedCentralID PMC5310819

• Wrestling the Giant: New Approaches for Assessing Titin Variant Pathogenicity. Circulation. Cardiovascular genetics Helle, E., Parikh, V. N. 2016; 9 (5): 392-394

  View details for DOI 10.1161/CIRCGENETICS.116.001594

  View details for PubMedID 27756780

• Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension JOURNAL OF CLINICAL INVESTIGATION Bertero, T., Oldham, W. M., Cottrill, K. A., Pisano, S., Vanderpool, R. R., Yu, Q., Zhao, J., Tai, Y., Tang, Y., Zhang, Y., Rehman, S., Sugahara, M., Qi, Z., Gorcsan, J., Vargas, S. O., Saggar, R., Saggar, R., Wallace, W. D., Ross, D. J., Haley, K. J., Waxman, A. B., Parikh, V. N., De Marco, T., Hsue, P. Y., Morris, A., Simon, M. A., Norris, K. A., Gaggioli, C., Loscalzo, J., Fessel, J., Chan, S. Y. 2016; 126 (9): 3313-3335

  Abstract

  Dysregulation of vascular stiffness and cellular metabolism occurs early in pulmonary hypertension (PH). However, the mechanisms by which biophysical properties of the vascular extracellular matrix (ECM) relate to metabolic processes important in PH remain undefined. In this work, we examined cultured pulmonary vascular cells and various types of PH-diseased lung tissue and determined that ECM stiffening resulted in mechanoactivation of the transcriptional coactivators YAP and TAZ (WWTR1). YAP/TAZ activation modulated metabolic enzymes, including glutaminase (GLS1), to coordinate glutaminolysis and glycolysis. Glutaminolysis, an anaplerotic pathway, replenished aspartate for anabolic biosynthesis, which was critical for sustaining proliferation and migration within stiff ECM. In vitro, GLS1 inhibition blocked aspartate production and reprogrammed cellular proliferation pathways, while application of aspartate restored proliferation. In the monocrotaline rat model of PH, pharmacologic modulation of pulmonary vascular stiffness and YAP-dependent mechanotransduction altered glutaminolysis, pulmonary vascular proliferation, and manifestations of PH. Additionally, pharmacologic targeting of GLS1 in this model ameliorated disease progression. Notably, evaluation of simian immunodeficiency virus-infected nonhuman primates and HIV-infected subjects revealed a correlation between YAP/TAZ-GLS activation and PH. These results indicate that ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis and anaplerosis, and thereby link mechanical stimuli to dysregulated vascular metabolism. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in PH.

  View details for DOI 10.1172/JCI86387

  View details for Web of Science ID 000382513400015

  View details for PubMedID 27548520

  View details for PubMedCentralID PMC5004943

• Early Outcomes After Extracardiac Conduit Fontan Operation Without Cardiopulmonary Bypass PEDIATRIC CARDIOLOGY McCammond, A. N., Kuo, K., Parikh, V. N., Abdullah, K., Balise, R., Hanley, F. L., Roth, S. J. 2012; 33 (7): 1078-1085

  Abstract

  Cardiopulmonary bypass is associated with a systemic inflammatory response. The authors hypothesized that avoiding cardiopulmonary bypass would lead to improved postoperative outcomes for patients undergoing the extracardiac Fontan operation, the final stage in surgical palliation of univentricular congenital heart defects. A review of the Children's Heart Center Database showed a total of 73 patients who underwent an initial Fontan operation at Lucile Packard Children's Hospital at Stanford between 1 November 2001 and 1 November 2006. These patients were divided into two groups: those who underwent cardiopulmonary bypass (n = 26) and those who avoided cardiopulmonary bypass (n = 47). Preoperative demographics, hemodynamics, and early postoperative outcomes were analyzed. The two groups had comparable preoperative demographic characteristics and hemodynamics except that the average weight of the off-bypass group was greater (17.9 ± 9.1 vs 14.2 ± 2.7 kg; P = 0.01). Intraoperatively, the off-bypass group trended toward a lower rate of Fontan fenestration (4.3 vs 19.2%; P = 0.09), had lower common atrial pressures (4.6 ± 1.4 vs 5.5 ± 1.5 mmHg; P = 0.05), and Fontan pressures (11.9 ± 2.1 vs 14.2 ± 2.4 mmHg; P ≤ 0.01), and required less blood product (59.1 ± 37.6 vs 91.9 ± 49.4 ml/kg; P ≤ 0.01). Postoperatively, there were no significant differences in hemodynamic parameters, postoperative colloid requirements, duration of mechanical ventilation, volume or duration of pleural drainage, or duration of cardiovascular intensive care unit or hospital stay. Avoiding cardiopulmonary bypass influenced intraoperative hemodynamics and the incidence of fenestration but did not have a significant impact on the early postoperative outcomes of children undergoing the Fontan procedure.

  View details for DOI 10.1007/s00246-012-0228-5

  View details for PubMedID 22349678

• Physiological consequences of social descent: studies in Astatotilapia burtoni JOURNAL OF ENDOCRINOLOGY Parikh, V. N., Clement, T., Fernald, R. D. 2006; 190 (1): 183-190

  Abstract

  In many species, social interactions regulate reproductive capacity, although the exact mechanisms of such regulation are unclear. Since social stress is often related to reproductive regulation, we measured the physiological signatures of change in reproductive state as they relate to short-term stress and the stress hormone cortisol. We used an African cichlid fish, Astatotilapia burtoni, with two distinct, reversible male phenotypes: dominant (territorial, T) males that are larger, more brightly colored, more aggressive, and reproductively competent and non-dominant males (non-territorial, NT) that are smaller, camouflage colored, and have regressed gonads. Male status, and hence reproductive competence, depends on social experience in this system. Specifically, if a T male is placed among larger male fish, it quickly becomes NT in behavior and coloration, but complete regression of its reproductive axis takes ca. 3 weeks (White et al. 2002). Reproduction in all vertebrates is controlled by the hypothalamic-pituitary-gonadal axis in which the key signaling molecule from the brain to the pituitary is GnRH1. Here, we subjected T males to territory loss, a social manipulation which results in status descent. We measured the effects of this status change in levels of circulating cortisol and testosterone as well as mRNA levels of GnRH1 and GnRH receptor-1 (GnRH-R1) in the brain and pituitary, respectively. Following short-term social suppression (4 h), no change was observed in plasma cortisol level, GnRH1 mRNA expression, GnRH-R1 mRNA expression, or plasma testosterone level. However, following a somewhat longer social suppression (24 h), cortisol and GnRH1 mRNA levels were significantly increased, and testosterone levels were significantly decreased. These results suggest that in the short run, deposed T males essentially mount a neural 'defense' against loss of status.

  View details for DOI 10.1677/joe.1.06755

  View details for Web of Science ID 000239385600021

  View details for PubMedID 16837622

• Androgen level and male social status in the African cichlid, Astatotilapia burtoni BEHAVIOURAL BRAIN RESEARCH Parikh, V. N., Clement, T. S., Fernald, R. D. 2006; 166 (2): 291-295

  Abstract

  In vertebrates, circulating androgen levels are regulated by the hypothalamic-pituitary-gonadal (HPG) axis through which the brain controls the gonads via the pituitary. Androgen levels ultimately depend on factors including season, temperature, social circumstance, age, and other variables related to reproductive capacity and opportunity. Previous studies with an African cichlid fish, Astatotilapia burtoni, suggested that changes in both testosterone and 11-ketotestosterone (11-KT), an androgen specific to teleost fish, depend on male social status. Here we characterize circulating plasma concentrations of testosterone and 11-KT in socially dominant (territorial) and socially subordinate (non-territorial) males. Territorial males have significantly higher circulating levels of both forms of androgen, which is another defining difference between dominant and subordinate males in this species. These results underscore how internal and external cues related to reproduction are integrated at the level of the HPG axis.

  View details for DOI 10.1016/j.bbr.2005.07.011

  View details for Web of Science ID 000234643600014

  View details for PubMedID 16143408

• Behavioral coping strategies in a cichlid fish: the role of social status and acute stress response in direct and displaced aggression HORMONES AND BEHAVIOR Clement, T. S., Parikh, V., Schrumpf, M., Fernald, R. D. 2005; 47 (3): 336-342

  Abstract

  The African cichlid fish, Astatotilapia burtoni, has a complex social system with a sophisticated social hierarchy that offers unique opportunities to understand how social rank and its physiological substrates relate to behavioral strategies. In A. burtoni, a small fraction of the males are dominant (T, territorial), as distinguished by being large, brightly colored, reproductively active, and aggressively defending territories. In contrast, the majority of males are non-dominant (NT, non-territorial), being smaller, drably colored, sexually immature, and typically schooling with females. The social system is regulated by aggressive interactions between males and behavioral responses to aggression can be direct or displaced with respect to the animal that acts. To determine whether direct and displaced behaviors are differentially exhibited by T and NT males, individuals were shown a video presentation of a dominant male displaying aggressively. Analysis of aggressive acts toward the video display and displaced activity toward a tank mate revealed that T males exhibited more direct behavior (toward the video display), while NT males engaged in more displaced behavior (toward tank mates). Because similar experiments with primates suggest that shifts in behavioral strategies are linked to changes in the stress response (as measured by circulating cortisol levels), we measured cortisol levels of T and NT males following exposure to the aggressive stimulus. Although in some animals subordinate males are reported to have higher cortisol levels, here we show that in A. burtoni the endocrine response to specific situations can vary considerably even among animals of the same status. Interestingly, NT males with intermediate cortisol levels showed more directed behavior while NT males with both high and low cortisol levels showed more displaced. This suggests an optimal physiological stress response in NT males that predisposes them to challenge aggressors perhaps making it more likely for them to ascend in status.

  View details for DOI 10.1016/j.yhbeh.2004.11.014

  View details for Web of Science ID 000227326100013

  View details for PubMedID 15708763