Victoria Parikh

All Publications

• 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

• 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

• 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

• 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

• 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

• Wrestling the Giant: New Approaches for Assessing Titin Variant Pathogenicity. Circulation. Cardiovascular genetics Helle, E., Parikh, V. N. 2016; 9 (5): 392–94

  View details for PubMedID 27756780

• 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