Browsing by Subject "Dilated cardiomyopathy"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Arrhythmia Mechanism and Dynamics in a Humanized Mouse Model of Inherited Cardiomyopathy Caused by Phospholamban R14del Mutation
    (American Heart Association, 2021) Raad, Nour; Bittihn, Philip; Cacheux, Marine; Jeong, Dongtak; Ilkan, Zeki; Ceholski, Delaine; Kohlbrenner, Erik; Zhang, Lu; Cai, Chen-Leng; Kranias, Evangelia G.; Hajjar, Roger J.; Stillitano, Francesca; Akar, Fadi G.; Pediatrics, School of Medicine
    Background: Arginine (Arg) 14 deletion (R14del) in the calcium regulatory protein phospholamban (hPLNR14del) has been identified as a disease-causing mutation in patients with an inherited cardiomyopathy. Mechanisms underlying the early arrhythmogenic phenotype that predisposes carriers of this mutation to sudden death with no apparent structural remodeling remain unclear. Methods: To address this, we performed high spatiotemporal resolution optical mapping of intact hearts from adult knock-in mice harboring the human PLNWT (wildtype [WT], n=12) or the heterozygous human PLNR14del mutation (R14del, n=12) before and after ex vivo challenge with isoproterenol and rapid pacing. Results: Adverse electrophysiological remodeling was evident in the absence of significant structural or hemodynamic changes. R14del hearts exhibited increased arrhythmia susceptibility compared with wildtype. Underlying this susceptibility was preferential right ventricular action potential prolongation that was unresponsive to β-adrenergic stimulation. A steep repolarization gradient at the left ventricular/right ventricular interface provided the substrate for interventricular activation delays and ultimately local conduction block during rapid pacing. This was followed by the initiation of macroreentrant circuits supporting the onset of ventricular tachycardia. Once sustained, these circuits evolved into high-frequency rotors, which in their majority were pinned to the right ventricle. These rotors exhibited unique spatiotemporal dynamics that promoted their increased stability in R14del compared with wildtype hearts. Conclusions: Our findings highlight the crucial role of primary electric remodeling caused by the hPLNR14del mutation. These inherently arrhythmogenic features form the substrate for adrenergic-mediated VT at early stages of PLNR14del induced cardiomyopathy.
  • Thumbnail Image
    Item
    Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry
    (American Medical Association, 2023) Jordan, Elizabeth; Kinnamon, Daniel D.; Haas, Garrie J.; Hofmeyer, Mark; Kransdorf, Evan; Ewald, Gregory A.; Morris, Alanna A.; Owens, Anjali; Lowes, Brian; Stoller, Douglas; Tang, W. H. Wilson; Garg, Sonia; Trachtenberg, Barry H.; Shah, Palak; Pamboukian, Salpy V.; Sweitzer, Nancy K.; Wheeler, Matthew T.; Wilcox, Jane E.; Katz, Stuart; Pan, Stephen; Jimenez, Javier; Fishbein, Daniel P.; Smart, Frank; Wang, Jessica; Gottlieb, Stephen S.; Judge, Daniel P.; Moore, Charles K.; Mead, Jonathan O.; Hurst, Natalie; Cao, Jinwen; Huggins, Gordon S.; Cowan, Jason; Ni, Hanyu; Rehm, Heidi L.; Jarvik, Gail P.; Vatta, Matteo; Burke, Wylie; Hershberger, Ray E.; DCM Precision Medicine Study of the DCM Consortium; Medical and Molecular Genetics, School of Medicine
    Importance: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. Design: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. Exposure: Presence of DCM. Main outcomes and measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). Results: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). Conclusion and relevance: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.
  • Thumbnail Image
    Item
    Neonatal lupus with left bundle branch block and cardiomyopathy: a case report
    (BMC, 2020-07-29) Rumancik, Brad; Haggstrom, Anita N.; Ebenroth, Eric S.; Pediatrics, School of Medicine
    Background Cardiac manifestations of neonatal lupus include an array of structural and conduction abnormalities due to placental transference of maternal anti-SSA/Ro and anti-SSB/La autoantibodies. Late-onset neonatal lupus cardiomyopathies, occurring outside the neonatal period, is an infrequently reported manifestation with unknown pathophysiology and poorly defined treatment regimens. Due to the rarity of this condition, additional studies and case reports are required to better understand and manage late-onset neonatal lupus cardiomyopathies. Case presentation A 4-week-old female, born to a mother with known anti-SSA/Ro and anti-SSB/La autoantibodies, presents with classic cutaneous manifestations for neonatal lupus and is found to have left bundle branch block, severely dilated cardiomyopathy with an ejection fraction of 25%, and a thin echogenic dyskinetic ventricular septum. Weekly second trimester and 30-week fetal echocardiograms showed no signs of structural or conduction abnormalities. There were no histologic signs of inflammation on cardiac tissue biopsy. After a complicated hospital course, she was successfully treated with biventricular pacemaker, intravenous immunoglobulin, and plasmapheresis. Conclusions We present a case of late-onset neonatal lupus with severe dilated cardiomyopathy, a dyskinetic ventricular septum, and left bundle branch block. To our knowledge, the dyskinetic ventricular septum has never been reported and left bundle branch block is rarely reported in NL. This case further validates the need for long term cardiac follow up for patients born with NL, even if lacking cardiac manifestations in the peripartum period. We characterize a unique presentation of a rare clinical entity, highlighting the diagnostic challenges, and describe a successful treatment course.
  • Thumbnail Image
    Item
    Pervasive nuclear envelope ruptures precede ECM signaling and disease onset without activating cGAS-STING in Lamin-cardiomyopathy mice
    (Elsevier, 2024) En, Atsuki; Bogireddi, Hanumakumar; Thomas, Briana; Stutzman, Alexis V.; Ikegami, Sachie; LaForest, Brigitte; Almakki, Omar; Pytel, Peter; Moskowitz, Ivan P.; Ikegami, Kohta; Medicine, School of Medicine
    Nuclear envelope (NE) ruptures are emerging observations in Lamin-related dilated cardiomyopathy, an adult-onset disease caused by loss-of-function mutations in Lamin A/C, a nuclear lamina component. Here, we test a prevailing hypothesis that NE ruptures trigger the pathological cGAS-STING cytosolic DNA-sensing pathway using a mouse model of Lamin cardiomyopathy. The reduction of Lamin A/C in cardio-myocyte of adult mice causes pervasive NE ruptures in cardiomyocytes, preceding inflammatory transcription, fibrosis, and fatal dilated cardiomyopathy. NE ruptures are followed by DNA damage accumulation without causing immediate cardiomyocyte death. However, cGAS-STING-dependent inflammatory signaling remains inactive. Deleting cGas or Sting does not rescue cardiomyopathy in the mouse model. The lack of cGAS-STING activation is likely due to the near absence of cGAS expression in adult cardiomyocytes at baseline. Instead, extracellular matrix (ECM) signaling is activated and predicted to initiate pro-inflammatory communication from Lamin-reduced cardiomyocytes to fibroblasts. Our work nominates ECM signaling, not cGAS-STING, as a potential inflammatory contributor in Lamin cardiomyopathy.
  • Thumbnail Image
    Item
    Progressive Left Ventricular Remodeling for Predicting Mortality in Children With Dilated Cardiomyopathy: The Pediatric Cardiomyopathy Registry
    (American Heart Association, 2024) Kantor, Paul F.; Shi, Ling; Colan, Steven D.; Orav, E. John; Wilkinson, James D.; Hamza, Taye H.; Webber, Steven A.; Canter, Charles E.; Towbin, Jeffrey A.; Everitt, Melanie D.; Pahl, Elfriede; Ware, Stephanie M.; Rusconi, Paolo G.; Lamour, Jacqueline M.; Jefferies, John L.; Addonizio, Linda J.; Lipshultz, Steven E.; Pediatric Cardiomyopathy Registry Investigators; Medical and Molecular Genetics, School of Medicine
    Background: Pediatric dilated cardiomyopathy often leads to death or cardiac transplantation. We sought to determine whether changes in left ventricular (LV) end-diastolic dimension (LVEDD), LV end-diastolic posterior wall thickness, and LV fractional shortening (LVFS) over time may help predict adverse outcomes. Methods and results: We studied children up to 18 years old with dilated cardiomyopathy, enrolled between 1990 and 2009 in the Pediatric Cardiomyopathy Registry. Changes in LVFS, LVEDD, LV end-diastolic posterior wall thickness, and the LV end-diastolic posterior wall thickness:LVEDD ratio between baseline and follow-up echocardiograms acquired ≈1 year after diagnosis were determined for children who, at the 1-year follow-up had died, received a heart transplant, or were alive and transplant-free. Within 1 year after diagnosis, 40 (5.0%) of the 794 eligible children had died, 117 (14.7%) had undergone cardiac transplantation, and 585 (73.7%) had survived without transplantation. At diagnosis, survivors had higher median LVFS and lower median LVEDD Z scores. Median LVFS and LVEDD Z scores improved among survivors (Z score changes of +2.6 and -1.1, respectively) but remained stable or worsened in the other 2 groups. The LV end-diastolic posterior wall thickness:LVEDD ratio increased in survivors only, suggesting beneficial reverse LV remodeling. The risk for death or cardiac transplantation up to 7 years later was lower when LVFS was improved at 1 year (hazard ratio [HR], 0.83; P=0.004) but was higher in those with progressive LV dilation (HR, 1.45; P<0.001). Conclusions: Progressive deterioration in LV contractile function and increasing LV dilation are associated with both early and continuing mortality in children with dilated cardiomyopathy. Serial echocardiographic monitoring of these children is therefore indicated.