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Understanding Heart Failure in Patients with Dilated Cardiomyopathy: A Direct Tissue Analysis from Explanted Human Hearts

  • Author / Creator
    Zhang, Hao
  • Background
    Chronic heart failure (HF) remains a rising global epidemic that affects both adults and children population. The causes of HF are heterogeneous, and syndromes are often complicated by concomitant disorders such as iron deficiency (ID) and diabetes. Comorbidities not only complicate the presentation and treatment of HF, but also play an instrumental role in its development. Thus, in recent years, elucidating and treating comorbidities have gained increasing importance in the management of HF.
    As the most prevalent malnutritional disease globally, iron deficiency often co-exists with HF regardless of abnormal blood cell parameters. Prior studies have confirmed its unfavorable impact on patients’ physical capacity and clinical outcomes, and iron supplementations exhibited remarkable benefits representing a promising therapeutic target. However, emerging evidence highlighted the presence of myocardial iron deficiency (MID) in several small HF cohorts, and consistently revealed a weak association with systemic iron status indicating distinct cardiac iron regulations. Furthermore, the diagnosis and pathophysiological implications of MID in HF patients remain largely unexplored.
    Dilated cardiomyopathy (DCM) represents the most common cause of terminal HF, and consequently, the most common indication for heart transplantation in adult and pediatric patients with HF. Despite similar phenotypes characterized as systolic dysfunction and eccentric ventricular dilation, the causes of DCM are also heterogeneous, which can be genetic, acquired (non-genetic) or a mixed form of both. The causative mutations account for up to one-third of idiopathic DCM cases and affect genes encoding structural components of desmosome, sarcomere, and nuclear envelop proteins, whereas the non-genetic forms of DCM can be a result of a variety of conditions such as viral infections, systemic autoimmune, endocrine, and neuromuscular diseases, and exposure to toxins, alcohol, or certain drugs. As such, the clinical course of this disease is remarkably variable. Most patients become symptomatic across a wide range of ages (20-60 years old), while infants and children can also be affected by DCM which accounts for up to 60% of all childhood cardiomyopathies. Pediatric DCM (P-DC) are pathologically distinct entities from their adult counterparts, with causes largely idiopathic and with age- and development-specific features in the immature failed hearts. However, current guideline-recommended medications for children and adolescents with HF are primarily extrapolated from adults and have been proven ineffective, which clearly indicates the disparate pathophysiology underlying the children’s failing hearts. Moreover, P-DC always occurs in the absence of common comorbidities seen in adult counterparts (A-DC), thereby offering an invaluable opportunity to examine the pathogenesis of primary DCM.

    Methods and Results
    We investigated end-stage dilated cardiomyopathic disease directly from explanted human heart specimens. In Chapter 3, the high prevalence of comorbid MID in adult HF patients and its poor correlation with hematopoietic indices were determined in the largest cohort of its kind to date. We assessed the pathophysiological role of MID in the remodeling progression to advanced HF. The feasibility of using cardiac magnetic resonance (CMR) imaging to non-invasively monitor this hidden disease in the human explants was further evaluated. Mechanistically, iron uptake pathways were found impeded in iron deficient failing hearts, coupled with pathologically elevated levels of ferroprotein in the sarcolemma. In Chapter 4, the explanted failing hearts from adults and children with DCM, and age-matched non-cardiomyopathic (NC) controls were examined. Unlike A-DC, P-DC demonstrated minimal myocardial remodeling characteristics with maintained contractile properties. Divergent transcriptomic and (phospho-)proteomic tissue phenotypes of P-DC were characterized by a systems biology approach, further complemented with an array of in vitro biomolecular validations on canonical pathways and functional assessments. Notably, P-DC exhibited remarkably dysfunctional mitochondrial electron carriers, namely, complex I, likely imputable to oxidative stress-induced cardiolipin peroxidation and remodeling.

    Conclusions
    Our studies demonstrated MID is an integral pathophysiology of HF, which exacerbates the pathological remodeling in adults driven primarily by dysfunctional mitochondria and inflamed oxidative stress within LV. CMR exhibits clinical potential as a non-invasive surrogate of myocardial iron status. Moreover, P-DC represents a clinically distinct entity warrants focused investigation. Defective electron transporting activities, specifically at complex I, in the absence of major adult-dominant cardiac remodeling, remain a potential target for treating pediatric HF patients. Our implementation of state-of-the-art multi-omics on explanted human hearts offers a unique opportunity to profile robust biosignatures to differentiate P-DC from adult counterparts and explore children-appropriate pharmaceutical targets.

  • Subjects / Keywords
  • Graduation date
    Fall 2022
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/r3-k66t-3d60
  • License
    This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.