Browsing by Author "Fine, Nowell M."
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- ItemOpen AccessDeterminants and Monitoring of Response to Disease-Modifying Therapy for Transthyretin Amyloidosis Cardiomyopathy: The ATTR-CM Therapy Study(2024-01-24) Shahi, Karan; Fine, Nowell M.; White, James A.; Howlett, Jonathan G.; Miller, Robert JH.Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a heart muscle disease characterized by the accumulation of misfolded transthyretin proteins as amyloid plaques in the myocardial interstitium. In 2020, tafamidis, a medication inhibiting the misfolding of transthyretin, received Health Canada's approval for treating ATTR-CM. However, substantial knowledge gaps persist in delivering optimal care and understanding predictors of response to tafamidis therapy. Over the past few years, there have been significant advancements in the clinical care of ATTR-CM. Improved diagnostic and staging techniques have resulted in higher rates of diagnosis, even among older patients not previously considered for invasive evaluation. Notably, tafamidis is the most expensive cardiovascular medication approved, with a list price of approximately $200,000 per patient per year. While Health Canada has defined criteria for initiating tafamidis, these are directly based on enrolment criteria for the international ATTR-ACT trial and may not fully reflect the current ATTR-CM patient population in the community. This project aimed to determine baseline predictors of adverse events in ATTR-CM patients treated with disease-modifying therapy, providing insights into determinants of prognosis and how markers of disease burden are serially impacted by treatment. The study's findings contribute to the development of evidence-based recommendations for guiding ATTR-CM disease monitoring and establish goals of therapy. These recommendations, rooted in evidence, seek to optimize patient care by offering a structured framework for monitoring ATTR-CM. Conducted as a retrospective cohort study, this research included 145 ATTR-CM patients followed by the Cardiac Amyloidosis Clinic, at the Libin Cardiovascular Institute (UofC). The results presented in this thesis contribute to an evidence-based approach for determining and monitoring the response to tafamidis therapy in ATTR-CM patients. The study reveals multiple parameters across clinical, biochemical, and cardiac imaging domains as predictors of major adverse outcomes (all-cause mortality, cardiovascular mortality and hospitalization). Tafamidis proves effective in attenuating disease progression, and specific baseline parameters can be used to assess variations in treatment. Importantly, initiating treatment during the early stages of the disease is pivotal, underscoring the critical role of early diagnosis. This conclusion emphasizes the imperative nature of timely intervention and ongoing observation in managing patients with ATTR-CM.
- ItemOpen AccessThe Development and Validation of a Novel Non-Invasive Assay Based on Cell Free-DNA to Detect Acute Allograft Rejection After Heart Transplantation(2019-08-22) Pattar, Sabrina Kaur; Greenway, Steven C.; Fine, Nowell M.; Riabowol, Karl T.Immune-mediated injury (rejection) of a transplanted organ is a serious problem that can lead to allograft dysfunction and patient death. The gold standard for diagnosing acute cellular rejection (ACR) after heart transplantation (HT) is the endomyocardial biopsy (EMB), an invasive procedure with significant limitations. Dying cells release fragments of DNA into the circulation and increased levels of donor-derived cell-free DNA (dd-cfDNA) have been associated with ACR. Current methods to measure dd-cfDNA employ single nucleotide polymorphisms (SNPs) but an epigenetics-based assay could also accurately quantify dd-cfDNA in recipient blood. This thesis aimed to validate the use of ventricle-specific methylation patterns in human cfDNA as an alternative and novel biomarker for ACR following HT. We hypothesized that dd-cfDNA released due to ACR-mediated injury could be quantified in recipient plasma based on epigenetic differences and would correlate better with tissue apoptosis than EMB-based rejection. We identified increased cellular apoptosis within the myocardium as the severity of ACR increased, which provided a biological rationale for the use of cfDNA as a biomarker for rejection. We also initiated validation of an alternative sequencing platform and panel of highly polymorphic SNPs, which may improve a previously-established SNP-based assay. Finally, we established a bioinformatic pipeline for the identification of ventricle-specific differentially methylated regions (DMRs). These DMRs underwent retrospective validation using cfDNA samples from adult HT patients, which were associated with a known biopsy-proven rejection grade, to demonstrate the ability of these novel blood biomarkers to non-invasively detect acute rejection following HT. In conclusion, we successfully demonstrated the efficacy of cfDNA as a biomarker for immune-mediated tissue injury and introduced the potential use of two ventricle-specific DMRs for the identification and quantification of cfDNA released from a donated heart due to ACR.
- ItemOpen AccessElectrocardiographic Parameters in the Assessment of Myocardial Fibrosis and Left Ventricular Systolic Function(2016) Narous, Mariam; Exner, Derek V.; Anderson, Todd J.; Fine, Nowell M.; White, James A.Assessment of cardiac structure and function is central to the care of patients with heart disease. Cardiac magnetic resonance (CMR) is the gold standard for such assessment, however it is expensive and oftentimes not readily accessible. We sought to evaluate the utility of electrocardiographic (ECG) and impedance-based parameters in estimating the amount of myocardial scar, left ventricular (LV) systolic function and myocardial deformation. Consecutive patients (n = 241; 42% female; mean age 55 years) undergoing clinical CMR and ECG assessments were recruited. ECG analysis was performed manually, using both the Modified Selvester Score (MSS) and the presence of fractionated QRS (fQRS) signals, and impedance testing using the Non-Invasive Cardiac System (NICaS). While MCS was of value, neither fQRS nor NICaS meaningfully predicted scar extent, LV systolic function. Or the amount of myocardial deformation. These results support additional investigation of the utility of the MSS in estimating cardiac structure and function among patients in whom cardiac imaging is clinically indicated.
- ItemOpen AccessHereditary transthyretin amyloidosis: a case report(2022-06-25) Lee, Angela; Fine, Nowell M.; Bril, Vera; Delgado, Diego; Hahn, ChristopherAbstract Background Hereditary transthyretin amyloidosis is an uncommon multisystem disorder caused by mutation of the transthyretin protein, leading to peripheral neuropathy often with autonomic features, cardiomyopathy, or a mixed phenotype. Multiple other organ systems can be involved with ophthalmologic, renal, hematologic, gastrointestinal, and/or genitourinary symptoms and signs. This often results in assessments by multiple specialists and significant delays before the diagnosis is recognized. With the recent advent of potentially lifesaving therapies, early diagnosis has become even more important. Our case highlights the protean aspects of this disease as well as the difficulty of making this diagnosis, especially in the absence of a clear family history. Case presentation We report the case of a 64-year-old man of East-Asian descent who presented with diarrhea, mild anemia, and symptoms of peripheral neuropathy. Numerous investigations and specialist evaluations did not identify a cause. Progression of neurologic symptoms and the development of new hematologic abnormalities ultimately led to consideration of hereditary transthyretin amyloidosis. The diagnosis was confirmed after re-examining previously acquired gastrointestinal biopsies and pursuing genetic testing, which confirmed a pathogenic mutation in the transthyretin gene. He was subsequently started on a novel gene-silencing therapy. On clinical follow-up 8 months after initiation of therapy, the patient described stabilization of previously progressive numbness, weakness, and weight loss with an unchanged neurologic examination and stable repeat electrophysiologic testing. Conclusions Hereditary transthyretin amyloidosis is a challenging disease to recognize in early stages owing to its multisystem and nonspecific manifestations. Recent approval of novel therapies highlights the importance of early diagnosis before irreversible organ damage occurs.
- ItemOpen AccessPhenotype-based prediction of incident cardiovascular hospitalization and inpatient care costs in patients referred for cardiovascular magnetic resonance imaging: Applications of traditional statistical modelling and machine learning(2021-09-24) Lei, Lucy Y; White, James A; Fine, Nowell M.; Lee, Joon; Quan, Hude; Josephson, Colin B.Background: Cardiovascular disease has an estimated lifetime prevalence of 48% in adults and imposes the highest economic burden on health care systems among noncommunicable diseases. These costs are largely related to chronic disease management, clinical procedures, and hospitalization, particularly for major adverse cardiovascular events (MACE). Importantly, health expenditures incurred by cardiovascular care are expected to increase substantially as the global population ages and life expectancies continue to rise. To improve health system efficiency and resource allocation in preparation for future cardiovascular care needs, it is necessary to improve baseline patient characterization and offer more accurate personalized risk predictions to optimally plan for opportunities to improve cardiovascular health while controlling costs.Aims: The aim of this thesis was to develop and validate models for the prediction of MACE and one-year cumulative inpatient care costs in a large cohort of patients referred for cardiovascular magnetic resonance imaging.Methods: Patients were recruited from the Cardiovascular Imaging Registry of Calgary, a prospective clinical outcomes registry that provides automated linkages of data abstracted from electronic health records, cardiovascular magnetic resonance imaging reports, and patient-reported health questionnaires. These data were used for predictive modelling using both traditional statistical methodologies and machine learning approaches.Results: Random survival forest and Cox proportional hazards models were developed for time-to-event prediction of hospitalization for MACE. Both models achieved time dependent AUCs of 0.83 in holdout validation. Patients with predicted risk in the upper tertile experienced 29- and 21-fold (p < 0.001) increased risk of MACE, respectively. A two-part hurdle model was developed for cost regression to predict one-year cumulative inpatient expenditures following cardiovascular magnetic resonance imaging. When binning the cost predictions into zero-, low-, and high-cost brackets, the model achieved 0.73 precision, 0.76 recall, and 0.74 F1. The best performing machine learning classification model combined predictions from random forest and artificial neural network algorithms to achieve 0.76 precision, 0.82 recall, and 0.79 F1.Conclusions: The results of this thesis demonstrate the prognostic capacity of multi-domain health data and its utility in the development of patient-specific risk models for adverse cardiovascular events and cumulative inpatient care costs. Additionally, while machine learning modelling methodologies offer advantages in handling large health care data sets, the interpretability of traditional statistical models remains valuable for delineating relationships between health-related variables and outcomes.
- ItemOpen AccessPrevalence, incidence and clinical outcomes of epicardial coronary artery disease among transthyretin amyloidosis cardiomyopathy patients(2023-03-08) Hassan, Rana; Miller, Robert J. H.; Howlett, Jonathan G.; White, James A.; Fine, Nowell M.Abstract Background Transthyretin amyloidosis cardiomyopathy (ATTR-CM) patients are often older and may be at risk for obstructive epicardial coronary artery disease (oeCAD). While ATTR-CM may cause small vessel coronary disease, the prevalence and clinical significance of oeCAD is not well described. Methods and results The prevalence and incidence of oeCAD and its association with all-cause mortality and hospitalization among 133 ATTR-CM patients with ≥ 1-year follow-up was evaluated. The mean age was 78 ± 9 years, 119 (89%) were male, 116 (87%) had wild-type and 17 (13%) had hereditary subtypes. Seventy-two (54%) patients underwent oeCAD investigations, with 30 (42%) receiving a positive diagnosis. Among patients with a positive oeCAD diagnosis, 23 (77%) were diagnosed prior to ATTR-CM diagnosis, 6 (20%) at the time of ATTR-CM diagnosis, and 1 (3%) after ATTR-CM diagnosis. Baseline characteristics between patients with and without oeCAD were similar. Among patients with oeCAD, only 2 (7%) required additional investigations, intervention or hospitalization after ATTR-CM diagnosis. After a median follow-up of 27 months there were 37 (28%) deaths in the study population, including 5 patients with oeCAD (17%). Fifty-six (42%) patients in the study population required hospitalization, including 10 patients with oeCAD (33%). There was no significant difference in the rates of death or hospitalization among ATTR-CM patients with and without oeCAD, and oeCAD was not significantly associated with either outcome by univariable regression analysis. Conclusions While oeCAD is prevalent in ATTR-CM patients, this diagnosis is frequently known at time of ATTR-CM diagnosis and characteristics are similar to patients without oeCAD.