Browsing by Author "Fine, Nowell"

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    ATTR amyloidosis during the COVID-19 pandemic: insights from a global medical roundtable
    (2021-05-06) Brannagan, Thomas H; Auer-Grumbach, Michaela; Berk, John L; Briani, Chiara; Bril, Vera; Coelho, Teresa; Damy, Thibaud; Dispenzieri, Angela; Drachman, Brian M; Fine, Nowell; Gaggin, Hanna K; Gertz, Morie; Gillmore, Julian D; Gonzalez, Esther; Hanna, Mazen; Hurwitz, David R; Khella, Sami L; Maurer, Mathew S; Nativi-Nicolau, Jose; Olugemo, Kemi; Quintana, Luis F; Rosen, Andrew M; Schmidt, Hartmut H; Shehata, Jacqueline; Waddington-Cruz, Marcia; Whelan, Carol; Ruberg, Frederick L
    Abstract Background The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing the ongoing coronavirus disease 2019 (COVID-19) pandemic has raised serious concern for patients with chronic disease. A correlation has been identified between the severity of COVID-19 and a patient’s preexisting comorbidities. Although COVID-19 primarily involves the respiratory system, dysfunction in multiple organ systems is common, particularly in the cardiovascular, gastrointestinal, immune, renal, and nervous systems. Patients with amyloid transthyretin (ATTR) amyloidosis represent a population particularly vulnerable to COVID-19 morbidity due to the multisystem nature of ATTR amyloidosis. Main body ATTR amyloidosis is a clinically heterogeneous progressive disease, resulting from the accumulation of amyloid fibrils in various organs and tissues. Amyloid deposition causes multisystem clinical manifestations, including cardiomyopathy and polyneuropathy, along with gastrointestinal symptoms and renal dysfunction. Given the potential for exacerbation of organ dysfunction, physicians note possible unique challenges in the management of patients with ATTR amyloidosis who develop multiorgan complications from COVID-19. While the interplay between COVID-19 and ATTR amyloidosis is still being evaluated, physicians should consider that the heightened susceptibility of patients with ATTR amyloidosis to multiorgan complications might increase their risk for poor outcomes with COVID-19. Conclusion Patients with ATTR amyloidosis are suspected to have a higher risk of morbidity and mortality due to age and underlying ATTR amyloidosis-related organ dysfunction. While further research is needed to characterize this risk and management implications, ATTR amyloidosis patients might require specialized management if they develop COVID-19. The risks of delaying diagnosis or interrupting treatment for patients with ATTR amyloidosis should be balanced with the risk of exposure in the health care setting. Both physicians and patients must adapt to a new construct for care during and possibly after the pandemic to ensure optimal health for patients with ATTR amyloidosis, minimizing treatment interruptions.
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    Four-Dimensional Blood Flow Analysis in Patients with Repaired Tetralogy of Fallot: Development of Novel Tools to Analyze Turbulence
    (2023-01-26) Hudani, Ashifa; Garcia, Julio; Greenway, Steven; White, James; Fine, Nowell
    Medical imaging modalities are used every day and everywhere to obtain valuable information on diagnosis and treatment to help improve patient management along with the future outcome for patients. They enable us to see and understand what is happening within our body without invasive procedures or the need for surgery. Furthermore, these imaging modalities can be used for many diseases and abnormalities that occur within the entire human body due to each modality acquiring a unique attribute in the way it interacts with our tissues resulting in a better understanding of the abnormality or the diseases. Some common imaging modalities that are frequently used today include Magnetic Resonance Imaging (MRI), X-Ray, Computed Tomography, and Ultrasound, just to name a few. Due to the unique ability of these imaging modalities to obtain information, much research and technological improvements have been discovered to obtain as much information as we can for the desired questions at hand. However, MRI is one of the imaging modalities that is known to be non-invasive, does not use ionizing radiation, is very versatile, and can produce high-quality images for many diseases and abnormalities. MRI is commonly used to evaluate the function and morphology of the entire heart along with the surrounding vessels. Furthermore, due to the powerful ability of this imaging modality, it can quantify and visualize blood flow enabling us to better understand the underlying pathophysiology of many cardiac diseases. With further research and development, a newly emerging technique within MRI known as 4D Flow MRI can quantify and visualize blood flow in all three directions (X, Y, Z) throughout the cardiac cycle. Hence, 4D Flow MRI provides us with information on the spatial and temporal progression of 3D blood flow within an entire volumetric coverage of any vascular or cardiac region of interest. Moreover, this imaging modality can retrospectively analyze the patterns of blood flow at any location within the volume of interest along with assessing abnormal hemodynamic fluctuations, especially in patients with Congenital Heart Diseases (CHD). However, currently, 2D MRI is the current imaging method that is used for flow analysis within these patient cohorts. This may be due to 2D MRI having a quicker acquisition time, larger signal-to-noise ratio, and a quicker/simpler post-processing time compared to 4D Flow MRI. Although, 4D Flow MRI provides us with additional information that cannot be obtained from 2D MRI which can help with patient management and clinical decision-making among patients with CHD. Hence, this thesis aims to evaluate how 4D Flow MRI can be used to evaluate turbulent kinetic energy (TKE) in the entire heart within patients with rTOF and healthy controls. Currently, there is very little literature evaluating TKE within this patient cohort, however, is seen to be elevated within the heart of this patient cohort. This thesis also aims to compare accelerated imaging techniques including k-t GRAPPA and compressed sensing on TKE measurements within the pulmonary artery and aorta of healthy controls. Currently, there is no research comparing the two techniques. Hence, this aim will provide further insight into if different accelerating techniques impact various hemodynamic measurements. Lastly, this thesis also aims to develop simple visualization techniques for the aorta, pulmonary artery, left atrium, left ventricle, right atrium, and right ventricle to facilitate reporting of hemodynamic parameters obtained from 4D Flow MRI within the entire heart.
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    Importance of blood volume on female cardiac, hemodynamic, and pulmonary responses to endurance exercise
    (2021-03-16) Pentz, Brandon; Montero Barril, David; Jalal Aboodarda, Saied; Raj, Satish; Fine, Nowell; Tyberg, John
    Purpose: The fundamental role of BV on cardiorespiratory responses to exercise have been well studied in young males. However, it is unknown whether these responses can be extrapolated in female populations. Therefore, the purpose of this thesis was to investigate the effect of a 10 % blood withdrawal on cardiac, hemodynamic, and pulmonary responses to exercise in females. Methods: Cardiac function was assessed during exercise using transthoracic echocardiography. Hemodynamic variables were measured using a non-invasive blood pressure monitoring system. Pulmonary variables were assessed in supine, left-lateral tilt position within a LBNP chamber to assess VO2max. BV was determined via the CO rebreathing technique. Submaximal workloads were performed at a constant workload of 100 W. Primary outcomes included LVEDV, SV, Q, HR, and VO2. Results: During submaximal exercise, following blood withdrawal, both LVEDV (P ≤ 0.030) and SV (P < 0.019) were reduced while Q was unchanged (P = 0.139) due to an augmented HR (P < 0.026). MAP (P < 0.015), SBP (P < 0.005), and DBP (P < 0.038) were reduced while VO2 was unaltered (P = 0.250). During maximal exercise, following blood withdrawal, there was a reduction in LVEDV and SV (≥ 10 % decrements, P ≤ 0.009). Peak Q was proportionally reduced (P < 0.001). Blood withdrawal induced a 10 % decrement in VO2peak (P < 0.001). Conclusion: Moderate blood withdrawal in females results in impairment of cardiac filling and SV with compensatory increases in HR to preserve Q at acute, constant load submaximal exercise. Thus, BV determines the relative exercise intensity at submaximal workloads. At maximal exercise, blood withdrawal impairs cardiac filling, output, and aerobic capacity in precise proportion to the magnitude of hypovolemia.
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    Investigating Pulmonary Vascular Disease in Patients with Long COVID using Methylation Patterns in Cell-free DNA
    (2024-06-26) Iqbal, Fatima; Greenway, Steven; Weatherald, Jason; Halloran, Kieran; Fine, Nowell; Gordon, Paul
    Introduction: Coronavirus-19 disease (COVID-19) continues to influence the health and quality of life of Canadians to this day, even after recovering from the initial infection itself. Long COVID is a heterogenous and multi-organ disease that captures a range of symptoms that are prevalent months after infection, including persistent breathlessness (dyspnea for >12 weeks post-infection). Hypoxia and inflammation are important potential mechanisms for long COVID that cause endothelial damage and changes to the pulmonary vasculature which may contribute to unexplained dyspnea. Tissue-specific damage can be characterized using fragments of DNA released into the circulation known as cell-free DNA (cfDNA). Importantly, these fragments retain epigenetic information that can be leveraged to determine the tissue of origin as well as disease-specific methylation changes. Objective: To develop a cfDNA methylation assay to characterize cell-specific damage in PVD groups and delimitate the role of PVD in long COVID. Specific Aims: Aim 1: Identify and validate DMRs for pulmonary cell types. Aim 2: Use Nanopore sequencing to find tissue and disease-specific DMRs. Aim 3: Associate levels of DMRs in patients with PVD and long COVID with clinical presentations. Key Results and Significance: We have validated the specificity of endothelial cell and pulmonary tissue DMRs against a tissue panel to quantify cell-specific injury in patient cfDNA. We have also performed Nanopore sequencing of cfDNA from patients with long COVID, Pulmonary Arterial Hypertension (PAH), and Chronic Thromboembolic Pulmonary Hypertension (CTEPH). We have used this data to demonstrate disease-specific methylation patterning. Our work has also highlighted some gaps to address in order to use the advantages of a PCR-free, Bisulfite-conversion-free and absolute quantification of cfDNA methylation via Nanopore sequencing.
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    P1.4 Hemodynamics of Pulmonary Hypertension: Application of the Reservoir-Wave Approach
    (2015-11-23) Ghimire, Anukul; Andersen, Mads; Burrowes, Lindsay; Bouwmeester, J. C.; Grant, Andrew; Belenkie, Israel; Fine, Nowell; Borlaug, Barry; Tyberg, John
    Abstract Using the reservoir-wave approach, previously we characterized pulmonary vasculature mechanics with multiple interventions in a canine model. In the present study, we measured high-fidelity pulmonary arterial (PA) pressure, Doppler flow velocity, and pulmonary capillary wedge pressure in 11 patients referred for evaluation of exertional dyspnea. The analysis was performed using the reservoir-wave approach; wave intensity analysis was subsequently utilized to characterize the PA wave pattern. Our objective was to identify specific abnormalities associated with pulmonary hypertension. Seven patients with varying PA pressures had reduced pulmonary vascular conductance (i.e., the amount of flow that the lungs can accept per pressure gradient), suggesting that these patients might benefit from pulmonary vasodilator therapy, some even in the absence of markedly elevated PA pressures. Right ventricular (RV) performance was assessed by examining the work done by the wave component of systolic PA pressure. Wave work, the non-recoverable energy expended by the RV to eject blood, varied directly with mean PA pressure. Wave pressure was partitioned into two components: forward-travelling and reflected backward-travelling waves. Among patients with lower PA pressures, we found pressure-decreasing backward waves that aided the RV during ejection, as previously reported in normal experimental animals. Among patients with higher PA pressures, we detected pressure-increasing backward waves that impede RV ejection. We conclude that it is important to measure pulmonary vascular conductance to properly assess the pulmonary vasculature. The reservoir-wave approach and wave intensity analysis may prove to be valuable tools to evaluate RV performance and may facilitate development of therapeutic strategies.
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    Pulmonary Hypertension: Insights From the Reservoir-Wave Approach
    (2016) Ghimire, Anukul; Tyberg, John; Fine, Nowell; Belenkie, Israel; Grant, Andrew
    We employed the reservoir-wave approach to analyze high-fidelity pulmonary arterial (PA) pressure and Doppler flow velocity in 11 patients with varying cardiac diseases. Our specific objectives were to (1) to characterize PA wave pattern and (2) evaluate right ventricular (RV) performance. Wave pressure was partitioned into its forward and backward components. Among patients with lower PA pressures, pressure-decreasing and flow-increasing reflected waves that assist RV ejection were detected. Among the more pulmonary hypertensive patients, pressure-increasing and flow-decreasing reflected waves that impede RV ejection were detected. The four patients with the highest PA pressures showed an early systolic deceleration in flow, which was found to coincide with reflected pressure-increasing, flow-decreasing waves. Wave work done by the RV increased with PA pressure, but expressed as a fraction of total RV work, did not change. The reservoir-wave approach may prove to be a valuable tool to characterize PA-RV interaction and evaluate RV performance.
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    Right ventricular insertion site fibrosis in a dilated cardiomyopathy referral population: phenotypic associations and value for the prediction of heart failure admission or death
    (2021-06-17) Mikami, Yoko; Cornhill, Aidan; Dykstra, Steven; Satriano, Alessandro; Hansen, Reis; Flewitt, Jacqueline; Seib, Michelle; Rivest, Sandra; Sandonato, Rosa; Lydell, Carmen P.; Howarth, Andrew G.; Heydari, Bobak; Merchant, Naeem; Fine, Nowell; White, James A.
    Abstract Background Dilated cardiomyopathy (DCM) is increasingly recognized as a heterogenous disease with distinct phenotypes on late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging. While mid-wall striae (MWS) fibrosis is a widely recognized phenotypic risk marker, other fibrosis patterns are prevalent but poorly defined. Right ventricular (RV) insertion (RVI) site fibrosis is commonly seen, but without objective criteria has been considered a non-specific finding. In this study we developed objective criteria for RVI fibrosis and studied its clinical relevance in a large cohort of patients with DCM. Methods We prospectively enrolled 645 DCM patients referred for LGE-CMR. All underwent standardized imaging protocols and baseline health evaluations. LGE images were blindly scored using objective criteria, inclusive of RVI site and MWS fibrosis. Associations between LGE patterns and CMR-based markers of adverse chamber remodeling were evaluated. Independent associations of LGE fibrosis patterns with the primary composite clinical outcome of heart failure admission or death were determined by multivariable analysis. Results The mean age was 56 ± 14 (28% female) with a mean left ventricular (LV) ejection fraction (LVEF) of 37%. At a median of 1061 days, 129 patients (20%) experienced the primary outcome. Any abnormal LGE was present in 306 patients (47%), inclusive of 274 (42%) meeting criteria for RVI site fibrosis and 167 (26%) for MWS fibrosis. All with MWS fibrosis showed RVI site fibrosis. Solitary RVI site fibrosis was associated with higher bi-ventricular volumes [LV end-systolic volume index (78 ± 39 vs. 66 ± 33 ml/m2, p = 0.01), RV end-diastolic volume index (94 ± 28 vs. 84 ± 22 ml/m2 (p < 0.01), RV end-systolic volume index (56 ± 26 vs. 45 ± 17 ml/m2, p < 0.01)], lower bi-ventricular function [LVEF 35 ± 12 vs. 39 ± 10% (p < 0.01), RV ejection fraction (RVEF) 43 ± 12 vs. 48 ± 10% (p < 0.01)], and higher extracellular volume (ECV). Patient with solitary RVI site fibrosis experienced a non-significant 1.4-fold risk of the primary outcome, increasing to a significant 2.6-fold risk when accompanied by MWS fibrosis. Conclusions RVI site fibrosis in the absence of MWS fibrosis is associated with bi-ventricular remodelling and intermediate risk of heart failure admission or death. Our study findings suggest RVI site fibrosis to be pre-requisite for the incremental development of MWS fibrosis, a more advanced phenotype associated with greater LV remodeling and risk of clinical events.