Browsing by Author "Howlett, Jonathan G."

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    Determinants 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.
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    Integration of longitudinal and circumferential strain predicts volumetric change across the cardiac cycle and differentiates patients along the heart failure continuum
    (2023-10-02) Samuel, T. J.; Oneglia, Andrew P.; Cipher, Daisha J.; Ezekowitz, Justin A.; Dyck, Jason R. B.; Anderson, Todd; Howlett, Jonathan G.; Paterson, D. I.; Thompson, Richard B.; Nelson, Michael D.
    Abstract Background Left ventricular (LV) circumferential and longitudinal strain provide important insight into LV mechanics and function, each contributing to volumetric changes throughout the cardiac cycle. We sought to explore this strain-volume relationship in more detail, by mathematically integrating circumferential and longitudinal strain and strain rate to predict LV volume and volumetric rates of change. Methods Cardiac magnetic resonance (CMR) imaging from 229 participants from the Alberta HEART Study (46 healthy controls, 77 individuals at risk for developing heart failure [HF], 70 patients with diagnosed HF with preserved ejection fraction [HFpEF], and 36 patients with diagnosed HF with reduced ejection fraction [HFrEF]) were evaluated. LV volume was assessed by the method of disks and strain/strain rate were assessed by CMR feature tracking. Results Integrating endocardial circumferential and longitudinal strain provided a close approximation of LV ejection fraction (EFStrain), when compared to gold-standard volumetric assessment (EFVolume: r = 0.94, P < 0.0001). Likewise, integrating circumferential and longitudinal strain rate provided a close approximation of peak ejection and peak filling rates (PERStrain and PFRStrain, respectively) compared to their gold-standard volume-time equivalents (PERVolume, r = 0.73, P < 0.0001 and PFRVolume, r = 0.78, P < 0.0001, respectively). Moreover, each integrated strain measure differentiated patients across the HF continuum (all P < 0.01), with the HFrEF group having worse EFStrain, PERStrain, and PFRStrain compared to all other groups, and HFpEF having less favorable EFStrain and PFRStrain compared to both at-risk and control groups. Conclusions The data herein establish the theoretical framework for integrating discrete strain components into volumetric measurements across the cardiac cycle, and highlight the potential benefit of this approach for differentiating patients along the heart failure continuum.
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    Prevalence, 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.