Cardiac structural and functional alterations in cancer cachexia

  • Author / Creator
    Kazemi Bajestani, Seyyed Mohammad Reza
  • Background: Cancer cachexia is referred to as a wasting condition, with skeletal muscle and fat loss. Although heart atrophy is recognized as a notable component of experimental cancer cachexia models, it has not been characterized in human studies. The contribution of cardiac structural and functional impairment to worsening performance status, fatigue progression and dyspnea, is known in the context of heart failure; however, the pertinent clinical information in cancer cachexia has never been examined. Cancer cachexia still does not have an approved therapy; regulatory agencies claim functional measures such as stair climbing test improvement as a clinical benefit of experimental agents, however, the matter of heart function and structure at baseline and its alteration over time (as a potential source of functional variation) is ignored. In the absence of any clinical evidence for cardiac structure or function changes in cachexia context, two retrospective evaluations of cardiac function were conducted in pursuit of preliminary evidence of either: a) altered cardiac function over time in renal cell carcinoma patients or, b) evidence of concurrent cachexia and abnormally low cardiac mass in cirrhosis patients with or without hepatocellular carcinoma. My major hypothesis through a longitudinal work was that heart is being atrophied and is dysfunctional in parallel to cancer cachexia progression. Methods: Three different clinical projects were considered for my PhD research (two retrospective/chart reviews and one longitudinal cohort study). In all these studies, standard of care computed tomography cross-sectional images were utilized to quantify skeletal muscle and fat. In the longitudinal study, we measured heart systolic [left ventricular ejection fraction (LVEF) and global longitudinal strain] and diastolic function in addition to left ventricular mass at baseline (before start of carboplatin-based therapy) and over time (4 months later) in patients with metastatic non-small cell lung cancer (n=72). Standard questionnaires for assessment of performance status, fatigue and dyspnea also were applied. For the first retrospective study, cirrhotic patients (n=100) with or without hepatocellular carcinoma were studied; values for left ventricular mass were abstracted from available echocardiography reports before liver transplant. For the second retrospective study in renal cell carcinoma patients (n=47), several multigated acquisition scans were gathered over one year of assessment to detect changes in LVEF. Results: For the first time we demonstrated the occurrence of left ventricular mass atrophy in a group of patients with progressive cachexia and non-small cell lung cancer. Atrophy of left ventricular mass (median overall -8.9%, p<0.001) occurred during 112±6 days; this loss was equal or greater than the loss of skeletal muscle (overall -6.2%, p<0.001). Atrophy >8.9% of left ventricular mass associated with loss of skeletal muscle (OR, 95% CI) [4.5 (1.4-14.8) p<0.01] and total adipose tissue [10.0 (2.7-36.7) (p<0.01)]. While LVEF and diastolic function changes over time were not associated with left ventricular mass atrophy, left ventricular mass loss was associated with decreased global longitudinal strain [6.6 (1.9-22.7); p<0.01], worsening of fatigue [6.6 (1.9-22.7) (p<0.01)], aggravated performance status [4.8 (1.3-18.3); p<0.05] and deteriorated dyspnea [9.3 (2.4-35.8); p<0.01]. In non-small cell lung cancer patients, while their performance status at baseline was sufficient to receive chemotherapy, and these patients were potentially eligible for clinical trials, we found different types of cardiac disorders that may lead to confounded functional measures in clinical trials. For instance we found 9 patients (12.8%) to have clinically-relevant cardiac disorders [7 patients with (LVEF <50%)]. Ten (14.3%) other patients showed to have diastolic dysfunction with preserved LVEF. In cirrhotic patients with most depleted left ventricular mass index (>1 SD below sex-specific mean value of left ventricular mass indexed by height2) compared to the patients with average left ventricular mass index, sarcopenia was more prevalent (70.6% vs. 27.3%; 6.4 (1.9–20.7); p = 0.002). Fat loss also showed a trend to be more prevalent in group of patients with low left ventricular mass index. In renal cell carcinoma patients multigated acquisition scan-defined cardio-toxicity appeared in 8/47 (17%) patients. This targeted therapy-induced cardio-toxicity was related to high fat mass at baseline [9.5 (1.1-86.0), p=0.04]; also the percentage of skeletal muscle loss over 1 year in patients with cardio-toxicity was greater than patients without cardiotoxicity [median loss -7.0% versus 0%, respectively; p=0.04]. Conclusion: Dynamic cardiac atrophy is reported for the first time in human patients with progressive cancer cachexia. Cardiac status in terms of structure and function should be recognized in further clinical trials.

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  • Graduation date
    Fall 2017
  • Type of Item
  • Degree
    Doctor of Philosophy
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    This thesis is made available by the University of Alberta Libraries 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.
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  • Citation for previous publication
    • Kazemi-Bajestani SM, Mazurak VC, Baracos V. Computed Tomography-defined Muscle and Fat Wasting are Associated with Cancer Clinical Outcomes. Semin Cell Dev Biol 2016; 54:2-10.
    • Kazemi-Bajestani SM, Becher H, Venner P, North S, Baracos V. High fat mass associates with occurrence of targeted therapy-induced left ventricular ejection fraction reduction in patients with renal cell carcinoma. Clin Nutr. 2017; pii: S0261-5614(17)30117-6.
    • Kazemi-Bajestani SM, Becher H, Montano-Loza AJ, Baracos VE. Skeletal muscle wasting and cardiac structural changes in cirrhotic patients with preserved left ventricular ejection fraction. Poster presentation in 7th International Conference of the Society on Sarcopenia,Cachexia and Wasting Disorders (SCWD), Kobe, Japan, 9-11 December 2013. J Cachexia, Sarcopenia and Muscle (4) 2013; 303.
    • Kazemi-Bajestani SM, Becher H, Butts C, Basappa NS, Smylie M, Joy A, Sangha R, Gallivan A, Chu Q, Baracos V. Development of cancer cachexia-associated cardiac atrophy over time in advanced non-small cell lung cancer: First report in human patients. Presented in Cachexia Conference, Paris, France, December 4th -6th 2015. J Cachexia Sarcopenia Muscle 2015; 6: 462.
    • Kazemi-Bajestani SM, Becher H, Ghosh S, Montano-Loza AJ, Baracos VE. Concurrent depletion of skeletal muscle, fat and left ventricular mass in patients with cirrhosis of the liver. J Cachexia Sarcopenia Muscle 2016; 7:97-9.
    • Kazemi-Bajestani SM, Becher H, Fassbender K, Chu Q, Baracos VE. Concurrent Evolution of Cancer Cachexia and Heart Failure: Bilateral Effects Exist. J Cachexia Sarcopenia Muscle 2014; 5(2):95-104.
    • Kazemi-Bajestani SM, Becher H, Venner P, North S, Baracos VE. Cachexia evolution in renal cell carcinoma patients and its relation with cardiac ejection fraction evaluated by MUGA scan. Oral presentation in cutting edge discovery session in 2nd cancer cachexia conference in Montreal, Canada, 26-28th September 2014. J Cachexi, Sarcopenia and Muscle 6 (1) 2015; 4.
  • Institution
    University of Alberta
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  • Supervisor / co-supervisor and their department(s)