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Cardio-metabolic Risk Factors in Chronic Lung Disease and Lung Transplantation

Jeff Park, BHSc1 and Dmitry Rozenberg, MD, PhD2

1Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada

2Division of Respirology, Temerty Faculty of Medicine, University of Toronto; Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada

Metabolic syndrome encompasses a constellation of cardio-metabolic risk factors such as hypertension, diabetes, dyslipidemia, and obesity, and is characterized by the presence of systemic inflammatory milieu associated with increased cardiovascular morbidity.1 Patients with chronic obstructive pulmonary disease (COPD) have multiple comorbidities, with cardio-metabolic risk factors being the most frequently reported comorbidity.2 Nearly half of patients with COPD have a co-existing metabolic syndrome associated with an increase in systemic inflammatory markers and physical inactivity.3 In light of the high burden of cardio-metabolic comorbidities, COPD is characterized as a multi-systemic syndrome with low-grade systemic inflammation.4–6 The implications of metabolic syndrome in COPD extend beyond the negative cardiovascular sequelae and can accentuate airflow obstruction (Figure 1).7

A high burden of cardio-metabolic risk factors has been reported in several chronic lung disease states including interstitial lung disease (ILD), cystic fibrosis (CF) and pulmonary hypertension (PH). In ILD patients, more than half had concomitant hypertension and other metabolic comorbidities, which have been shown to be associated with increased mortality.8 Furthermore, a large cohort study involving over 10,000 ILD patients found that ischemic heart disease and myocardial infarction were independent of any pre-existing cardio-metabolic risk factors, suggestive of an underlying systemic inflammatory process similar to COPD.9 Amongst CF patients, increasing survival has led to a greater emphasis on cardio-metabolic risk factors. Cystic fibrosis-related diabetes (CFRD) is a unique type of diabetes arising from insulin insufficiency secondary to destruction of pancreatic islets.10 More than half of adults with CF develop CFRD, which is associated with a decline in lung function and increased mortality.10 Metabolic syndrome was also commonly observed in a study of 640 patients with PH confirmed by right heart catheterization with a reported prevalence of 39%.11 The REVEAL registry highlighted that comorbidities associated with PH such as hypertension, diabetes, obesity, and concomitant COPD were associated with significant reductions in 6-minute walk distance (6MWD), whereas diabetes and COPD in the PH population were associated with increased mortality risk.12

Patients with end-stage lung disease are surviving longer with increased comorbidities, which has been associated with increased prevalence of metabolic risk factors in lung transplant candidates and recipients. A complex of factors including abnormal energy metabolism and immunosuppressive agents can contribute to the development of new-onset metabolic risk factors following lung transplantation.13–15 Silverborn et al. demonstrated that by three-years post-transplant, 90% of LTx recipients developed at least one metabolic risk factor and 40% developed at least two cardio-metabolic risk factors comprised of hypertension, hypercholesterolemia, or diabetes.13 More recently, Savioli et al. demonstrated that by one-year post-transplant, 84% of the patients without any pre-existing cardio-metabolic risk factors developed at least one risk factor, while 24% met criteria for metabolic syndrome.15 Metabolic syndrome was defined by the presence of three or more criterion including increased waist circumference, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure and fasting glucose.15 Obesity was shown to be an independent risk factor for primary graft dysfunction following lung transplantation, suggesting the role of systemic inflammation in early transplant outcomes.16 Furthermore, a recent abstract from our group presented at the American Thoracic Society Conference in 2021 highlighted the association between increased cardio-metabolic risk factors and lower 6MWD post-lung transplantion.17 Hence, cardio-metabolic risk factors are becoming increasingly relevant in the context of chronic lung disease and lung transplantation and their effects on clinical outcomes requires further study.

Pulmonary rehabilitation is an essential component in chronic lung disease management, which is effective in improving symptoms, exercise capacity and quality of life.18 It is still uncertain how cardio-metabolic risk factors affect responses to pulmonary rehabilitation.2,19,20 In a cohort of 2,962 COPD patients, Crisafulli et al. showed that the presence of any metabolic disease (systemic hypertension, diabetes or dyslipidemia) was negatively associated with improvements in 6MWD after pulmonary rehabilitation [OR= 0.57 95% CI (0.49 to 0.67), p = 0.001].2 A subsequent study found that cardio-metabolic risk factors as defined by the presence of one or more conditions such as hypertension, diabetes and dyslipidemia did not affect 6MWD recovery post-transplant, while another study identified metabolic disease as a positive predictor.19,20 In a randomized controlled trial by Budnevskiy et al. of COPD patients with metabolic syndrome, a tailored pulmonary rehabilitation program compared to standard care alone led to improvement in quality of life as measured by St George’s Respiratory Questionnaire and COPD assessment test. This highlights the benefits of patient-centered education, exercise training and nutritional support in the management of patients with significant comorbidities.21,22 The inconsistencies across the studies may be explained in part by the failure to capture the severity of the metabolic diseases, which were commonly categorized in a dichotomous fashion based simply on the presence or absence of the metabolic risk factor. Furthermore, studies used different methods to define clinically important differences in 6MWD. Further research elucidating the effects of cardio-metabolic risk factors on exercise capacity following pulmonary rehabilitation may be beneficial, but it should be highlighted that evidence from randomized controlled trials suggest that patients with cardio-metabolic risk factors benefit from tailored therapies that address weight loss and physical activity levels.21,22

In summary, cardio-metabolic risk factors and metabolic syndrome are prevalent in chronic lung disease and lung transplant recipients. The underlying systemic inflammatory milieu may contribute to not only adverse cardiovascular complications but also declining lung function and poor quality of life. The literature remains equivocal with respect to the effects of cardio-metabolic risk factors on pulmonary rehabilitation outcomes in chronic lung diseases, and further studies are needed to characterize the clinical implications of these risk factors on rehabilitation response.




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No conflicts of interest
Dmitry Rozenberg receives funding support from the Sandra Faire and Ivan Fecan Professorship in Rehabilitation Medicine