https://orcid.org/0000-0002-4406-8555
Shows the hypothesis regarding cardiac wasting associated dysfunction, and associated implications for clinical practice and future research development.
Cardiac wasting in chronic diseases
Cardiac wasting (i.e. the loss of heart muscle) has been observed in late stages of several chronic diseases that are linked to whole body cachexia—including heart failure.1 Likewise, this has also been seen in severely malnourished patients with anorexia nervosa.2 Studies that assessed cardiac wasting in preclinical models found that the main mechanisms responsible for cardiac wasting include disrupted cardiomyocyte ultrastructure, fibrosis, and proteolysis.3 Cardiac wasting can occur due to several reasons such as increased levels of inflammatory cytokines and other circulating factors such as oncometabolites and neurohormones, tissue hypoxia, volume overload, chemical stress (including chemotherapy and other anti-cancer therapy), metabolic, and oxidative stress.4,5
In the classical cardiotoxicity inspired approach to cardio-oncology, most preclinical and clinical research is focusing on better understanding of the precise effects of anti-cancer therapy on the heart in patients with cancer and how this may cause increased inflammatory and oxidative stress on cardiomyocytes.6 We strongly believe, however, that cardiac wasting occurs also independent of cardiotoxic cancer therapy and may lead to cardiac dysfunction resembling heart failure.4,7 A better understanding of this phenomenon at the preclinical and clinical level may enrich research in the field of cardio-oncology several-fold in terms of the prevalence of heart failure.
Current knowledge of cardiac wasting in patients with cancer
In 2014, a first, small study retrospectively looking at five patients with cancer found extensive fibrotic areas in the heart muscle of these patients post mortem.8 In 2017, a second retrospective study of 177 patients dying of cancer assessed their autopsy reports found that patients with cachexia vs. patients without cachexia had a 19% lower cardiac mass.9 In 2019, Kazemi-Bajestani et al.10 provided the first prospective evidence of cardiac wasting in patients with cancer. They included a small group of 50 patients with non-small cell lung cancer before chemotherapy administration and followed them up after two–four weeks after completion of chemotherapy administration. They found ∼9% reduced left ventricular (LV) mass after in total of four months of follow-up. Cardiac wasting was associated with reduced global longitudinal strain. Physical function status was not assessed in these patients, and the study was underpowered for a meaningful mortality analysis. Very recently data were published on 300 prospectively included patients with cancer of mostly advanced disease and mixed aetiologies without presence of overt cardiovascular disease at inclusion.7 Cancer patients on average had a 13% lower LV mass than healthy controls, with particularly low LV mass seen in patients with cachexia. During on average four months of follow-up of 90 patients, LV mass declined by 9.3%. Presence of cardiac wasting was found irrespective of anti-cancer therapy (cardiotoxic, non-cardiotoxic therapy, or therapy naïve). Reduced LV mass was associated with reduced physical functioning status (lower 6 min walking distance, hand grip strength, and stair-climbing power) and independently associated with increased all-cause mortality. It is important whether and how LV mass is adjusted since LV mass was only prognostic when regarded as absolute values or adjusted for height.2 When LV mass was adjusted for body surface area (a formula derived from height and importantly also body weight), the prognostic association was not seen anymore—i.e. when one declining weight measure (of LV mass) was adjusted for another weight measure (of body weight) prognostic information is lost.
The reduction of LV mass was associated with thinning of the LV walls, reduction of LV size, and reduced stroke volume. Those patients who had cardiac wasting during follow-up also presented with higher baseline values of interleukin (IL)-6 and (nominally) higher C-reactive protein—whereas tumour necrosis factor (TNF) and IL-1β were not elevated.7
The pathophysiological mechanism behind cancer-associated cardiac wasting is complicated. At the core of the underlying physiology lies a metabolic imbalance leading to increased catabolic shifts in cardiac tissue. Tian et al.11 discovered altered gene expression in cancer-bearing rodents, revealing an up-regulation in brain natriuretic peptide (BNP), a decrease in peroxisome proliferator-activated receptor (PPAR), and a myosin heavy chain (MHC) isoform shift from an ‘adult’ to an ‘embryonic’ phenotype. This isoform shift correlates with amplified glucose utilization, diminished fatty acid oxidation, systolic dysfunction, mitochondrial dysfunction, and a generalized decline in heart function. MHC isoform transition and lower total expression of myosin heavy chain proteins were related with destabilized sarcomeres of cardiac myocytes in a proteomic investigation of a colon-26 (C26) tumour animal model. However, it is important to note that a gap still exists in the area of pathology studies, particularly one delineating the heart-failure gene expression profile indicative of cancer-related cardiac atrophy. Thus, we call for further preclinical and clinical research in this area.
We found that patients with cancer-related cardiac wasting during follow-up also presented with lower stroke volume and with (a probably compensatory) higher heart rate as well as lower blood pressure and more frequent anaemia—resembling changes similar to the ones observed in heart failure.7
Significant reductions in cardiac mass can also be seen in several conditions like weightlessness, extended bed rest, and other states of ventricular unloading. In a study observing healthy individuals undergoing 12 weeks of bed rest, there was a notable decline of 15% in the LV mass index.12 Additionally, de Groot et al.13 reported a 25% drop in LV mass in individuals with spinal cord injury who did not exercise, which begs the question of whether physical inactivity in advanced stages of cancer may be a contributor to cardiac plasticity and overall cardiac atrophy. Future studies need to explore whether cardiac atrophy is a consequence of immobility in these patients or a result of direct cancer effects.
One needs to bear in mind that cardiac mass loss could also be related to the general process of skeletal muscle loss. The heart may be affected as a secondary consequence, alongside skeletal muscle wasting, substantial fat loss linked to anorexia, and overall catabolism. As a result of the wasting disease cascade, cancer cachexia may lead to heart dysfunction. However, in a recent study,14 sarcopenia has even been noted in obese cancer patients indicating that perhaps cardiac atrophy in cancer may be independent of that of skeletal muscle wasting in cancer. Nevertheless, due to potential bilateral effects, it is important to screen patients for muscular wasting as well as cardiac wasting. The use of cardiac imaging techniques combined with skeletal computed tomography scans may elucidate the concurrent wasting of skeletal and cardiac muscle.
Moreover, cardiac wasting is a late-onset phenomenon in cancer patients, therefore, it may be of interest to explore plasma biomarkers. There is evidence that high-sensitivity troponin (hs-Tn) and BNP/NT-proBNP can detect chemotherapy-induced cardiotoxicity. Some inflammatory biomarkers, such as C-reactive protein, TNF, and IL-6, appear to be reliable predictors of cancer cachexia/muscle wasting. Future studies should evaluate the role of hs-Tn and BNP/NT-proBNP in predicting cardiac cachexia.6 Given the complex pathophysiology of cachexia, a panel of biomarkers should be employed for diagnosis, prognosis, and therapeutic response rather than only one highly sensitive, specific biomarker.
Recent studies have highlighted that exercise could stimulate remodelling of the heart through activation of cardiac myocyte gene expression leading to an improvement in cardiac mass and function. Interestingly, Parry and Hayward15 found that when 344 rats were inoculated with MatBIII tumour cells, exercise enhanced LV developed pressure by inhibiting the shift of the cardiac MHC isoform from α to β. Such findings indicate the potential role of exercise in cardiac regeneration and reversal of cancer-mediated cardiac atrophy which may be worthwhile to explore in future studies.
Implication for clinical practice and future research development
Preventing or reversal of cancer-related cardiac wasting requires dedicated attention in future trials given its detrimental effects on quality of life and mortality (Graphical Abstract). To be of value, mechanistic/surrogate endpoints need to portray an important aspect of pathophysiology, should be related to patient prognosis, and potentially undergo sizeable changes in reasonably short periods of time. In addition, such endpoints should be readily assessable in standardized ways with high precision, which is also the case for LV mass when assessed by echocardiography or cardiac magnetic resonance imaging. Such endpoints need to be responsive to appropriate therapy and predict clinical benefits well. Further research is imperative to identify the development and stages of cardiac cachexia in cancer patients and delineate it from cachexia due to chronic illnesses. Ongoing trials [like EMPATICC, NCT05636774 (https://clinicaltrials.gov/study/NCT05636774)] and future trials should help to build knowledge on how predictive changes in LV mass are for the clinical benefit of patients regarding symptoms, quality of life, exercise capacity, and mortality.
Permission statement
The authors declare that all illustrations and figures in the manuscript are entirely original and do not require reprint permission.
Declarations
Disclosure of Interest
M.S.A. reports no conflict of interest. T.R. has received personal fees outside the submitted work from: AstraZeneca, Bayer, Novartis, Pfizer, and Daiichy Sankyo. T.R. is co-founder of Bimyo, a company focusing on the development of cardioprotective peptides. J.L.Z.: speaker honoraria from Pfizer, Novartis, Bayer, and Daichii. M.S.K. has served as an advisory board for Bayer. U.L. has received research grants to the institution from Abbott, Amgen, Bayer, and Novartis.
