• Cardiac lipid metabolism changes in mice after heart failure
• Deleting the potential target enzyme ATGL halts this process
• Lipidomics discovered links between mice and human lipidome remodulation after heart failure
HEART failure occurs when the organ progressively loses its capacity to pump blood to the rest of the body. The condition is typically caused by damage to cardiac tissue through myocardial infarction, coronary artery disease, or genetics. Patients may experience fatigue, shortness of breath, irregular heartbeat, edema, metabolic changes, and kidney dysfunction; comorbidities may include hypertension, obesity, or diabetes.
Cardiovascular diseases, which include heart failure, are the leading cause of death worldwide. Moreover, the global incidence of heart failure is increasing; however, accurate diagnostics and effective therapies both remain elusive.
Characterization of the lipidome – that is, the distribution and concentration of lipid classes and species in the whole body or a specific tissue – has recently emerged as a tool to identify risk factors for cardiovascular diseases and further conditions.
Heart failure is accompanied by an increase in lipid metabolism in adipose tissue, cardiac tissue, and other organs. As a result, the lipidome – which is hypothesized to modulate heart function – is altered. Moreover, a growing body of evidence suggests a key role for cross-tissue/organ communication in physiology and pathology. These processes have not been comprehensively characterized in heart failure.
Hence, lipidomic analyses during heart failure may elucidate the mechanisms of disease, identify novel therapeutic targets, and represent a non-invasive diagnostic tool. To explore these possibilities, an interdisciplinary group of scientists and clinicians from Charité examined lipid metabolism during left-sided systolic heart failure in mice and humans. Their results suggest that lipid metabolism in adipose tissue may regulate cardiac tissue function.
Transverse Aortic Constriction (TAC) in mice: A schematic depicting the constriction of the transverse aortic arch. Bacmeister et al., Basic Res. Cardiol. (2019), doi: 10.1007/s00395-019-0722-5
Heart failure can be replicated in mice by constricting the aorta, the vessel that carries blood from the heart to the rest of the body. Following the procedure, mice exhibit signs of heart failure, including: altered cardiac tissue morphology, reduced cardiac function, and expression of genes linked to cardiac failure. However, mice lacking adipose triglyceride lipase (ATGL) – an enzyme that catalyzes lipid metabolism in adipose tissue – were protected from these deleterious effects.
Lipidomics of cardiac tissue was conducted to investigate the link between the deletion of ATGL and lipid metabolism, lipid composition, and heart failure. The lipidomics analysis identified 225 distinct lipid species from 18 lipid classes: phospholipids such as phosphatidylcholines, phosphatidylethanolamines, and cardiolipins were the most abundant.
ATGL-KO alters the cardiac lipidome during pressure overload: Lipidomics analysis of heart tissue samples (left ventricle) isolated 11 weeks after intervention from wild-type (wt) and ATGL-KO mice with (TAC) and without (sham) heart failure replication. Adjusted p-values are indicated: *p<0.05 vs wild-type sham, **p<0.01 vs wild-type sham. Salatzki & Foryst-Ludwig et al., PGen (2018), doi: 10.1371/journal.pgen.1007171
Following left-sided systolic heart failure, 14 out of the 225 lipid species were upregulated in the murine cardiac tissue samples. Yet, the absence of adipose triglyceride lipase weakened these changes in the cardiac lipid composition.
The largest change was an increase in phosphatidylethanolamine species, lipids which consist of a glycerol backbone attached to one phosphoethanolamine and two fatty acids. High levels of phosphatidylethanolamines have previously been linked to reduced cell membrane integrity and subsequent cell death, and these lipid-mediated processes may also be involved in the pathology of cardiac failure.
Altered lipid species levels in human blood plasma samples: Lipidomics analysis of blood plasma samples from patients with left-sided systolic heart failure (HFrEF) compared against patients without heart failure (control). Salatzki & Foryst-Ludwig et al., PGen (2018), doi: 10.1371/journal.pgen.1007171
To confirm the discovered lipid composition changes in mice, lipidomics was applied to human blood plasma samples from male patients with and without left-sided systolic heart failure. In humans, 147 lipid species from 13 lipid classes were identified. In comparison to the murine tissue samples, phosphatidylcholines, triacylglycerols, and sterol lipids such as cholesterol and cholesteryl esters were the most abundant in human blood plasma.
In patients with heart failure, eight out of the 147 lipid species were upregulated in the blood plasma samples. Three of these were phosphatidylethanolamines – notably the same three phosphatidylethanolamine species as in the cardiac tissue from the mouse model. This is a strong indicator for a link between the blood lipidome and the cardiac tissue lipidome.
The three elevated PE species in mouse and human following heart failure: Molecular structures of the three phosphatidylethanolamines species (PE 16:0;0_18:1;0, PE 16:0;0_18:2;0, and PE 18:2;0_18:0;0) which are elevated in murine cardiac tissue samples and human blood plasma samples following left-sided systolic heart failure.
Overall, this study demonstrates that, in both humans and mice, the lipidome is altered during heart failure. Moreover, the results from murine cardiac tissue suggest that these changes are at least partly regulated by lipid metabolism in adipose tissue, which may represent a therapeutic opportunity. Future work will probe the mechanisms underlying these observations.
Lipid metabolism is altered in many physiological and pathological processes, for example, certain cardiovascular and inflammatory diseases are reflected in plasma lipidome. Lipidomic analyses enable researchers to compare changes in lipid metabolism with biological function. For example, the technique revealed the importance of lipid metabolism in adipose tissue and phosphatidylethanolamine species in the pathology of cardiac failure.
Lipotype Lipidomics can identify differential regulation of lipid species during physiological and pathological processes, including heart failure. These data may describe disease mechanisms, identify therapeutic targets, or serve as a diagnostic or prognostic tool. For example, lipidomics risk score allows to predict risk for cardiovascular diseases and diabetes.
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Charité is one of the largest university hospitals in Europe. Nearly 5,000 researchers are engaged in the development of innovations in the field of medicine with a focus on the interface between basic and patient-oriented research.
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