Interaction between adipose tissue and sympathetic neurons contributes to cardiac arrhythmia

A recent study published in Cell Reports Medicine, found a link between the frequency of apnea events during the rapid eye movement (REM) phase and the degree of verbal memory impairment in older adults at risk for developing Alzheimer's disease. Verbal memory refers to the cognitive ability to retain and recall information presented verbally or in written form, and is particularly vulnerable to Alzheimer's disease.

A study by a group of scientists from China examined the independent connections between epicardial adipose tissue and the sympathetic nervous system with cardiac arrhythmia using in vitro co-culture of adipocytes, cardiomyocytes and sympathetic neurons. They found that the adipose tissue-nervous system axis plays an important role in arrhythmogenesis.

Abnormalities in the formation and conduction of electrical impulses due to electrical or structural abnormalities in the heart can lead to cardiac arrhythmias. These abnormalities may be either genetic or related to acquired heart disease. Studies have shown that sympathetic neurons play a significant role in the pathogenesis of cardiac arrhythmia. Activation of abnormal electrical circuits and disturbances in ventricular repolarization due to inappropriate stimulation of the sympathetic nervous system have been associated with ventricular fibrillation and tachycardia, atrial fibrillation, and even cardiac death.

Recent studies have also shown that epicardial adipose tissue is strongly associated with the occurrence of atrial fibrillation, ventricular fibrillation and ventricular tachycardia. In addition, because epicardial adipose tissue is adjacent to the myocardium without tissue separating their contact, inflammatory cytokines and adipokines secreted by epicardial adipose tissue can alter electrical and cardiac structure. However, it remains unclear whether epicardial adipose tissue and sympathetic neurons interact and how their interaction influences arrhythmogenesis.

About the Study In the present study, the researchers circumvented the limitations presented by the lack of suitable models of human diseases and the difficulties in obtaining and propagating sufficient amounts of cardiac, neural and adipose tissue by generating cardiomyocytes, adipocytes and sympathetic neurons in vitro from stem cells and establishing models of co- culture to study the interactions between epicardial adipose tissue and sympathetic neurons and their effect on cardiomyocytes.

Plasma samples were obtained from the peripheral vein and coronary sinus of 53 participants, including healthy controls and patients with paroxysmal or persistent atrial fibrillation. Epicardial adipose tissue has also been obtained from patients with persistent atrial fibrillation who have undergone open heart surgery.

Human pluripotent stem cells and induced pluripotent stem cells derived from adipogenic stem cells, human embryonic stem cells and embryonic fibroblasts have been used to generate cell lines and cultures. A sequential induction strategy was used to generate sympathetic neurons, where nerve cells were derived from human pluripotent stem cells and then cultured in differentiation medium.

Adipogenic stem cells were cultured in adipocyte differentiation medium to perform adipocyte differentiation and obtain epicardial adipose tissue. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to measure the expression of white, brown, and beige adipose tissue markers. A two-dimensional monolayer differentiation technique was used to obtain cardiomyocytes from human pluripotent stem cells.

Results Results showed that cardiomyocytes cultured with epicardial adipose tissue and sympathetic neurons, but not either, exhibited significant electrical abnormalities, an arrhythmic phenotype, and abnormalities in calcium ion (Ca2+) signaling.

In addition, the study showed that leptin secreted by epicardial adipose tissue can activate the release of neuropeptide Y by sympathetic neurons. This neuropeptide binds to the Y1 receptor on cardiomyocytes and causes cardiac rhythm abnormalities by affecting the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) and the sodium (Na2+)/calcium (Ca2+) exchanger.

Conclusion Overall, the results indicated that interactions between epicardial adipose tissue and sympathetic neurons lead to an arrhythmic phenotype in cardiomyocytes. The study found that this phenotype is caused by stimulation of sympathetic neurons by leptin secreted by adipocytes, leading to the release of neuropeptide Y. This neuropeptide binds to the Y1 receptor and affects the activity of CaMKII and the Na2+/Ca2+ exchanger, causing abnormal heart rhythms.