Mechanisms of Cardiac Disorders related to Obesity

Dear Colleagues,

Even before COVID-19, the USA’s obese population had been steadily increasing, according to Centers for Disease Control and Prevention (CDC) [1]. Obesity-related cardiovascular disease morbidity and mortality have been widely studied [2]. Risk factors such as hypertension, dyslipidemia, insulin resistance in type-2 diabetes, atrial fibrillation, cellular hypertrophy, inflammation, and metabolism have been recognized [3]. Understandably, these risk factors are often related to the excessive amount of adipose tissue in the heart.

Excessive adipose tissue increases the release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), sets up insulin-resistance, promotes the production of reactive oxygen species (ROS), and increases LDL while decreasing HDL levels [3]. Over time, these pathophysiological changes can induce the remodeling of myocardium and cardiovascular vessels.

Obesity-induced hypertension has been studied the most, due to the prevalence of hypertension across the nation [4]. According to the CDC, 108 million middle-aged Americans have hypertension (a systolic blood pressure ≥ 130 mmHg or a diastolic blood pressure ≥ 80 mmHg). Close to 500,000 deaths in the US were attributed to hypertension, either as a primary or contributing cause, in 2018. IL-6 and TNF-α contribute to left ventricular hypertrophy and renal dysfunction that consequently affects sodium reabsorption. ROS-mediated oxidative stress and inflammation induce endothelial dysfunction, the key to vascular malfunction. All of these contribute to hypertension.

Another widely studied cardiac disorder in obesity is obesity-induced electrical remodeling of the heart [5]. Incidents of sudden cardiac death (SCD) occur significantly more often in obesity [6,7]. Excessive adipose tissue on the epicardium, especially in the supraventricular area, contributes to altered ion channel expression and function, providing molecular mechanisms to the genesis of atrial fibrillation [8,9]. Altered potassium channel expression and properties also contribute to long-QT in the ventricle [10]. Both atrial fibrillation and long-QT predispose the heart to SCD [11–13].

Although decades of research have revealed important underlying mechanisms of cardiac disorders, many questions remain. First, the majority of obese animals are male. Whether the knowledge learned from these studies can be applied to females is unclear. Since there is a clear difference in the phenotypes of hypertension, hypertrophy, and arrhythmias in males and females, the translational significance of mechanistic studies in male obese animals remains an open question. Second, during the progression of obesity, when the pathophysiological phenotype occurs is unknown. It would help diagnosis if the molecular events causing the early development of the disorders were identified. Rapid advances in molecular and cell technology, such as next-generation sequencing and omics, as well as the induced human stem cell cardiac models, will help us to understand the molecular mechanisms of sex-specific obesity-related cardiac disorders.

References

1. CDC-obesity. New CDC data finds adult obesity is increasing. Available online: https://www.cdc.gov/media/releases/2020/s0917-adult-obesity-increasing.html (accessed on 7 January 2020)
2. Khan, S.S.; Ning, H.; Wilkins, J.T.; Allen, N.; Carnethon, M.; Berry, J.D.; Sweis, R.N.; Lloyd-Jones, D.M. Association of Body Mass Index With Lifetime Risk of Cardiovascular Disease and Compression of Morbidity. JAMA Cardiol. 2018, 3, 280–287, doi:10.1001/jamacardio.2018.0022.
3. Van Gaal, L.F.; Mertens, I.L.; De Block, C.E. Mechanisms Linking Obesity with Cardiovascular Disease. Nature 2006, 444, 875–80.
4. CDC-hypertension. Facts About Hypertension in the United States. https://www.cdc.gov/bloodpressure/facts.htm (accessed on 7 January 2020).
5. Lavie, C.J.; Pandey, A.; Lau, D.H.; Alpert, M.A.; Sanders, P. Obesity and Atrial Fibrillation Prevalence, Pathogenesis, and Prognosis. Am. Coll. Cardiol. 2017, 70, 2022–2035, doi:10.1016/j.jacc.2017.09.002.
6. Duflou, J.; Virmani, R.; Rabin, I.; Burke, A.; Farb, A.; Smialek, J. Sudden death as a result of heart disease in morbid obesity. Hear. J. 1995, 130, 306–313, doi:10.1016/0002-8703(95)90445-x.
7. Finocchiaro, G.; Papadakis, M.; Dhutia, H.; Cole, D.; Behr, E.R.; Tome, M.; Sharma, S.; Sheppard, M.N. Obesity and sudden cardiac death in the young: Clinical and pathological insights from a large national registry.  J. Prev. Cardiol. 2018, 25, 395–401, doi:10.1177/2047487317751291.
8. Fox, C.S.; Parise, H.; D’Agostino, S.R.B.; Lloyd-Jones, D.M.; Vasan, R.S.; Wang, T.J.; Levy, D.; Wolf, P.A.; Benjamin, E.J. Parental Atrial Fibrillation as a Risk Factor for Atrial Fibrillation in Offspring. JAMA 2004, 291, 2851–2855, doi:10.1001/jama.291.23.2851.
9. McCauley, M.D.; Hong, L.; Sridhar, A.; Menon, A.; Perike, S.; Zhang, M.; Da Silva, I.B.; Yan, J.; Bonini, M.G.; Ai, X.; et al. Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation. Arrhythmia Electrophysiol. 2020, 13, doi:10.1161/circep.120.008296.
10. Huang, H.; Amin, V.; Gurin, M.; Wan, E.; Thorp, E.; Homma, S.; Morrow, J.P. Diet-induced obesity causes long QT and reduces transcription of voltage-gated potassium channels. Mol. Cell. Cardiol. 2013, 59, 151–158, doi:10.1016/j.yjmcc.2013.03.007.
11. Eisen, A.; Ruff, C.T.; Braunwald, E.; Nordio, F.; Corbalán, R.; Dalby, A.; Dorobantu, M.; Mercuri, M.; Lanz, H.; Rutman, H.; et al. Sudden Cardiac Death in Patients with Atrial Fibrillation: Insights From the ENGAGE AF‐TIMI 48 Trial. Am. Hear. Assoc. 2016, 5, doi:10.1161/jaha.116.003735.
12. Meyer, J.S.; Mehdirad, A.; I Salem, B.; Kulikowska, A.; Kulikowski, P. Sudden arrhythmia death syndrome: importance of the long QT syndrome. Fam. Physician 2003, 68, 483–8.
13. Berul, C.I. Neonatal long QT syndrome and sudden cardiac death. Pediatr. Cardiol. 2000, 11, 47–54, doi:10.1016/s1058-9813(00)00035-7.

Prof. HanGang Yu
Guest Editor

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• obesity-related
• sex-specific
• cardiovascular disease associated morbidity and mortality
• cardiac disorders
• hypertrophy
• gene expression