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Hearing Loss and Circulating Markers of Endothelial Dysfunction

Sarant, Julia, PhD; Harris, David, PhD; Mangoni, Arduino, A., PhD; McEvoy, Mark, PhD

doi: 10.1097/01.HJ.0000533798.71848.74
Journal Club

From left: Dr. Sarant is a senior research fellow in audiology and speech pathology at the University of Melbourne, where Dr. Harris is a professor of econometrics. Dr. Mangoni is the head of clinical pharmacology at Flinders University. Dr. McEvoy is an associate professor in clinical epidemiology and biostatistics at the University of Newcastle.

Hearing loss is highly prevalent in older people, affecting around 25 percent of American adults aged 65 to 74 and 50 percent of those aged 75 and older (NIH, 2016). The number of people affected by this disability continues to rise, as does the associated cost that affects individuals in terms of their quality of life and society. Several co-morbidities often accompany age-related hearing loss, including endothelial dysfunction and increased cardiovascular risk, and there is evidence of significantly higher rates of cardiovascular disease among people with hearing loss (Circulation. 2016;134:A19010). Hearing loss has significantly negative effects on quality of life, mental health, and physical function. Therefore, finding potentially modifiable risk factors and markers for hearing loss should be a public health priority. Our world-first study investigated the association between hearing loss and circulating markers for endothelial dysfunction that are potentially modifiable through lifestyle and drug interventions (Otol Neurotol. 2018 Apr;39(4):e280).

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Endothelial cells form the linings of every blood vessel in the body, almost every cell of which requires a blood supply. They comprise a one-cell-thick layer called the endothelium, and are also found in the inner walls of the heart and the lymphatic vessels. The endothelium acts as a barrier between blood and the rest of the body while allowing some chemicals and white blood cells to move from blood to tissue or for waste and carbon dioxide to move from tissue to blood. Endothelial cells also facilitate the movement of plasma and other cell components throughout the vascular system. They are responsible for maintaining homeostasis, creating new blood vessels, and regulating inflammatory processes. Dysfunction of endothelial cells is associated with diabetes and inflammatory, cardiovascular, and immune diseases.

Methylarginines are well-recognized markers of endothelial dysfunction and cardiovascular disease. They have been found to be elevated in the blood serum of people with diabetes, coronary artery disease, kidney disease, hypertension, and other diseases (Ann Med. 2000;32:293; Ann Med; 40:180; J Am Soc Nephrol. 2008;19:388). There is a 54 percent higher prevalence of hearing loss among people with a history of cardiovascular disease than in the general population (JSLHR. 2005;48:473). Over the past six decades, several studies have reported on the significant negative effects of cardiovascular disease on the peripheral and central auditory systems (Am J Audiol. 2010;19:9). Considering the cochlea's rich blood supply and sensitivity to disruptions in blood flow, it is possible that higher-circulating methylarginine concentrations could impair endothelial function—and therefore blood flow to the cochlea—and contribute to hearing loss.

Until now, only one study has examined the relationship between hearing loss and serum concentrations of methylarginines (Ren Fail. 2008;30(9):877). This study on 40 patients with kidney disease found that high-frequency hearing loss was predicted by higher methylarginine blood serum concentrations, providing support for the theory that hearing loss may be caused by vascular problems. Our recent study investigated whether there is a relationship between serum concentrations of methylarginines and hearing loss in a population-based cohort of older adults. We hypothesized that higher serum concentrations of the methylarginines—asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) would be associated with poorer hearing.

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The Hunter Valley Community Study involved 630 participants for audiometric evaluations and serum methylarginine concentration measurement. Pure tone audiometry was used to measure air and bone conduction thresholds at 0.5 to 4 kHz for both ears using standard audiometric procedures in a sound-treated facility. Blood serum was collected at the time of the audiometric evaluation to measure the participant's ADMA and SDMA. Using better ear pure tone average (PTA), the prevalence of hearing loss in this sample was 52 percent: 48 percent of participants had a mild loss, 3.5 percent had a moderate loss, and 0.2 percent had a severe or greater loss. Hearing loss prevalence increased with age. There were more women than men with mild hearing loss (particularly older women), more men than women with moderate hearing loss, and only women with severe hearing loss in the sample.

A statistically significant association was found between higher serum concentrations of ADMA and L-arginine, an ADMA precursor, and greater hearing loss for men, particularly those over 75 years old. This indicates that endothelial dysfunction may be associated with hearing loss across different populations. This finding has potential clinical significance if the association between ADMA and hearing loss is causal, as serum methylarginine concentrations can be modified through pharmacotherapeutic and lifestyle interventions. In contrast, ADMA concentration was not associated with hearing loss for women, but a higher concentration of serum L-arginine was associated with reduced hearing loss in older women (over 70 years old). This finding may reflect gender differences in the role of L-arginine in hearing loss.

More large population-based studies are required to confirm these findings and to investigate whether the relationship between serum methylarginines and hearing loss is causal. If there is found to be a causal relationship, it will be important to conduct further research on the effects of lowering blood serum methylarginines on hearing loss or of bypassing this mechanism by introducing nitric oxide donors. Noting the prevalence of endothelial dysfunction and cardiovascular disease in older people, preventing hearing loss through this mechanism could significantly affect the incidence of hearing loss in this population. It may also be beneficial to investigate whether higher serum methylarginine concentrations may be a useful biomarker to predict hearing loss.

Journal Club Highlight

Serum Methylarginines and Hearing Loss in a Population-based Cohort of Older Adults.

McEvoy M, Harris DC, Mangoni AA, Sarant JZ.

Otol Neurotol. 2018 Apr;39(4):e280-e291.

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