As shown in Table 1, hypertension is considered as one of the most common comorbidities of SSNHL. Animal experiments also showed that the blood flow in different parts of the cochlea was reduced by nearly 80% in hypertensive rats exposed to noise and 50–60% in hypertensive rats fed with an atherogenic diet (27). The cochlea is supplied by the cochlear artery, a terminal artery without any collateral vessels to compensate for any occlusion of the blood vessel. Thrombosis or vasospasm of the internal auditory artery is one of the main hypotheses to explain SSNHL. Hypertension may induce atherosclerotic changes and result in cochlear microcirculation disturbance.

A study elucidated that patients with dysrhythmia showed a significantly higher risk of SSNHL (28). Even after the adjustment of confounders, the incidence of SSNHL in the dysrhythmia group was higher than that in the comparison group. This finding suggests that hemodynamic instability due to dysrhythmia resulting in impaired blood perfusion to the inner ear can lead to SSNHL.

A retrospective cohort study showed that the prevalence of SSNHL was 1.29 per 1,000 person-years among diabetic patients, which was 1.54-fold higher compared with non-diabetic subjects (20). In addition, earlier studies revealed that hearing impairment also occurred in the opposite ear, especially in high frequencies (29). Compared with diabetic patients without SSNHL, the glycated hemoglobin value was significantly higher in diabetes patients with SSNHL, and SSNHL patients with type-2 diabetes had more severe hearing loss (30). Moreover, a cohort study demonstrated that during 14 years of follow-up, a significantly lower percentage of diabetes patients with metformin use developed SSNHL compared with those without metformin intake, indicating that metformin use appeared to reduce the risk of developing SSNHL among diabetes patients (31).

Researchers found that the animal model of type-2 diabetes and obesity exhibited significantly elevated auditory brainstem response (ABR) thresholds. Regarding histological findings, outer hair cell degeneration and spiral ganglion cell loss were present in the middle and basal turns of the cochlear. This study indicates that diabetes and obesity may lead to early sensorineural hearing loss (32).

Microangiopathy may be one of the mechanisms underlying the association between diabetes and SSNHL. Other mechanisms, including upregulation of vascular endothelial growth factor, inducible nitric oxide synthase, and endothelial nitric oxide synthase, may be involved in the pathogenesis of cochlea functional loss (33).

Previous studies have demonstrated that patients with SSNHL had significantly higher plasma concentrations of cholesterol, triglyceride, lipoprotein A, and low-density lipoprotein cholesterol compared with controls (34, 35).

Animal experiments revealed that after a high-fat diet for 4 months, guinea pigs' inner ears showed impaired hearing sensitivity and pathologic alterations of the cochlear, especially in the basal turn and stria vascularis (36). It has also been reported that cholesterol had different distributions among outer hair cell membranes. Furthermore, after being incubated with water-soluble cholesterol, the outer cell's lateral wall stiffness parameter increased, which impaired the activity of the outer hair cells (37). In addition, Sikora et al. found that after being fed a high-fat diet, chinchillas exposed to noise exhibited more severe hearing loss at high frequency and significantly greater hair cell loss than those in chinchillas fed with a normal diet (38).

Overall, the pathophysiological mechanism of SSNHL caused by hyperlipidemia is through the modification of the microstructure of the stria vascularis and the composition and the electromotility of the outer hair cells by elevated cholesterol, thereby increasing the cochlea's vulnerability to noise. Moreover, hyperlipidemia promotes hyperviscosity, contributes to endothelial function damage, and decreases nitric oxide release. Consequently, it promotes the formation of atheromatous plaque, which might cause occlusion of the cochlear artery, therefore resulting in SSNHL (39, 40).

A retrospective cohort study showed that children with iron deficiency anemia (IDA) demonstrated an increased likelihood of SSNHL (25). Another study also confirmed the link of SSNHL with IDA. In this study, absolute latencies for all ABR waves and interpeak latencies (except I-III interval) were significantly longer in children with IDA than in non-anemic infants (54). A population-based study also showed a significantly higher prevalence of prior IDA among participants with SSNHL compared with the controls, especially in those less than 60 years old. The researchers suggested that patients with IDA, especially those younger than 60 years, should be more aggressively surveyed to reduce hearing-related morbidities (26).

In the animal experiment, an electrophysiological study revealed that the incidence of an auditory threshold elevation of more than 15 dB was 31.85% in the iron-deficient (ID) rats, whereas it was unchanged in all the control animals. The main cochlear histopathological changes were strial atrophy and reduction of spiral ganglion cells in ID rats. So the authors concluded that the observed anomalies may be attributed solely to iron deficiency of the cochlear tissue (55).

The main cochlear pathological changes of SSNHL in ID rats were the synchronous abnormal activity of the iron-containing enzymatic, including succinic dehydrogenase and peroxidase, which in turn would disturb cell respiration and initiate peroxidative damage to the inner ear cells, resulting in a significant reduction of spiral ganglion cells and rapid damage of stereocilia of the outer and inner hair cells (56, 57).

It has been reported that 16–40% of leukemia patients had otolaryngological symptoms, such as SSNHL, vertigo, tinnitus, facial paralysis, and infection (58, 59). Among hematologic malignancies, SSNHL has often been described as the initial presentation in patients with acute lymphocytic leukemia. However, recent studies have indicated that both acute and chronic leukemia were associated with SSNHL (60, 61).

Lin et al. (53) reported that during the 20 years, they had identified 14 cases of SSNHL among patients with hematological disorders, i.e., leukemia or aplastic anemia. Most of these patients presented an abnormal mean hearing level, cervical vestibular-evoked myogenic potential test, ocular vestibular-evoked myogenic potential test, and caloric test results, exhibiting a significant sequential decline in inner ear function.

Chae et al. (62) documented a case of chronic myelogenous leukemia with the first manifestation being SSNHL, and the patient's hearing was restored after leukapheresis and chemotherapy without steroids. The authors presumed that cochlear vessel occlusion as a result of elevated blood viscosity may be responsible for this patient's hearing loss.

Numerous studies have demonstrated histopathological changes in the temporal bones of patients with leukemia. These histopathological changes include leukemic infiltration, inner ear hemorrhage, infection (58, 59, 63), and hyperviscosity syndrome (64, 65).

FMD is a simple, non-invasive, and highly repeatable method to assess endothelial function. The mechanism of FMD is that after compression of the brachial artery for some minutes, the increased blood flow can induce shear stress, which can activate the endothelium to release nitric oxide with the consequence of vasodilation. This phenomenon can be monitored by ultrasonography. Diminished FMD is an early sign of subclinical atherosclerosis and is associated with coronary atherosclerosis (105–107). Recently, researchers also found reduced FMD among SSNHL patients (12, 77).

EPCs are circulating cells, and their properties are similar to embryonal angioblasts. They can differentiate into mature endothelial cells. Increased EPCs have been found in case of acute vascular damage such as limb ischemia, acute myocardial infarction, or vascular trauma. By contrast, decreased EPCs were linked to a higher incidence of cardiovascular events (108, 109).

By analyzing peripheral blood CD34⁺KDR⁺CD133⁺ cells, researchers found that the circulating levels of EPCs were much lower in SSNHL patients compared with controls (90). The results of this study confirm the existence of endothelial dysfunction in SSNHL patients.

Increased expression of some molecules is the early evidence of endothelial dysfunction. The activated endothelial cells can increase the expression of soluble ICAM-1 and soluble VCAM-1, and these molecules can mediate leukocyte adhesion to the endothelium and activate atherosclerosis formation (89, 110).

One prospective case–control study showed higher ICAM-1 and VCAM-1 in SSNHL patients (89). However, inconsistent results have been documented by another study, indicating that there was no difference between ICAM-1 and VCAM-1 between SSNHL patients and the controls. The authors considered that the role of soluble adhesion molecules in the pathogenesis of SSNHL remained unclear and needed further investigation (88).

The balanced reactive oxygen species (ROS) and antioxidant system can maintain the normal physiological oxidative status in living organisms. On the contrary, the imbalance between ROS and total antioxidant capacity is thought to be a potential pathogenetic mechanism leading to endothelial dysfunction. If excessive ROS are not buffered by the cellular antioxidants, they can react with cellular macromolecules and promote lipid peroxidation, which may cause DNA damage and induce protein and nucleic acid modifications (111).

Recent studies have reported a significantly higher ROS in SSNHL patients, as well as oxidative stress status, supporting the vascular impairment involvement in ISSNHL etiopathogenesis (91, 112). The microcirculation disturbance due to an ischemic event may relate to increased oxidative stress, which may synergistically account for endothelial damage, especially in terminal microvascular systems (91, 113).

Other findings also reflect the involvement of oxidative stress in SSNHL. In a successive pioneering study, Cadoni et al. described an association between SSNHL and low serum levels of the antioxidant Co-enzyme Q (CoQ) (76).

Hyperhomocysteinemia is considered to be a cardiovascular and thromboembolic risk factor for atheromatous and vascular events (114). Homocysteine can promote platelet aggregation, hypercoagulability, oxidative stress response, endothelial impairment, and smooth muscle cell proliferation (115).

As an important regulator of homocysteine, folate is a coenzyme necessary for one-carbon metabolism. Low levels of folate may contribute to increased plasma levels of homocysteine (92). Lower serum folate and higher homocysteine levels have been found among SSNHL patients than among controls (92).

In general, it is known that endothelial dysfunction has a primary role in regulating vascular tone by modifying lipoproteins, thrombogenesis, and transformation of circulating monocytes into foam cells (82). Moreover, it can counterbalance pro-aggregation and anti-aggregation properties or even regulate coagulation conditions by mediums such as heparin. If endothelial dysfunction exists, the blood supply to the inner ear will be disturbed because of the sudden and transient thrombotic event, which could explain the nature of SSNHL (77, 92).