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Endothelial function and cardiovascular risk in patients with Idiopathic Sudden Sensorineural Hearing Loss
Atherosclerosis 225 (2012) 511e516
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Endothelial function and cardiovascular risk in patients with Idiopathic Sudden Sensorineural Hearing Loss Marco Matteo Ciccone a, *, Francesca Cortese a, Mariangela Pinto a, Concetta Di Teo a, Fara Fornarelli a, Michele Gesualdo a, Antonia Mezzina b, Evelina Sabatelli b, Pietro Scicchitano a, Nicola Quaranta b a b
Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy Section of Otolaryngology, Department of Ophthalmology and Otolaryngology, University of Bari, Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 July 2012 Received in revised form 1 October 2012 Accepted 2 October 2012 Available online 11 October 2012
Objective: To evaluate cardiovascular risk factors and pre-clinical atherosclerosis in subjects affected by Idiopathic Sudden Sensorineural Hearing Loss (ISSHL). Methods: In this study, 29 ISSHL patients and 29 healthy controls were evaluated. All of the patients underwent a complete audiovestibular and clinical evaluation. Carotid intima-media thickness (C-IMT) and flow-mediated dilation (FMD) of the brachial artery were assessed as early markers of atherosclerosis. Results: Our results showed that FMD was significantly lower in the ISSHL patients than in the controls (5.6 1.6% vs. 7.7 3.7%, p < 0.01). Moreover, the total cholesterol and low density lipoprotein cholesterol were significantly higher in the ISSHL patients than in the controls (p < 0.05). The two groups did not differ with regards to C-IMT and other cardiovascular risk factors. Vestibular involvement was shown to be associated with lower FMD values (4.1 1.7% vs. 5.8 1.5%, p < 0.05). No relationship was found between C-IMT and vestibular involvement. Finally, multiple logistic regression highlighted the finding that only FMD values seemed to predispose individuals to developing ISSHL (p ¼ 0.03, OR: 1.4). Conclusions: ISSHL seemed to be associated with vascular endothelial dysfunction and an increased cardiovascular risk, which supports the hypothesis of a vascular aetiology for this disease. Ó 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cardiovascular risk Idiopathic Sudden Sensorineural Hearing Loss Carotid intima-media thickness Flow-mediated dilation
1. Introduction Idiopathic Sudden Sensorineural Hearing Loss (ISSHL) is commonly defined as a hearing loss of at least 30 dB over 3 contiguous test frequencies occurring within a 72-h period [1]. The estimated incidence of ISSHL is approximately 10/100,000 person-yrs, which is equally distributed between gender and sides affected [2]. Although approximately 60% of the patients undergo a spontaneous full or partial recovery, permanent deafness remains in a significant percentage [3]. It is hypothesised that ISSHL is caused by damage to the cochlea, the cochlear nerve, the sound transmission system from the cochlea to the brain, or any other portion of the central auditory nervous system. Despite detailed investigation, the main cause remains unknown in most cases [4]. Several theories have attempted to explain the pathogenesis of ISSHL. The vascular hypothesis suggests that ISSHL is a result of vascular disruption and subsequent ischaemia of the above
* Corresponding author. Piazza G. Cesare 11, 70124 Bari, Italy. Tel.: þ39 080 5478791; fax: þ39 080 5478796. E-mail address: [email protected] (M.M. Ciccone). 0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.024
mentioned structures [5]. Because a recurrence of ISSHL in hypertensive, diabetes and dyslipidaemia patients has been observed, atherosclerosis and its associated risk factors may play a role in ISSHL pathogenesis [6]. The carotid intima-media thickness (C-IMT) and flow-mediated dilation (FMD) of the brachial artery represent early indices of subclinical atherosclerosis, which is associated with coronary atherosclerosis [7e10]. Both C-IMT and FMD are simple, noninvasive and useful diagnostic tools for the assessment of individual cardiovascular risk. The aim of our study was to use C-IMT and FMD to assess the cardiovascular status of ISSHL patients and to compare the results with those of subjects with normal hearing. 2. Materials and methods 2.1. Study population In this study, 29 consecutive subjects suffering from ISSHL [19 males, mean age: 54 15 yrs] and 29 control subjects (18 males, mean age: 46 16 yrs) were investigated.
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ISSHL diagnosis was defined as a hearing loss of at least 30 dB in three contiguous frequencies occurring within a 72-h period [1]. The exclusion criteria for ISSHL patients were as follows: fluctuating cochlea-vestibular dysfunction suggestive of endolymphatic hydrops (history of vertigo with either fluctuating hearing loss, aural pressure or episodic tinnitus preceding the ISSHL episode); cerebello-pontine angle pathology at MRI; a history of otologic surgery; head and/or neck trauma or barotrauma in the 10 weeks prior to ISSHL diagnosis; MRI findings suggestive for congenital cochlear malformations; otitis media in the last 10 weeks; neurologic disorders predisposing to deafness; recent use of ototoxic medications; neoplasm within the previous two years; or other major diseases (such as heart failure, severe lung disease, or liver or renal dysfunction). The control subjects had normal bilateral hearing (audiometric values in normal ranges according to age) and no history of cardiovascular diseases. The subjects underwent a general physical examination, assessment of laboratory blood parameters and an audiovestibular and ultrasound (C-IMT and FMD) evaluation. Patients were informed about the aim of the study and signed consent forms. The study was approved by the Institutional Review Board of Bari University General Hospital and carried out in accordance with the principles of the Helsinki Declaration. 2.2. Clinical and laboratory evaluation The demographic and clinical characteristics are shown in Table 1. Height (cm), weight (kg) and blood pressure were measured, and body mass index (BMI) (kg/m2) was calculated. A fasting blood sample was obtained for measuring plasma glucose, total cholesterol (TC), high (HDL-C) and low (LDL-C) density lipoprotein cholesterol, triglycerides (TG), fibrinogen, erythrocyte sedimentation rate (ESR), pro-thrombin international normalised ratio (PT-INR) and haematocrit. The patients were classified as follows: hypertensive in the case of systolic/diastolic blood pressure values 140/90 mmHg, or presently using anti-hypertensive medication [11]; dyslipidaemic when TC 200 mg/dl, LDL-C 130 mg/dl, HDL-C < 45 mg/dl, TG 150 mg/dl or presently using lipid-lowering agents [11]; diabetic when fasting glucose level was 126 mg/dl or presently undergoing pharmacologic treatment [11]; and obese or overweight when BMI was 30 kg/m2 or ranged from 25 kg/m2 to 29.9 kg/m2, respectively [11]. Each participant was considered a “current daily smoker” if he or she had regularly smoked at least 5 cigarettes/day during the previous 3 months or had stopped smoking less than 1 year before his/her admittance to our department [11]. 2.3. Audiovestibular investigation All of the patients underwent a standard evaluation that consisted of a pure-tone speech audiometry, impedance audiometry, otoacoustic emissions (OAE), bithermal caloric testing of the vestibular function, auditory brainstem response (ABR), vestibular evoked myogenic potentials (VEMPs) and MRI of the internal auditory canal and posterior cranial fossa. The air conduction puretone average (PTA) was obtained by averaging the air conduction thresholds at 0.25, 0.5, 1, 2, 3, 4 and 8 kHz. Pure-tone and speech audiometry were tested every 48 h until hospital discharge. Hearing improvement was calculated as a relative improvement of hearing thresholds using the contralateral ear as the baseline. All of the patients were treated with the standard sudden deafness protocol, which included carbogen (95% CO2 and 5% O2) inhalation, pentoxifylline, vitamin C, magnesium and oral steroids (prednisone
Table 1 The demographic and clinical characteristics of the study populations (patients and controls).
Men Age (yrs) BMI (kg/m2) Total cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglycerides (mg/dl) Fasting blood glucose (mg/dl) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Smoking Arterial hypertension Diabetes Dyslipidaemia PT-INR HCT (%) Fibrinogen (mg/dl) ESR (mm/h) FMD (%) Mean C-IMT (mm) Right C-IMT (mm) Left C-IMT (mm) Statins Nitrates Angiotensin-converting enzyme inhibitors Beta blockers Angiotensin receptor blockers Calcium channel blockers
ISSHL group (n ¼ 29)
Control group (n ¼ 29)
P-value
19 (66) 54 15 28 5 188 33 48 10 118 27 109 45 96 24
18 (62) 46 16 26 6 171 29 49 13 101 28 105 51 97 18
0.78 0.07 0.21 0.04 0.74 0.02 0.77 0.46
129 14
125 11
0.17
84 8
80 9
0.08
7 (24) 17 (58) 3 (10) 12 (41) 1.09 0.22 40 7 290 71 15 15 5.6 1.6 0.64 0.15 0.64 0.19 0.64 0.14 10 (34%) 0 (0%) 10 (34%)
4 (14) 12 (41) 5 (17) 11 (38) 1.07 0.15 38 6 280 68 15 10 7.7 3.7 0.67 0.16 0.67 0.16 0.68 0.18 10 (34%) 0 (0%) 9 (31%)
0.5 0.29 0.7 1.00 0.75 0.19 0.67 0.32 0.005 0.61 0.43 0.7 1.000 1.000 0.5
6 (21%) 7 (24%)
8 (28%) 4 (14%)
0.38 0.25
5 (17%)
4 (14%)
0.5
The data are given as the means standard deviation or numbers and percentages; p < 0.05. BMI: body mass index; C-IMT: common carotid intima-media thickness; ESR: erythrocyte sedimentation rate; FMD: flow-mediated dilation; HCT: haematocrit; HDL-C: high density lipoprotein cholesterol; ISSHL: Idiopathic Sudden Sensorineural Hearing Loss; LDL-C: low density lipoprotein cholesterol; PT-INR: pro-thrombin international normalised ratio.
at 1 mg/kg per day). Patients who required specific therapy for diabetes, hypertension or dyslipidaemia were treated in association with the proposed standard therapy. 2.4. Carotid IMT evaluation For the C-IMT evaluation, the patients were placed in the supine position; their neck was extended and contralaterally turned approximately 45 . The C-IMT was defined as the distance between the lumen-intima and media-adventitia borders of the vessel, which were ultrasonographically identified by a double hypoechoic line [12]. First, we explored the carotid arteries to exclude the possible presence of an atherosclerotic plaque. Afterwards, we bilaterally calculated the C-IMT with scans of the lengthwise axis. The C-IMT value was obtained as the arithmetical mean of the values calculated from the following three zones: 1. Proximal zone: approximately 2 cm above the flow-divider; 2. Distal zone: approximately 1/2 cm above the flow-divider; 3. Middle zone. 2.5. Brachial artery FMD evaluation Endothelial function was assessed by FMD with a highresolution ultrasonograph (Philips Sonos 5500) connected to an image analysis system certified by the CNR of Pisa (MVE II). A long
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axis projection of the brachial artery at the level of the anteecubital fossa was performed by the same blinded physician in a quiet and temperature controlled (22e24 C) room. The electronic probe was positioned 4e5 cm above the elbow to obtain a longitudinal vascular scan of the right brachial artery. The probe was maintained in the correct position by a mechanical arm. The baseline diameter of the brachial artery was measured from the anterior to the posterior intima for 1 min. After resting for 1 min, a sphygmomanometer cuff was placed near the transducer on the upper arm and then inflated to 50 mmHg above the systolic blood pressure (200e 220 mmHg) for 5 min. The cuff was then rapidly deflated. A reactive brachial artery hyperaemia was initiated, and the diameter of the artery was recorded for 3 min. The patient rested for 5 min; reactive hyperaemia and the maximum flow velocity in the brachial artery was obtained with pulseewave Doppler. The sample volume was obtained from the centre of the artery and a correction angle at 70 , at rest. The data were collected during the first 15 s after cuff deflation, and the average of 3 measurements were taken. The maximum velocities that were considered normal were between 50 and 70 cm/s. Reactive hyperaemia was calculated as the ratio between the maximum velocity and the baseline [10]. All of the measurements were performed within 24e48 h from the beginning of the audiovestibular investigation and the start of therapy. 2.5.1. Statistical analysis The data are given as mean values standard deviation. Categorical variables are given as frequencies and percentages.
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Between-group comparisons were analysed by t-test for independent samples or t-test for matched pair samples if the distribution was normal, as determined by the KolmogoroveSmirnov test and the Lilliefors test. As for nonparametric methods, we used the ManneWhitney U test for two independent samples or the Wilcoxon Test for dependent samples. Frequencies were compared using the Chi-squared or Fisher’s exact test. Correlation analysis was performed with the Spearman rank order correlation. Logistic regression analyses were used to assess the association of variables with ISSHL, and odds ratios (ORs) with their 95% confidence intervals (CIs) were calculated. P < 0.05 was considered statistically significant. Analyses were performed using STATISTICA 7 software (StatSoft Inc., Tulsa, Oklahoma). 3. Experimental results The data obtained are shown in Table 1. According to our results, the TC and LDL-C values were significantly higher in the ISSHL patients than in the controls (188 33 mg/dl vs. 171 29 mg/dl, p < 0.05). No significant differences were found with respect to the C-IMT values (both right and left C-IMT) (p ¼ ns). Significantly lower FMD values were found in ISSHL patients compared with controls (5.6 1.6 vs. 7.7 3.7, p < 0.01); however, these values were not associated with hearing loss in the affected ear (p ¼ ns, Fig. 1A). A significant correlation (p ¼ 0.02) was found between the PTA of the contralateral ear and FMD values (Fig. 1B).
Fig. 1. A: Correlation between pure-tone average (PTA) of the affected side at admission and flow-mediated dilation (FMD) of the brachial artery. B: Correlation between PTA of the contralateral ear at admission and FMD. C: Correlation between Delta (PTA affected ear e PTA contralateral ear) and PTA contralateral ear. D: Correlation between PTA of the affected ear at admission and at discharge.
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The degree of hearing loss, which was calculated as the PTA of the affected ear minus the PTA of contralateral ear, was inversely correlated with the PTA of the contralateral ear (p ¼ 0.02). That is, patients with higher degrees of hearing loss had better contralateral PTA (Fig. 1C). A statistically significant link was found between vestibular involvement and lower FMD values, which was indicative of endothelial dysfunction (p < 0.05); however, no correlations were found among the presence of tinnitus, aural fullness, vertigo, contralateral stapedial reflexes, pathological ABR, VEMPs or OAE compared with FMD and C-IMT values (p ¼ ns) (Table 2). We observed a statistically significant increase in C-IMT values in dyslipidaemic patients (p ¼ 0.03) as well as lower FMD values in hypertensive patients (p ¼ 0.02, Table 2). Moreover, patients with sudden deafness of the left ear had lower FMD values than those affected on the right side (4.9 1.3 vs. 6.3 1.6, p ¼ 0.04); however, these groups had similar C-IMT values (0.66 0.1 vs. 0.62 0.2, p ¼ ns). At discharge (after approximately 10 days), we recorded a significant improvement in the hearing level of the overall population (mean PTA at admission vs. mean PTA at discharge: 60 22 dB vs. 40 23 dB, p < 0.001). The degree of hearing loss at admission could be considered an important prognostic factor for these patients, showing a direct relationship between the hearing loss at admission and at discharge (r ¼ 0.62, p < 0.001, Fig. 1D). Finally, the multiple logistic regression highlighted that only FMD values seemed to be related to ISSHL development (OR: 0.663, p ¼ 0.022, Table 3). That is, in patients suffering from ISSHL, a lower FMD value could independently explain the reduction in hearing. 4. Discussion ISSHL is a very interesting but not yet well-defined clinical condition. Several hypotheses have attempted to explain its pathogenesis [13]. According to the viral theory, ISSHL is due to a herpes simplex virus infection; however, no specific serological profiles or response to antiviral treatment has been reported [14]. Others have hypothesised that ISSHL is an immune-mediated disease due to its response to steroids. Nevertheless, impaired immunity and/or clinical evolution that is compatible with an autoimmune cause are not observed in every case [15,16]. The cochlear membrane rupture theory postulates that a possible perilymph fistula, due to physical effort, barotrauma or a Valsalva manoeuvre, may be the cause of ISSHL [17,18]. ISSHL could also be the result of an ear microcirculation alteration due to genetic pro-thrombotic susceptibility or cardiovascular risk factors [5e7]. A recent multicentre case-control study demonstrated that the sole predictive factor of final hearing
loss/impairment was the severity of the initial hearing loss [19]. A systematic review [20] showed a vascular aetiology for ISSHL in only 2.8% of patients, while 71% of them remain “idiopathic”, even though other evidence supports the vascular involvement theory at the base of ISSHL [19,20]. A higher blood viscosity may determine damage in ear microcirculation that can produce chronic hearing loss [21,22]. Our group has already [23,24] demonstrated an increased expression of adhesion molecules and a reduced percentage of circulating endothelial progenitor cells in ISSHL patients. Furthermore, Balletshofer et al. [25] found that 5 of 6 ISSHL patients had evidence of endothelial dysfunction, which confirms that a microcirculation disorder is involved in the pathogenesis of the disease. An endothelial dysfunction could predispose one to the development of a pro-thrombotic state due to the increase in the vascular wall, even at the level of the ear [23,24]. It is able to counterbalance pro-aggregation and anti-aggregation properties, or it is even able to balance coagulation conditions by means of factors such as heparin. When the endothelium cannot explicitly perform its own duties, adhesion molecules [23], endothelial progenitor cells [24] and, consequently, pro-inflammatory vascular conditions could alter the blood supply to the ear because of the sudden and transient thrombotic event, which could explain the nature of ISSHL. Considering that the cochlear vascular tree is a terminal type, an abrupt interruption of vascular flow due to endothelial damage could impair cochlear membrane functions. FMD, acting as a clear early marker of endothelial dysfunction, could help in identifying patients at a high risk for ISSHL. There is an increased rate of previous cardiovascular disease in ISSHL patients [25e27]. Aimoni et al. [28] found that the risk of ISSHL increased with the number of cardiovascular risk factors, and a similar case-control study [18] highlighted the fact that 12% of ISSHL patients had a history of cardiovascular disease, compared with only 3% of controls. Furthermore, Ballesteros et al. [26] found higher rates of hypertension, diabetes and previous cardiovascular disease in ISSHL patients. Furthermore, two large Taiwanese and Japanese population surveys demonstrated a higher incidence of hypertension and diabetes in ISSHL patients and a greater risk for stroke in patients with a history of ISSHL [27,29]. Our results confirmed that ISSHL patients were at higher cardiovascular risk, which suggests the vascular genesis of cochlear damage. Compared with age- and sex-matched controls, ISSHL patients had significantly higher levels of TC and LDL-C, and 41% of these patients met the criteria for dyslipidaemia diagnosis [11]. The two groups did not differ according to traditional cardiovascular risk factors (arterial hypertension, diabetes and dyslipidaemia, p ¼ ns, Table 1). Moreover, we found significantly lower FMD values in ISSHL patients than in the control group (5.6% vs. 7.7%, p < 0.01), and similar C-IMT
Table 2 The influence of symptoms and pathological signs on flow-mediated dilation and common carotid intima-media thickness. FMD (%) Presencea Tinnitus (n ¼ 27) Fullness (n ¼ 21) Vertigo (n ¼ 5) CSR (n ¼ 22) ABR (n ¼ 15) VEMPs (n ¼ 8) OAE (n ¼ 3) Vestibular involvement (n ¼ 4) Dyslipidaemia (n ¼ 12) Diabetes (n ¼ 3) Hypertension (n ¼ 17)
5.6 5.8 5.3 5.8 5.2 6.1 5.1 4.1 5.2 6.1 5.05
1.6 1.8 1.7 1.2 1.9 2.2 0.7 1.7 1.7 0.2 1.2
C-IMT Absencea 5.1 5.06 5.7 5.1 6.1 5.4 5.7 5.8 5.9 5.6 6.4
0.2 0.1 0.7 2.6 1.3 1.4 1.7 1.5 1.6 1.7 1.8
P-value
Presencea
0.37 0.21 0.64 0.1 0.25 0.73 0.43 0.047 0.16 0.13 0.021
0.64 0.65 0.64 0.66 0.69 0.64 0.57 0.63 0.71 0.69 0.67
0.2 0.2 0.1 0.1 0.1 0.2 0.1 0.2 0.1 0.1 0.1
Absencea 0.6 0.64 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6
0.07 0.1 0.16 0.17 0.17 0.12 0.16 0.15 0.14 0.16 0.17
P-value 0.67 0.88 0.95 0.36 0.09 0.61 0.45 0.78 0.037 0.43 0.29
The data are given as the mean values standard deviation. ABR: auditory brainstem response; C-IMT: common carotid intima-media thickness; CSR: contralateral stapedial reflex; FMD: flow-mediated dilation; OAE: otoacoustic emissions; VEMPs: vestibular evoked myogenic potentials. a Of audiovestibular symptoms and signs and/or cardiovascular risk factors.
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5. Conclusions
Table 3 Multivariate predictors of Idiopathic Sudden Sensorineural Hearing Loss. Findings
Odds ratio (95% CI)
P-value
Gender (male) Age (yrs) BMI (kg/m2) Total cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglycerides (mg/dl) Glycaemia (mg/dl) Fibrinogen (mg/dl) ESR (mm/h) FMD (%) Mean C-IMT (mm)
4.082 1.048 0.939 0.977 1.013 1.046 1.010 0.995 1.007 0.928 0.663 0.060
0.158 0.196 0.466 0.317 0.759 0.098 0.273 0.806 0.298 0.058 0.022 0.332
(3.086e5.078) (1.012e1.084) (0.853e1.025) (0.954e1.000) (0.970e1.056) (1.019e1.073) (1.001e1.019) (0.975e1.015) (1.000e1.014) (0.888e0.968) (0.483e0.843) (2.842e2.962)
515
CI: Confidence Interval; C-IMT: common carotid intima-media thickness; ESR: erythrocyte sedimentation rate; FMD: flow-mediated dilation; HDL-C: high density lipoprotein cholesterol; ISSHL: Idiopathic Sudden Sensorineural Hearing Loss; LDLC: low density lipoprotein cholesterol.
values between these two groups (p ¼ ns, Table 1). These observations suggest the presence of a functional vessel subversion that is not yet able to produce anatomical damage (C-IMT values of ISSHL subjects were within the normal range). In the ISSHL group, lower FMD values were associated with vestibular involvement and arterial hypertension (p ¼ 0.04 and p ¼ 0.02, respectively). Higher C-IMT values were associated with dyslipidaemia (p ¼ 0.03) (Table 2). Both hypertension and dyslipidaemia appeared to expose patients to a higher atherosclerotic risk [8,9]. Moreover, we found lower FMD values in patients with ISSHL of the left ear compared with patients with ISSHL in the right ear (4.9 1.3 vs. 6.3 1.6, p ¼ 0.04). This interesting finding has never been reported before and warrants further investigation. No correlation was found between the degree of hearing loss of the affected ear at admission and FMD values (p ¼ ns, Fig. 1A); however, a statistically significant correlation (p ¼ 0.02) was found between hearing thresholds of the contralateral ear and FMD values (Fig. 1B). Additionally, we found an inverse correlation between hearing loss at admission and hearing thresholds in the contralateral ear (p ¼ 0.02, Fig. 1C). These findings led us to suppose the presence of an adaptive mechanism in the contralateral ear to compensate for the hearing loss [30]. Furthermore, the reverse relationship between the contralateral PTA levels and FMD values, as expressed in Fig. 1B, seems to support our hypothesis on the vascular role in ISSHL genesis. Fig. 1B showed that patients with lower FMD values had a greater hearing loss (expressed by PTA) than for patients with high FMD values. This result seems to suggest that an endothelial systemic impairment, as outlined by FMD, could reduce the ear cochlea skill in detecting sounds that induce deafness. Naturally, additional research is needed to confirm such a hypothesis. Furthermore, the direct relationship between the hearing thresholds at admission and hearing outcome (p < 0.001, Fig. 1D), despite the improvement due to treatment, directed our attention to the importance of a timely diagnosis and hospitalisation to initiate the attack therapy as soon as possible. The prompt action is necessary to recover reasonable residual hearing function. Finally, the logistic regression analysis identified FMD as the only predictive factor predisposing ISSHL development (Table 3). In this selected population, hearing loss seemed to be determined by vascular dysfunction. Nevertheless, a major limit of our study is the small sample size that was considered. For this reason, new advanced, controlled and randomised trials should be performed to establish and confirm our results. Furthermore, future studies to complete this research should involve the evaluation of FMD after patients are discharged following an improvement in hearing level.
In conclusion, although assigning specific mechanisms for the hearing loss of these patients is only speculative, endothelial dysfunction might play an important role in the physiopathology of hearing loss by the means of microvascular disturbances and cochlear inflammatory processes. The evidence of increased cardiovascular risk factors and endothelial dysfunction highlight the importance of carefully evaluating the cardiovascular health of patients affected by ISSHL. Further studies in this area are required. Source of funding None to declare. Conflicts of interests None to declare. Disclosures None to declare. References [1] Stachler RJ, Chandrasekhar SS, Archer SM, et al. Clinical practice guideline: sudden hearing loss. American Academy of Otolaryngology-Head and Neck Surgery. Otolaryngol Head Neck Surg 2012;146:S1e35. [2] Byl FJ. Sudden hearing loss: eight years’ experience and suggested prognostic table. Laryngoscope 1984;94:647e61. [3] Chang N, Ho K, Kuo W. Audiometric patterns and prognosis in sudden sensorineural hearing loss in southern Taiwan. Otolaryngol Head Neck Surg 2005;133:916e22. [4] Ramos HVL, Yamashita H, Barros FA, Souza ACV, Yamaoka WY, Penido NO. Magnetic resonance imaging in sudden deafness. Rev Bras Otorrinolaringol 2005;71:422e6. [5] Weng SF, Chen YS, Liu TC, Hsu CJ, Tseng FY. Prognostic factors of sudden sensorineural hearing loss in diabetic patients. Diabetes Care 2004;27: 2560e1. [6] Rudack C, Langer C, Stoll W, Rust S, Walter M. Vascular risk factors in sudden hearing loss. Thromb Haemost 2006;95:454e61. [7] Ciccone MM, Scicchitano P, Zito A, et al. Correlation between coronary artery disease severity, left ventricular mass index and carotid intima media thickness, assessed by radio-frequency. Cardiovasc Ultrasound 2011;9:32. [8] Ciccone MM, Marzullo A, Mizio D, et al. Can carotid plaque histology selectively predict the risk of an acute coronary syndrome? Int Heart J 2011;52: 72e7. [9] Ciccone MM, De Pergola G, Porcelli MT, et al. Increased carotid IMT in overweight and obese women affected by Hashimoto’s thyroiditis: an adiposity and autoimmune linkage? BMC Cardiovasc Disord 2010;10:22. [10] Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257e65. [11] Perk J, De Backer G, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J 2012;33: 1635e701. [12] Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim carotid intima-media thickness consensus (2004e2006). Cerebrovasc Dis 2007;23:75e80. [13] Ziegler EA, Hohlweg-Majert B, Maurer J, Mann WJ. Epidemiological data of patients with sudden hearing loss e a retrospective study over a period of three years. Laryngorhinootologie 2003;82:4e8. [14] Merchant SN, Durand ML, Adams JC. Sudden deafness: is it viral? ORL J Otorhinolaryngol Relat Spec 2008;70:52e62. [15] García-Berrocal JR, Trinidad A, Ramírez-Camacho R, Verdaguer JM, Ibañez A. Immunologic work-up study for inner ear disorders: looking for a rational strategy. Acta Otolaryngol 2005;125:814e8. [16] Toubi E, Ben-David J, Kessel A, Halas K, Sabo E, Luntz M. Immune-mediated disorders associated with idiopathic sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 2004;113:445e9. [17] Goodhill V. Sudden deafness and window rupture. Laryngoscope 1971;81: 1462e74. [18] Maier W, Fradis M, Kimpel S, Schipper J, Laszig R. Results of exploratory tympanotomy following sudden unilateral deafness and its effects on hearing restoration. Ear Nose Throat J 2008;87:438e51.
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[19] Mosnier I, Stepanian A, Baron G, et al. Cardiovascular and thromboembolic risk factors in idiopathic sudden sensorineural hearing loss: a case-control study. Audiol Neurootol 2011;16:55e66. [20] Chau JK, Lin JR, Atashband S, Irvine RA, Westerberg BD. Systematic review of the evidence for the etiology of adult sudden sensorineural hearing loss. Laryngoscope 2010;120:1011e21. [21] Gatehouse S, Gallacher JE, Lowe GD, Yarnell JW, Hutton RD, Ising I. Blood viscosity and hearing levels in Caerphilly collaborative heart disease study. Arch Otolaryngol Head Neck Surg 1989;115:1227e30. [22] Gatehouse S, Lowe GD. Whole blood viscosity and red cell filterability as factors in sensorineural hearing impairment in the elderly. Acta Otolaryngol Suppl 1990;476:37e43. [23] Quaranta N, Ramunni A, Brescia P, D’Elia A, Vacca A, Ria R. Soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1 in sudden hearing loss. Otol Neurotol 2008;29:470e4. [24] Quaranta N, Ramunni A, De Luca C, et al. Endothelial progenitor cells in sudden sensorineural hearing loss. Acta Otolaryngol 2011;131:347e50.
[25] Balletshofer BM, Stock J, Rittig K, et al. Acute effect of rheopheresis on peripheral endothelial dysfunction in patients suffering from sudden hearing loss. Ther Apher Dial 2005;9:385e90. [26] Ballesteros F, Alobid I, Tassies D, et al. Is there an overlap between sudden neurosensorial hearing loss and cardiovascular risk factors? Audiol Neurootol 2008;14:139e45. [27] Lin HC, Chao PZ, Lee HC. Sudden sensorineural hearing loss increases the risk of stroke. A 5-year follow-up study. Stroke 2008;39:2744e8. [28] Aimoni C, Bianchini C, Borin M, et al. Diabetes, cardiovascular risk factors and idiopathic sudden sensorineural hearing loss: a case-control study. Audiol Neurotol 2010;15:111e5. [29] Teranishi M, Katayama N, Uchida Y, Tominaga M, Nakashima T. Thirty-year trends in sudden deafness from four nationwide epidemiological surveys in Japan. Acta Otolaryngol 2007;127:1259e65. [30] Tschopp K, Schillinger C, Schmid N, Rausch M, Bilecen D, Scheffler K. Detection of central auditory compensation in unilateral deafness with functional magnetic resonance tomography. Laryngorhinootologie 2000;79:753e7.
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Endothelial function and cardiovascular risk in patients with Idiopathic Sudden Sensorineural Hearing Loss Marco Matteo Ciccone a, *, Francesca Cortese a, Mariangela Pinto a, Concetta Di Teo a, Fara Fornarelli a, Michele Gesualdo a, Antonia Mezzina b, Evelina Sabatelli b, Pietro Scicchitano a, Nicola Quaranta b a b
Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy Section of Otolaryngology, Department of Ophthalmology and Otolaryngology, University of Bari, Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 July 2012 Received in revised form 1 October 2012 Accepted 2 October 2012 Available online 11 October 2012
Objective: To evaluate cardiovascular risk factors and pre-clinical atherosclerosis in subjects affected by Idiopathic Sudden Sensorineural Hearing Loss (ISSHL). Methods: In this study, 29 ISSHL patients and 29 healthy controls were evaluated. All of the patients underwent a complete audiovestibular and clinical evaluation. Carotid intima-media thickness (C-IMT) and flow-mediated dilation (FMD) of the brachial artery were assessed as early markers of atherosclerosis. Results: Our results showed that FMD was significantly lower in the ISSHL patients than in the controls (5.6 1.6% vs. 7.7 3.7%, p < 0.01). Moreover, the total cholesterol and low density lipoprotein cholesterol were significantly higher in the ISSHL patients than in the controls (p < 0.05). The two groups did not differ with regards to C-IMT and other cardiovascular risk factors. Vestibular involvement was shown to be associated with lower FMD values (4.1 1.7% vs. 5.8 1.5%, p < 0.05). No relationship was found between C-IMT and vestibular involvement. Finally, multiple logistic regression highlighted the finding that only FMD values seemed to predispose individuals to developing ISSHL (p ¼ 0.03, OR: 1.4). Conclusions: ISSHL seemed to be associated with vascular endothelial dysfunction and an increased cardiovascular risk, which supports the hypothesis of a vascular aetiology for this disease. Ó 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Cardiovascular risk Idiopathic Sudden Sensorineural Hearing Loss Carotid intima-media thickness Flow-mediated dilation
1. Introduction Idiopathic Sudden Sensorineural Hearing Loss (ISSHL) is commonly defined as a hearing loss of at least 30 dB over 3 contiguous test frequencies occurring within a 72-h period [1]. The estimated incidence of ISSHL is approximately 10/100,000 person-yrs, which is equally distributed between gender and sides affected [2]. Although approximately 60% of the patients undergo a spontaneous full or partial recovery, permanent deafness remains in a significant percentage [3]. It is hypothesised that ISSHL is caused by damage to the cochlea, the cochlear nerve, the sound transmission system from the cochlea to the brain, or any other portion of the central auditory nervous system. Despite detailed investigation, the main cause remains unknown in most cases [4]. Several theories have attempted to explain the pathogenesis of ISSHL. The vascular hypothesis suggests that ISSHL is a result of vascular disruption and subsequent ischaemia of the above
* Corresponding author. Piazza G. Cesare 11, 70124 Bari, Italy. Tel.: þ39 080 5478791; fax: þ39 080 5478796. E-mail address: [email protected] (M.M. Ciccone). 0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.024
mentioned structures [5]. Because a recurrence of ISSHL in hypertensive, diabetes and dyslipidaemia patients has been observed, atherosclerosis and its associated risk factors may play a role in ISSHL pathogenesis [6]. The carotid intima-media thickness (C-IMT) and flow-mediated dilation (FMD) of the brachial artery represent early indices of subclinical atherosclerosis, which is associated with coronary atherosclerosis [7e10]. Both C-IMT and FMD are simple, noninvasive and useful diagnostic tools for the assessment of individual cardiovascular risk. The aim of our study was to use C-IMT and FMD to assess the cardiovascular status of ISSHL patients and to compare the results with those of subjects with normal hearing. 2. Materials and methods 2.1. Study population In this study, 29 consecutive subjects suffering from ISSHL [19 males, mean age: 54 15 yrs] and 29 control subjects (18 males, mean age: 46 16 yrs) were investigated.
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ISSHL diagnosis was defined as a hearing loss of at least 30 dB in three contiguous frequencies occurring within a 72-h period [1]. The exclusion criteria for ISSHL patients were as follows: fluctuating cochlea-vestibular dysfunction suggestive of endolymphatic hydrops (history of vertigo with either fluctuating hearing loss, aural pressure or episodic tinnitus preceding the ISSHL episode); cerebello-pontine angle pathology at MRI; a history of otologic surgery; head and/or neck trauma or barotrauma in the 10 weeks prior to ISSHL diagnosis; MRI findings suggestive for congenital cochlear malformations; otitis media in the last 10 weeks; neurologic disorders predisposing to deafness; recent use of ototoxic medications; neoplasm within the previous two years; or other major diseases (such as heart failure, severe lung disease, or liver or renal dysfunction). The control subjects had normal bilateral hearing (audiometric values in normal ranges according to age) and no history of cardiovascular diseases. The subjects underwent a general physical examination, assessment of laboratory blood parameters and an audiovestibular and ultrasound (C-IMT and FMD) evaluation. Patients were informed about the aim of the study and signed consent forms. The study was approved by the Institutional Review Board of Bari University General Hospital and carried out in accordance with the principles of the Helsinki Declaration. 2.2. Clinical and laboratory evaluation The demographic and clinical characteristics are shown in Table 1. Height (cm), weight (kg) and blood pressure were measured, and body mass index (BMI) (kg/m2) was calculated. A fasting blood sample was obtained for measuring plasma glucose, total cholesterol (TC), high (HDL-C) and low (LDL-C) density lipoprotein cholesterol, triglycerides (TG), fibrinogen, erythrocyte sedimentation rate (ESR), pro-thrombin international normalised ratio (PT-INR) and haematocrit. The patients were classified as follows: hypertensive in the case of systolic/diastolic blood pressure values 140/90 mmHg, or presently using anti-hypertensive medication [11]; dyslipidaemic when TC 200 mg/dl, LDL-C 130 mg/dl, HDL-C < 45 mg/dl, TG 150 mg/dl or presently using lipid-lowering agents [11]; diabetic when fasting glucose level was 126 mg/dl or presently undergoing pharmacologic treatment [11]; and obese or overweight when BMI was 30 kg/m2 or ranged from 25 kg/m2 to 29.9 kg/m2, respectively [11]. Each participant was considered a “current daily smoker” if he or she had regularly smoked at least 5 cigarettes/day during the previous 3 months or had stopped smoking less than 1 year before his/her admittance to our department [11]. 2.3. Audiovestibular investigation All of the patients underwent a standard evaluation that consisted of a pure-tone speech audiometry, impedance audiometry, otoacoustic emissions (OAE), bithermal caloric testing of the vestibular function, auditory brainstem response (ABR), vestibular evoked myogenic potentials (VEMPs) and MRI of the internal auditory canal and posterior cranial fossa. The air conduction puretone average (PTA) was obtained by averaging the air conduction thresholds at 0.25, 0.5, 1, 2, 3, 4 and 8 kHz. Pure-tone and speech audiometry were tested every 48 h until hospital discharge. Hearing improvement was calculated as a relative improvement of hearing thresholds using the contralateral ear as the baseline. All of the patients were treated with the standard sudden deafness protocol, which included carbogen (95% CO2 and 5% O2) inhalation, pentoxifylline, vitamin C, magnesium and oral steroids (prednisone
Table 1 The demographic and clinical characteristics of the study populations (patients and controls).
Men Age (yrs) BMI (kg/m2) Total cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglycerides (mg/dl) Fasting blood glucose (mg/dl) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Smoking Arterial hypertension Diabetes Dyslipidaemia PT-INR HCT (%) Fibrinogen (mg/dl) ESR (mm/h) FMD (%) Mean C-IMT (mm) Right C-IMT (mm) Left C-IMT (mm) Statins Nitrates Angiotensin-converting enzyme inhibitors Beta blockers Angiotensin receptor blockers Calcium channel blockers
ISSHL group (n ¼ 29)
Control group (n ¼ 29)
P-value
19 (66) 54 15 28 5 188 33 48 10 118 27 109 45 96 24
18 (62) 46 16 26 6 171 29 49 13 101 28 105 51 97 18
0.78 0.07 0.21 0.04 0.74 0.02 0.77 0.46
129 14
125 11
0.17
84 8
80 9
0.08
7 (24) 17 (58) 3 (10) 12 (41) 1.09 0.22 40 7 290 71 15 15 5.6 1.6 0.64 0.15 0.64 0.19 0.64 0.14 10 (34%) 0 (0%) 10 (34%)
4 (14) 12 (41) 5 (17) 11 (38) 1.07 0.15 38 6 280 68 15 10 7.7 3.7 0.67 0.16 0.67 0.16 0.68 0.18 10 (34%) 0 (0%) 9 (31%)
0.5 0.29 0.7 1.00 0.75 0.19 0.67 0.32 0.005 0.61 0.43 0.7 1.000 1.000 0.5
6 (21%) 7 (24%)
8 (28%) 4 (14%)
0.38 0.25
5 (17%)
4 (14%)
0.5
The data are given as the means standard deviation or numbers and percentages; p < 0.05. BMI: body mass index; C-IMT: common carotid intima-media thickness; ESR: erythrocyte sedimentation rate; FMD: flow-mediated dilation; HCT: haematocrit; HDL-C: high density lipoprotein cholesterol; ISSHL: Idiopathic Sudden Sensorineural Hearing Loss; LDL-C: low density lipoprotein cholesterol; PT-INR: pro-thrombin international normalised ratio.
at 1 mg/kg per day). Patients who required specific therapy for diabetes, hypertension or dyslipidaemia were treated in association with the proposed standard therapy. 2.4. Carotid IMT evaluation For the C-IMT evaluation, the patients were placed in the supine position; their neck was extended and contralaterally turned approximately 45 . The C-IMT was defined as the distance between the lumen-intima and media-adventitia borders of the vessel, which were ultrasonographically identified by a double hypoechoic line [12]. First, we explored the carotid arteries to exclude the possible presence of an atherosclerotic plaque. Afterwards, we bilaterally calculated the C-IMT with scans of the lengthwise axis. The C-IMT value was obtained as the arithmetical mean of the values calculated from the following three zones: 1. Proximal zone: approximately 2 cm above the flow-divider; 2. Distal zone: approximately 1/2 cm above the flow-divider; 3. Middle zone. 2.5. Brachial artery FMD evaluation Endothelial function was assessed by FMD with a highresolution ultrasonograph (Philips Sonos 5500) connected to an image analysis system certified by the CNR of Pisa (MVE II). A long
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axis projection of the brachial artery at the level of the anteecubital fossa was performed by the same blinded physician in a quiet and temperature controlled (22e24 C) room. The electronic probe was positioned 4e5 cm above the elbow to obtain a longitudinal vascular scan of the right brachial artery. The probe was maintained in the correct position by a mechanical arm. The baseline diameter of the brachial artery was measured from the anterior to the posterior intima for 1 min. After resting for 1 min, a sphygmomanometer cuff was placed near the transducer on the upper arm and then inflated to 50 mmHg above the systolic blood pressure (200e 220 mmHg) for 5 min. The cuff was then rapidly deflated. A reactive brachial artery hyperaemia was initiated, and the diameter of the artery was recorded for 3 min. The patient rested for 5 min; reactive hyperaemia and the maximum flow velocity in the brachial artery was obtained with pulseewave Doppler. The sample volume was obtained from the centre of the artery and a correction angle at 70 , at rest. The data were collected during the first 15 s after cuff deflation, and the average of 3 measurements were taken. The maximum velocities that were considered normal were between 50 and 70 cm/s. Reactive hyperaemia was calculated as the ratio between the maximum velocity and the baseline [10]. All of the measurements were performed within 24e48 h from the beginning of the audiovestibular investigation and the start of therapy. 2.5.1. Statistical analysis The data are given as mean values standard deviation. Categorical variables are given as frequencies and percentages.
513
Between-group comparisons were analysed by t-test for independent samples or t-test for matched pair samples if the distribution was normal, as determined by the KolmogoroveSmirnov test and the Lilliefors test. As for nonparametric methods, we used the ManneWhitney U test for two independent samples or the Wilcoxon Test for dependent samples. Frequencies were compared using the Chi-squared or Fisher’s exact test. Correlation analysis was performed with the Spearman rank order correlation. Logistic regression analyses were used to assess the association of variables with ISSHL, and odds ratios (ORs) with their 95% confidence intervals (CIs) were calculated. P < 0.05 was considered statistically significant. Analyses were performed using STATISTICA 7 software (StatSoft Inc., Tulsa, Oklahoma). 3. Experimental results The data obtained are shown in Table 1. According to our results, the TC and LDL-C values were significantly higher in the ISSHL patients than in the controls (188 33 mg/dl vs. 171 29 mg/dl, p < 0.05). No significant differences were found with respect to the C-IMT values (both right and left C-IMT) (p ¼ ns). Significantly lower FMD values were found in ISSHL patients compared with controls (5.6 1.6 vs. 7.7 3.7, p < 0.01); however, these values were not associated with hearing loss in the affected ear (p ¼ ns, Fig. 1A). A significant correlation (p ¼ 0.02) was found between the PTA of the contralateral ear and FMD values (Fig. 1B).
Fig. 1. A: Correlation between pure-tone average (PTA) of the affected side at admission and flow-mediated dilation (FMD) of the brachial artery. B: Correlation between PTA of the contralateral ear at admission and FMD. C: Correlation between Delta (PTA affected ear e PTA contralateral ear) and PTA contralateral ear. D: Correlation between PTA of the affected ear at admission and at discharge.
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The degree of hearing loss, which was calculated as the PTA of the affected ear minus the PTA of contralateral ear, was inversely correlated with the PTA of the contralateral ear (p ¼ 0.02). That is, patients with higher degrees of hearing loss had better contralateral PTA (Fig. 1C). A statistically significant link was found between vestibular involvement and lower FMD values, which was indicative of endothelial dysfunction (p < 0.05); however, no correlations were found among the presence of tinnitus, aural fullness, vertigo, contralateral stapedial reflexes, pathological ABR, VEMPs or OAE compared with FMD and C-IMT values (p ¼ ns) (Table 2). We observed a statistically significant increase in C-IMT values in dyslipidaemic patients (p ¼ 0.03) as well as lower FMD values in hypertensive patients (p ¼ 0.02, Table 2). Moreover, patients with sudden deafness of the left ear had lower FMD values than those affected on the right side (4.9 1.3 vs. 6.3 1.6, p ¼ 0.04); however, these groups had similar C-IMT values (0.66 0.1 vs. 0.62 0.2, p ¼ ns). At discharge (after approximately 10 days), we recorded a significant improvement in the hearing level of the overall population (mean PTA at admission vs. mean PTA at discharge: 60 22 dB vs. 40 23 dB, p < 0.001). The degree of hearing loss at admission could be considered an important prognostic factor for these patients, showing a direct relationship between the hearing loss at admission and at discharge (r ¼ 0.62, p < 0.001, Fig. 1D). Finally, the multiple logistic regression highlighted that only FMD values seemed to be related to ISSHL development (OR: 0.663, p ¼ 0.022, Table 3). That is, in patients suffering from ISSHL, a lower FMD value could independently explain the reduction in hearing. 4. Discussion ISSHL is a very interesting but not yet well-defined clinical condition. Several hypotheses have attempted to explain its pathogenesis [13]. According to the viral theory, ISSHL is due to a herpes simplex virus infection; however, no specific serological profiles or response to antiviral treatment has been reported [14]. Others have hypothesised that ISSHL is an immune-mediated disease due to its response to steroids. Nevertheless, impaired immunity and/or clinical evolution that is compatible with an autoimmune cause are not observed in every case [15,16]. The cochlear membrane rupture theory postulates that a possible perilymph fistula, due to physical effort, barotrauma or a Valsalva manoeuvre, may be the cause of ISSHL [17,18]. ISSHL could also be the result of an ear microcirculation alteration due to genetic pro-thrombotic susceptibility or cardiovascular risk factors [5e7]. A recent multicentre case-control study demonstrated that the sole predictive factor of final hearing
loss/impairment was the severity of the initial hearing loss [19]. A systematic review [20] showed a vascular aetiology for ISSHL in only 2.8% of patients, while 71% of them remain “idiopathic”, even though other evidence supports the vascular involvement theory at the base of ISSHL [19,20]. A higher blood viscosity may determine damage in ear microcirculation that can produce chronic hearing loss [21,22]. Our group has already [23,24] demonstrated an increased expression of adhesion molecules and a reduced percentage of circulating endothelial progenitor cells in ISSHL patients. Furthermore, Balletshofer et al. [25] found that 5 of 6 ISSHL patients had evidence of endothelial dysfunction, which confirms that a microcirculation disorder is involved in the pathogenesis of the disease. An endothelial dysfunction could predispose one to the development of a pro-thrombotic state due to the increase in the vascular wall, even at the level of the ear [23,24]. It is able to counterbalance pro-aggregation and anti-aggregation properties, or it is even able to balance coagulation conditions by means of factors such as heparin. When the endothelium cannot explicitly perform its own duties, adhesion molecules [23], endothelial progenitor cells [24] and, consequently, pro-inflammatory vascular conditions could alter the blood supply to the ear because of the sudden and transient thrombotic event, which could explain the nature of ISSHL. Considering that the cochlear vascular tree is a terminal type, an abrupt interruption of vascular flow due to endothelial damage could impair cochlear membrane functions. FMD, acting as a clear early marker of endothelial dysfunction, could help in identifying patients at a high risk for ISSHL. There is an increased rate of previous cardiovascular disease in ISSHL patients [25e27]. Aimoni et al. [28] found that the risk of ISSHL increased with the number of cardiovascular risk factors, and a similar case-control study [18] highlighted the fact that 12% of ISSHL patients had a history of cardiovascular disease, compared with only 3% of controls. Furthermore, Ballesteros et al. [26] found higher rates of hypertension, diabetes and previous cardiovascular disease in ISSHL patients. Furthermore, two large Taiwanese and Japanese population surveys demonstrated a higher incidence of hypertension and diabetes in ISSHL patients and a greater risk for stroke in patients with a history of ISSHL [27,29]. Our results confirmed that ISSHL patients were at higher cardiovascular risk, which suggests the vascular genesis of cochlear damage. Compared with age- and sex-matched controls, ISSHL patients had significantly higher levels of TC and LDL-C, and 41% of these patients met the criteria for dyslipidaemia diagnosis [11]. The two groups did not differ according to traditional cardiovascular risk factors (arterial hypertension, diabetes and dyslipidaemia, p ¼ ns, Table 1). Moreover, we found significantly lower FMD values in ISSHL patients than in the control group (5.6% vs. 7.7%, p < 0.01), and similar C-IMT
Table 2 The influence of symptoms and pathological signs on flow-mediated dilation and common carotid intima-media thickness. FMD (%) Presencea Tinnitus (n ¼ 27) Fullness (n ¼ 21) Vertigo (n ¼ 5) CSR (n ¼ 22) ABR (n ¼ 15) VEMPs (n ¼ 8) OAE (n ¼ 3) Vestibular involvement (n ¼ 4) Dyslipidaemia (n ¼ 12) Diabetes (n ¼ 3) Hypertension (n ¼ 17)
5.6 5.8 5.3 5.8 5.2 6.1 5.1 4.1 5.2 6.1 5.05
1.6 1.8 1.7 1.2 1.9 2.2 0.7 1.7 1.7 0.2 1.2
C-IMT Absencea 5.1 5.06 5.7 5.1 6.1 5.4 5.7 5.8 5.9 5.6 6.4
0.2 0.1 0.7 2.6 1.3 1.4 1.7 1.5 1.6 1.7 1.8
P-value
Presencea
0.37 0.21 0.64 0.1 0.25 0.73 0.43 0.047 0.16 0.13 0.021
0.64 0.65 0.64 0.66 0.69 0.64 0.57 0.63 0.71 0.69 0.67
0.2 0.2 0.1 0.1 0.1 0.2 0.1 0.2 0.1 0.1 0.1
Absencea 0.6 0.64 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6
0.07 0.1 0.16 0.17 0.17 0.12 0.16 0.15 0.14 0.16 0.17
P-value 0.67 0.88 0.95 0.36 0.09 0.61 0.45 0.78 0.037 0.43 0.29
The data are given as the mean values standard deviation. ABR: auditory brainstem response; C-IMT: common carotid intima-media thickness; CSR: contralateral stapedial reflex; FMD: flow-mediated dilation; OAE: otoacoustic emissions; VEMPs: vestibular evoked myogenic potentials. a Of audiovestibular symptoms and signs and/or cardiovascular risk factors.
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5. Conclusions
Table 3 Multivariate predictors of Idiopathic Sudden Sensorineural Hearing Loss. Findings
Odds ratio (95% CI)
P-value
Gender (male) Age (yrs) BMI (kg/m2) Total cholesterol (mg/dl) HDL-C (mg/dl) LDL-C (mg/dl) Triglycerides (mg/dl) Glycaemia (mg/dl) Fibrinogen (mg/dl) ESR (mm/h) FMD (%) Mean C-IMT (mm)
4.082 1.048 0.939 0.977 1.013 1.046 1.010 0.995 1.007 0.928 0.663 0.060
0.158 0.196 0.466 0.317 0.759 0.098 0.273 0.806 0.298 0.058 0.022 0.332
(3.086e5.078) (1.012e1.084) (0.853e1.025) (0.954e1.000) (0.970e1.056) (1.019e1.073) (1.001e1.019) (0.975e1.015) (1.000e1.014) (0.888e0.968) (0.483e0.843) (2.842e2.962)
515
CI: Confidence Interval; C-IMT: common carotid intima-media thickness; ESR: erythrocyte sedimentation rate; FMD: flow-mediated dilation; HDL-C: high density lipoprotein cholesterol; ISSHL: Idiopathic Sudden Sensorineural Hearing Loss; LDLC: low density lipoprotein cholesterol.
values between these two groups (p ¼ ns, Table 1). These observations suggest the presence of a functional vessel subversion that is not yet able to produce anatomical damage (C-IMT values of ISSHL subjects were within the normal range). In the ISSHL group, lower FMD values were associated with vestibular involvement and arterial hypertension (p ¼ 0.04 and p ¼ 0.02, respectively). Higher C-IMT values were associated with dyslipidaemia (p ¼ 0.03) (Table 2). Both hypertension and dyslipidaemia appeared to expose patients to a higher atherosclerotic risk [8,9]. Moreover, we found lower FMD values in patients with ISSHL of the left ear compared with patients with ISSHL in the right ear (4.9 1.3 vs. 6.3 1.6, p ¼ 0.04). This interesting finding has never been reported before and warrants further investigation. No correlation was found between the degree of hearing loss of the affected ear at admission and FMD values (p ¼ ns, Fig. 1A); however, a statistically significant correlation (p ¼ 0.02) was found between hearing thresholds of the contralateral ear and FMD values (Fig. 1B). Additionally, we found an inverse correlation between hearing loss at admission and hearing thresholds in the contralateral ear (p ¼ 0.02, Fig. 1C). These findings led us to suppose the presence of an adaptive mechanism in the contralateral ear to compensate for the hearing loss [30]. Furthermore, the reverse relationship between the contralateral PTA levels and FMD values, as expressed in Fig. 1B, seems to support our hypothesis on the vascular role in ISSHL genesis. Fig. 1B showed that patients with lower FMD values had a greater hearing loss (expressed by PTA) than for patients with high FMD values. This result seems to suggest that an endothelial systemic impairment, as outlined by FMD, could reduce the ear cochlea skill in detecting sounds that induce deafness. Naturally, additional research is needed to confirm such a hypothesis. Furthermore, the direct relationship between the hearing thresholds at admission and hearing outcome (p < 0.001, Fig. 1D), despite the improvement due to treatment, directed our attention to the importance of a timely diagnosis and hospitalisation to initiate the attack therapy as soon as possible. The prompt action is necessary to recover reasonable residual hearing function. Finally, the logistic regression analysis identified FMD as the only predictive factor predisposing ISSHL development (Table 3). In this selected population, hearing loss seemed to be determined by vascular dysfunction. Nevertheless, a major limit of our study is the small sample size that was considered. For this reason, new advanced, controlled and randomised trials should be performed to establish and confirm our results. Furthermore, future studies to complete this research should involve the evaluation of FMD after patients are discharged following an improvement in hearing level.
In conclusion, although assigning specific mechanisms for the hearing loss of these patients is only speculative, endothelial dysfunction might play an important role in the physiopathology of hearing loss by the means of microvascular disturbances and cochlear inflammatory processes. The evidence of increased cardiovascular risk factors and endothelial dysfunction highlight the importance of carefully evaluating the cardiovascular health of patients affected by ISSHL. Further studies in this area are required. Source of funding None to declare. Conflicts of interests None to declare. Disclosures None to declare. References [1] Stachler RJ, Chandrasekhar SS, Archer SM, et al. Clinical practice guideline: sudden hearing loss. American Academy of Otolaryngology-Head and Neck Surgery. Otolaryngol Head Neck Surg 2012;146:S1e35. [2] Byl FJ. Sudden hearing loss: eight years’ experience and suggested prognostic table. Laryngoscope 1984;94:647e61. [3] Chang N, Ho K, Kuo W. Audiometric patterns and prognosis in sudden sensorineural hearing loss in southern Taiwan. Otolaryngol Head Neck Surg 2005;133:916e22. [4] Ramos HVL, Yamashita H, Barros FA, Souza ACV, Yamaoka WY, Penido NO. Magnetic resonance imaging in sudden deafness. Rev Bras Otorrinolaringol 2005;71:422e6. [5] Weng SF, Chen YS, Liu TC, Hsu CJ, Tseng FY. Prognostic factors of sudden sensorineural hearing loss in diabetic patients. Diabetes Care 2004;27: 2560e1. [6] Rudack C, Langer C, Stoll W, Rust S, Walter M. Vascular risk factors in sudden hearing loss. Thromb Haemost 2006;95:454e61. [7] Ciccone MM, Scicchitano P, Zito A, et al. Correlation between coronary artery disease severity, left ventricular mass index and carotid intima media thickness, assessed by radio-frequency. Cardiovasc Ultrasound 2011;9:32. [8] Ciccone MM, Marzullo A, Mizio D, et al. Can carotid plaque histology selectively predict the risk of an acute coronary syndrome? Int Heart J 2011;52: 72e7. [9] Ciccone MM, De Pergola G, Porcelli MT, et al. Increased carotid IMT in overweight and obese women affected by Hashimoto’s thyroiditis: an adiposity and autoimmune linkage? BMC Cardiovasc Disord 2010;10:22. [10] Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257e65. [11] Perk J, De Backer G, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J 2012;33: 1635e701. [12] Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim carotid intima-media thickness consensus (2004e2006). Cerebrovasc Dis 2007;23:75e80. [13] Ziegler EA, Hohlweg-Majert B, Maurer J, Mann WJ. Epidemiological data of patients with sudden hearing loss e a retrospective study over a period of three years. Laryngorhinootologie 2003;82:4e8. [14] Merchant SN, Durand ML, Adams JC. Sudden deafness: is it viral? ORL J Otorhinolaryngol Relat Spec 2008;70:52e62. [15] García-Berrocal JR, Trinidad A, Ramírez-Camacho R, Verdaguer JM, Ibañez A. Immunologic work-up study for inner ear disorders: looking for a rational strategy. Acta Otolaryngol 2005;125:814e8. [16] Toubi E, Ben-David J, Kessel A, Halas K, Sabo E, Luntz M. Immune-mediated disorders associated with idiopathic sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 2004;113:445e9. [17] Goodhill V. Sudden deafness and window rupture. Laryngoscope 1971;81: 1462e74. [18] Maier W, Fradis M, Kimpel S, Schipper J, Laszig R. Results of exploratory tympanotomy following sudden unilateral deafness and its effects on hearing restoration. Ear Nose Throat J 2008;87:438e51.
516
M.M. Ciccone et al. / Atherosclerosis 225 (2012) 511e516
[19] Mosnier I, Stepanian A, Baron G, et al. Cardiovascular and thromboembolic risk factors in idiopathic sudden sensorineural hearing loss: a case-control study. Audiol Neurootol 2011;16:55e66. [20] Chau JK, Lin JR, Atashband S, Irvine RA, Westerberg BD. Systematic review of the evidence for the etiology of adult sudden sensorineural hearing loss. Laryngoscope 2010;120:1011e21. [21] Gatehouse S, Gallacher JE, Lowe GD, Yarnell JW, Hutton RD, Ising I. Blood viscosity and hearing levels in Caerphilly collaborative heart disease study. Arch Otolaryngol Head Neck Surg 1989;115:1227e30. [22] Gatehouse S, Lowe GD. Whole blood viscosity and red cell filterability as factors in sensorineural hearing impairment in the elderly. Acta Otolaryngol Suppl 1990;476:37e43. [23] Quaranta N, Ramunni A, Brescia P, D’Elia A, Vacca A, Ria R. Soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1 in sudden hearing loss. Otol Neurotol 2008;29:470e4. [24] Quaranta N, Ramunni A, De Luca C, et al. Endothelial progenitor cells in sudden sensorineural hearing loss. Acta Otolaryngol 2011;131:347e50.
[25] Balletshofer BM, Stock J, Rittig K, et al. Acute effect of rheopheresis on peripheral endothelial dysfunction in patients suffering from sudden hearing loss. Ther Apher Dial 2005;9:385e90. [26] Ballesteros F, Alobid I, Tassies D, et al. Is there an overlap between sudden neurosensorial hearing loss and cardiovascular risk factors? Audiol Neurootol 2008;14:139e45. [27] Lin HC, Chao PZ, Lee HC. Sudden sensorineural hearing loss increases the risk of stroke. A 5-year follow-up study. Stroke 2008;39:2744e8. [28] Aimoni C, Bianchini C, Borin M, et al. Diabetes, cardiovascular risk factors and idiopathic sudden sensorineural hearing loss: a case-control study. Audiol Neurotol 2010;15:111e5. [29] Teranishi M, Katayama N, Uchida Y, Tominaga M, Nakashima T. Thirty-year trends in sudden deafness from four nationwide epidemiological surveys in Japan. Acta Otolaryngol 2007;127:1259e65. [30] Tschopp K, Schillinger C, Schmid N, Rausch M, Bilecen D, Scheffler K. Detection of central auditory compensation in unilateral deafness with functional magnetic resonance tomography. Laryngorhinootologie 2000;79:753e7.