The physiological changes that occur within and around the optic nerve are central to its viability and function. Glaucoma, though common, is only substantially understood in the context of elevated intraocular pressure, but in the absence of IOP level above statistically normal levels, it largely remains obscure. The study evaluated how cardiac autonomic function might influence the development of glaucoma in the two major variants of open-angle glaucoma that cannot be explained by other physiological or anatomical abnormalities.
The difference in the mean age of the NTG group compared to the Control group was not statistically significant but both were significantly lower than high-tension primary open-angle glaucoma (HTG). This can be attributable to the age-matching of participants enrolled into normal-tension glaucoma (NTG) group versus Control which was not applied to the HTG group since the major risk factor of elevated IOP has been well highlighted in the literature. Similar to findings in this study, the literature on glaucoma in Africa and other developing countries has reported mean ages in the sixth and seventh decades for patients presenting with POAG including normal-tension glaucoma [14–17]. Meanwhile, Ajite et al, Majeed et al and Riccadonna et al reported an average age within the sixth decade of life in the NTG subset of primary glaucoma patients in their study [18–20] The older mean age of the HTG group attests to the epidemiological findings of the increasing prevalence of POAG with age and the fact that the chronicity of the disease often results in late presentation long after the actual onset of the disease among blacks. More often than not, NTG in individuals with little or no visual impairment is detected as incidental findings during routine eye screening or while an individual is being evaluated for an unrelated complaint.
The disease severity as assessed by the degree of optic disc cupping was significantly different between the glaucoma study groups and Control group while there was no difference in the best-corrected visual acuity. Expectedly, the mean IOP in the HTG was significantly higher than that of NTG and Control, while there was no significant difference between the IOP of NTG and Control. The majority of the subjects in the glaucoma groups were using topical anti-glaucoma medications particularly Timolol which is a beta-blocker and Brimonidine, an alpha agonist. Both of them are known to have chronotropic and hypotensive effects on the heart following significant systemic absorption [21, 22] However, Stewart et al did not find any statistically significant difference in the exercise heart rate and blood pressure of subjects placed on topical Timolol, Brimonidine, Timolol/Brimonidine combination and placebo as against systemically administered formulations [23]. The subjects in our study had administered their topical medications at least 2 hours before the conduct of the cardiac autonomic function tests. However, it is not clear if significant systemic absorption could have occurred and sustained with a single drop of medication of approximately 25–50µL with the conjunctival sac’s capacity limited to just about 10µL, to cause a significant cardiovascular effect. This study showed that while the baseline PR interval was significantly longer in the NTG and HTG groups compared to the control, there was no difference in the PR intervals of users and non-users of topical beta-blockers. Considering the pharmacodynamics and pharmacokinetics of topically administered eye medications and the minute amount of systemic absorption of 0.5% concentration of commercially available Timolol and Brimonidine [21–23], we believe that the topical medication would have little or no effect on the result of cardiac autonomic function tests by the time they were conducted.
The pattern of distribution of systemic comorbidities such as systemic hypertension and the use of systemic medications were not statistically significant. The concept that hypertension is due to a derangement of sympathetic and parasympathetic cardiovascular regulation is one of the most widely accredited and tested hypotheses in cardiovascular research. Although this hypothesis has found support in experimental models of hypertension, there is no similarly conclusive evidence in humans [24]. A considerable proportion of participants across the three study groups were hypertensive and on medications particularly calcium channel blockers. Just like many other previously published studies [25–27], subjects with systemic hypertension were not excluded since such exclusion could alter the actual characteristics of glaucoma patients and introduce statistical bias of lower baseline values of some cardiovascular parameters such as blood pressure. Most of the anti-hypertensive medications used by participants enrolled in the study are not known to have significant cardiogenic effects that may significantly affect the cardiac autonomic response.[28] Besides, cardiac autonomic response post-medication does not remarkably differ from the pre-medication state following long-term antihypertensive use because of baroreflex reset after the initial reflex activation brought about by the unloading of arterial baroreceptors in response to an acute fall in blood pressure [24, 29]. Exception to the baroreflex reset phenomenon has been demonstrated with centrally-acting agents, beta receptor blockers, blockers of the renin-angiotensin system, or mineralocorticoid receptor antagonists and to some extent, thiazides and short-acting calcium channel blockers [24], majority of which were exclusion criteria for this study.
The Valsalva ratio was significantly higher in the NTG group than in the HTG and control group in our study. This finding differ from that of Mapstone et al, Bojić et al and Khan et al [30–32]. The authors reported that the Valsalva ratio was significantly higher among control than POAG. However, they did not classify into high-tension and normal-tension glaucoma. Bojić et al reported that although significant difference existed with the Valsalva ratio, the average values continued to be within the normal range. These authors believed that the Valsalva manoeuvre test is more accurate than other cardiovascular tests in the definition of autonomic dysfunction in glaucoma subjects. They also suggested that probably glaucoma reflects a systemic disease, not only an eye disease. The mean Valsalva ratio for POAG reported in our study and the values reported by other authors for POAG were within Ewing’s recommended normal range of 1.20 and above [33]. The mean Valsalva ratio of the NTG group in our study was higher than that reported by Ogunlade et al among healthy young Nigerian adults [34].
The significantly higher values in this study suggest that the NTG group has exaggerated parasympathetic autonomic response as a result of significantly longer post-strain RR interval indicating more intense post-strain bradycardia. Higher Valsalva ratio could have also occurred as a result of the excessive rise of heart rate (parasympathetic withdrawal and sympathetic activation) in the face of declining blood pressure during the strain or excessive relative post-strain reduction of heart rate (parasympathetic response) in response to the rapid overshoot of arterial blood pressure or a combination of the aforementioned. Khan reported a significantly lower Valsalva heart rate among NTG patients [35]. Our study demonstrated that the higher VR in NTG patients reflects exaggerated baroreceptors response as evidenced by the significantly reduced post-strain heart rate (Table 5).
Valsalva manoeuvre causes an increase in intrathoracic pressure, reduces venous cardiac return, and increases venous pressure resulting in a drop of arterial pressure during the strain phase [36]. Valsalva manoeuvre also causes a reduction in ocular blood flow and associated rapid surge in intraocular pressure far over the upper limit of the normal range have been recorded [35, 37, 38]. Krist et al reported a higher prevalence of activities or diseases that result in frequent, transient increase in intrathoracic and intraabdominal pressures in the medical history of patients with NTG (45%) than among POAG (11%) patients further highlighting the possible effect of Valsalva manoeuvre on the optic nerve head perfusion [39].
The retina is considered to have one of the highest oxygen-consumption per unit weight of all the tissues of the body, surpassing even that of the brain. Neurons including retinal ganglion cells, unlike glia, depend almost entirely on oxidative metabolism for their energy supply. Whereas glial cells can survive for long periods under anoxic conditions, neurons are the first cells to die when oxygen is lacking [40]. The high energy requirement and near-total dependency of retinal ganglion cells on oxidative metabolism make them extremely vulnerable to energy exhaustion and eventual functional failure [41]. The simultaneous reduction of ocular blood flow, the large increase in intraocular pressure and increase venous pressure in the uveal circulation and episcleral vessels during the Valsalva manoeuvre results in reduced ocular perfusion and oxygen supply to the neurons [37, 42]. Valsalva-like manoeuvres (VM) are performed frequently in daily life without knowing it, when moderately forceful attempted exhalation is made against a closed airway during many physiological and pathological conditions and activities, such as coughing, sneezing, laughing, straining, singing, vomiting, lifting heavy objects, playing wind instruments and obstructive sleep apnea [37, 39, 42–45].
The significantly higher Valsalva ratio in the NTG group in this study suggests that such individuals might have an inappropriate cardiovascular response to stimuli similar to the Valsalva manoeuvre they may be regularly exposed to, resulting in considerable bradycardia and intermittent hypoxic state within and around the optic nerve. This could result in repeated mild reperfusion injuries, oxidative stress, and apoptotic cell death with chronic retinal ganglion cell loss similar to high-tension primary open-angle glaucoma [46]. The findings of this study reinforced the vascular theory of glaucomatous optic neuropathy in NTG. The continued progression of optic nerve head damage reported in individuals with initially high-tension POAG despite clinically-controlled IOP might also be a result of underlying cardiac autonomic dysfunction [47].
The evidence suggesting increased parasympathetic activity among glaucoma patients in this study was further supported by the significantly prolonged mean resting PR interval in both the HTG and NTG groups compared to the control group (Table 4). The PR interval represents the atrioventricular conduction time modulated by the ANS which is prolonged or shortened by the parasympathetic and sympathetic divisions respectively [48]. When the conduction time through the atrioventricular node is delayed by increased parasympathetic stimulation or sympathetic withdrawal, it causes a prolonged PR interval. Since resting cardiac conduction is chiefly under the influence of parasympathetic regulation [49], then the relatively prolonged mean resting PR intervals of the HTG and NTG groups may likely be due to relative overstimulation by the parasympathetic system. Further evidence supporting increased parasympathetic stimulation was noted among the HTG with the significantly prolonged mean maximum RR intervals during the deep breathing test, mean minimum RR at/around the 15th beat and mean maximum RR interval at/around the 30th beat post-standing compared to the corresponding values of the control group (Table 5). Prolonged RR interval may therefore be a reason for concern in conditions and occupation that require prolonged period of expiratory effort.
Riccadonna et al reported that their 24-hour BP monitoring and heart rate monitoring study have suggested that NTG patients have abnormal autonomic modulation of cardiovascular responses during both night and day [20]. The degree of cardiac autonomic dysfunction was reported to be more marked in patients with more severe forms of glaucoma. However, the index study did find such a significant relationship.
In conclusion, this study established that there was increased cardiovascular parasympathetic activity in the NTG and HTG groups with possible implications for optic nerve blood flow.