Time-domain ratios are HRV-alone measures often utilized to detect diabetic autonomic neuropathy (DAN) as an early indicator of cardiovascular autonomic neuropathy (CAN). Time-domain ratios include the exhalation–inhalation (E/I) ratio, Valsalva ratio, and the 30:15 ratio. The E/I ratio is from the DB or paced breathing challenge. While a relaxed patient breaths at six breaths per minute, the interval between the two heartbeats (HBI) at peak exhalation is computed. Similarly, HBI is computed for peak inhalation. The ratio of these two time intervals is the E/I ratio. The Valsalva ratio is computed as the ratio of the longest HBI to the shortest HBI during a fifteen second Valsalva maneuver. For the 30:15 ratio, the patient is asked to perform a rapid head-up postural change (PC; i.e., standing or tilt) followed by 5 min of quiet standing. The 30:15 ratio is then computed as the ratio of the HBI 30 s after the PC to the HBI 15 s after the PC. All three of these ratios indicate more or less variability in instantaneous HR (IHR), and normal is considered to be values higher than an age-dependent threshold.

Autonomic neuropathy may be described in terms of resting tachycardia, orthostasis, orthostatic tachycardia and bradycardia syndromes, hyperhidrosis, sleep apnea, exercise intolerance, silent ischemia, or silent myocardial infarction. These disturbances, if left untreated, usually proceed to CAN. CAN is a process characterized by progressive damage to the autonomic nerve fibers that innervate the heart and blood vessels, resulting in abnormalities in HR control, vascular dynamics, and organ function [27, 28]. The CAN process leads to CVD and early cardiac death. The American Diabetes Association and the American Association of Clinical Endocrinologists have included as part of the standard of care among diabetic patients ANS testing, shortly after diagnosis and “more than once per year” [38, 39] (p. S37), [40, 41]. CAN is marked by increased morbidity and mortality associated with progressive retinal degeneration, progressive kidney failure, and progressive heart failure (potentially including cardiomyopathy) [27, 28]. In this way, CAN leads to significantly reduced life expectancy, increased numbers of medications that must be taken, and increased hospitalization rates [42]. CAN, known as a “silent killer,” carries a 50 % mortality rate. In diabetic patients, CAN is associated with a 500 % increase in mortality over a 5-year period [42]. Aggressive disease management is recommended in these patients and is the goal of treatment [27, 28, 42]. Disease management, however, is often confounded by autonomic imbalance and the symptoms caused by the imbalance, leading to the addition of therapies that often exacerbate the primary disease. The establishment and maintenance of autonomic balance improves outcomes [42] and may enhance quality of life and reduce morbidity and mortality. CAN has been quantitatively defined as very low, resting, parasympathetic activity [6]. CAN indicates increased risk of sudden cardiac death. CAN, compounded by a relative sympathetic excess (SE), is associated with high risk of sudden cardiac death [43].

All three time-domain ratios are HRV-alone measures. By definition, they all are measures of the total autonomic activity as it relates to variations in IHR [1, 2]. In other words, they are mixed measures of P and S activity. Moreover, changes in any of the three time-domain ratios (including the Valsalva ratio) are qualitative, or relative, indices of changes in the parasympathetic activity. Again, by definition [6], the time-domain ratios are measures of more or less variation in IHR. More variation is caused by higher-frequency activity. Sympathetic activity is known to be low frequency limited [6]. However, the parasympathetic activity is not. Therefore, more (or less) higher-frequency activity of the PSNS causes more (or less) variation in IHR. As discussed in the previous paragraph, CAN and its association with increased morbidity and mortality and high risk of sudden cardiac death [44] require specific quantification of P and S activity. HRV-alone measures provide quantitative, or relative, measures of the total autonomic activity. Three patient examples are presented to illustrate the clinical impact of this difference.

Patient 144 is a 25-year-old, 5′4″, 170 lb female diagnosed with hypertension, asthma, fibromyalgia, and mastocytosis. The patient was prescribed 6.25 mg carvedilol bid after baseline P&S assessment. Improvements with medication include lower BP, decreased headaches, and increased HRV as indicated by the time-domain ratios (see Table 3.1). Typically, the Valsalva ratio is incorrectly regarded as a sympathetic index. It is known that hypertension is associated with high sympathetic activity [45]. If the Valsalva ratio were truly an index of sympathetic activity, Patient 144 should have demonstrated normal Valsalva ratio prior to treatment. This is not the case. Rather, her Valsalva ratio is low (see the top graph, Fig. 3.3) which, by definition [1, 2], indicates a relatively low level of the parasympathetic activity, substantiating the previous interpretation. Hypertension is associated with high sympathetic activity which may induce low parasympathetic activity. Carvedilol is a double cocktail, including two adrenergic (sympathetic) antagonists: an alpha-blocker and a beta-blocker. The normalization of the Valsalva ratio posttreatment (see the bottom graph Fig. 3.3) is a result of reducing sympathetic activity by sympathetic blockade, thereby normalizing parasympathetic activity, as indicated by the normalization of the Valsalva ratio. HRV assessment does not answer the question of whether too much P or S activity is demonstrated. The patient also presented with mastocytosis, asthma, and fibromyalgia. Since the parasympathetic activity is associated with growth, mastocytosis may be associated with abnormal parasympathetic stimulation of the mast cells. It is known that asthma (and COPD) patients are presenting with early CVD. From an autonomic perspective, CVD is associated with SE and asthma is associated with PE. Perhaps the low Valsalva ratio, indicating low parasympathetic activity, suggests SE is induced by beta-2 adrenergic agonist (bronchodilator). This may be an early indicator of (preclinical) CVD or hypertension. Independent P&S measures are needed to fully document this patient’s condition. Further, the pain from fibromyalgia may present as SE (associated with heightened pain sensitivity, tachycardia or hypertension, and nighttime sleeplessness) and PE (associated with fatigue, poor circulation, possible gastrointestinal upset, etc.), exacerbating the SE. While carvedilol helps to relieve SE associated with CVD, hypertension, and pain, it may exacerbate asthma and underlying PE associated with fibromyalgia. Since there are no known upper limits to the time-domain ratios, PE cannot be detected with time-domain ratios. Upon follow-up P&S assessment, Patient 144 demonstrated higher E/I and 30:15 ratios, indicating more relative parasympathetic activity. Therefore, the time-domain ratios alone do not help to titrate therapy specifically for the individual, thereby limiting overall management of the patient.

The P&S results are presented in Table 3.2. Borderline indications with symptoms are considered abnormal. Patient 144’s pretreatment results show three abnormal values : (1) her parasympathetic response to DB is borderline low, indicating the presence of autonomic dysfunction prior to autonomic neuropathy; (2) her parasympathetic response to Valsalva is borderline high, indicating PE; and (3) her sympathetic response to standing is borderline low, indicating SW. Patient 144’s DB response is displayed in the top graph in Fig. 3.4. The gray area indicates the age-adjusted normal ranges. The area between gray and green is borderline abnormal. Her PE in response to Valsalva is displayed in the middle graph in Fig. 3.4. Since Valsalva challenge is a sympathetic challenge, the parasympathetic activity is expected to decrease. Her parasympathetic response is a 385.3 % increase over rest (baseline). Due to the symptoms, this increase is near enough to the borderline region (400–600 %) to be considered abnormal. As discussed above, PE is associated with fibromyalgia. The bottom graph in Fig. 3.4 presents the patient’s P&S responses to PC (standing). The normal physiological parasympathetic response to standing (F) is a decrease from resting (A). This is represented by the vertical blue line down from “A” to “F.” The normal physiological sympathetic response to standing (F) is an increase from (A) of more than 120 % but less than 500 %. The bottom insert in Fig. 3.4 displays her low sympathetic response in response to standing, indicating SW. Patient 144’s BP response to standing is a 5 mmHg drop, indicating possible orthostasis. SW, also indicating poor blood volume and possibly poor circulation, may also exacerbate the symptoms of fibromyalgia.

P&S monitoring posttreatment results include a normalization in the parasympathetic response to DB and to Valsalva. Her parasympathetic response to Valsalva is now a 246.8 % change from resting. These results support the relief of clinical symptoms. The relief is further documented in the changes in her resting responses. The effect of the therapy, carvedilol, is shown in the resting results (see Table 3.2). Her initial baseline or resting sympathetic (Bx S) response decreases as expected. This is accompanied by an increase in her resting parasympathetic (Bx P) response. Overall, her SB became closer to 1.0. Although SW upon standing persists, the magnitude of the sympathetic abnormality and the magnitude of the abnormal BP response are both decreased. Often, relief of SW is realized with proper daily hydration. P&S monitoring provides more details regarding the patient’s condition.

Patient 145 is a 41-year-old, 5′9″, 210 lb male diagnosed with autonomic dysfunction, dyslipidemia, and nonalcoholic steatohepatitis (NASH) syndrome. The patient was prescribed 25 mg nortriptyline bid after the baseline P&S assessment. Improvements with medication include decreased syncopal episodes (postprandial fainting). The time-domain ratio history is presented in Table 3.3. Fainting is associated with PE [45]. It is known that the PSNS uniquely innervates the gastrointestinal tract. Therefore, postprandial fainting may confirm PE. PE cannot be documented with time-domain ratios. The pretreatment HRV-alone assessment indicates the patient’s ANS is well maintained (time-domain ratios are all normal). Only from symptoms is autonomic dysfunction indicated. Low-dose nortriptyline, an anticholinergic, acts to reduce the parasympathetic activity. From the first posttreatment HRV-alone assessment (over a year earlier), Patient 145 demonstrates decreases in the Valsalva and 30:15 ratios and an increase in the E/I ratio. The E/I ratio change is counterintuitive. It suggests an increase in relative parasympathetic activity (again, higher time-domain ratios indicate more variability in IHR, which indicates more parasympathetic activity relative to sympathetic activity). The anticholinergic should have reduced this measure. The DB challenge (from which the E/I ratio is computed) is a model of patient responses after a large meal and prior to sleeping for the night. The fact that the E/I ratio increases may indicate that, while the symptoms have been relieved, P and S have not yet returned to balance. Without the sympathetic measure, this cannot be objectively confirmed. If the Valsalva ratio is considered a relative sympathetic measure (which it is not), the small decrease in the Valsalva ratio is also counterintuitive. As argued above, given that the Valsalva ratio is a relative parasympathetic measure, then there is no confusion, except perhaps to suggest that a greater decrease may have been expected. The low 30:15 ratio results (see Fig. 3.5) from the first posttreatment study correlate with the expected outcomes from an anticholinergic. After a year on the therapy, the E/I ratio is slightly lower than prior to treatment, and the Valsalva and 30:15 ratios have rebounded and are significantly higher than pretreatment. Without a knowledge of sympathetic activity, these HRV-alone results seem to indicate that Patient 145 has had his autonomic balance restored and perhaps may be weaned from the therapy (if a follow-up study shows stability; if not, perhaps reduce therapy to maintenance dosing). More specific P&S measures would enable these types of therapy options. The patient also presented with autonomic dysfunction, dyslipidemia, and NASH syndrome. Specifying the autonomic dysfunction is not possible with time-domain ratios. Neither dyslipidemia nor NASH syndrome has known autonomic implications. Therefore, further insight into autonomic dysfunction is not possible with the HRV-alone information.

Patient 145’s P&S monitoring results confirm syncope. The top graph in Fig. 3.6 presents the parasympathetic (blue) and sympathetic (red) trend data for the P&S study. The six phases of the study, as indicated by the letters across the top of the graph, are as follows: A) resting baseline (Bx, 5 min), B) deep breathing (DB, 1 min), C) baseline (1 min), D) Valsalva challenge (1:35 min), E) baseline (2 min), and F) PC challenge (standing, 5 min). Typical normal responses for a 24-year-old subject are presented in the bottom graph in Fig. 3.6. From the trend plots in the top graph in Fig. 3.6, the patient’s resting baseline (A) response seems to be within normal limits. This is confirmed in the “A: Baseline” response plot (upper left graph) in Fig. 3.8. Again, the gray area indicates normal resting P&S activity. Normal SB is indicated in the area between the outer diagonal lines.

Patient 145’s resting response (the point “A”) is in the middle of the gray area, confirming a normal resting response. This also indicates no autonomic neuropathy. Patient 145’s parasympathetic response to DB (section “B” in the patient’s trend plot, Fig. 3.6) also seems to be within normal limits. This is confirmed in the “B: Deep Breathing” response plot (upper right graph, Fig. 3.8). The DB response data are age adjusted, and the normal range is presented in the gray area. Between gray and green are the borderline areas. The patient’s DB response is borderline low. Patient 145’s sympathetic response to Valsalva (section “D” in the patient’s trend plot, Fig. 3.6) seems low. This is confirmed in the “D: Valsalva” response plot (lower left graph) in Fig. 3.8. The plot is similar in form to that for DB. The lower right graph in Fig. 3.8 presents the PC (stand) responses for Patient 145, averaged over 5 min. The averaging process often masks the instantaneous SE seen in the trend plot (see the top graph in Fig. 3.6; the peak (red) sympathetic response to PC (section “F”) is comparable or taller than that for Valsalva (section “D”); this is physiologically abnormal). In addition to the instantaneous findings (trend plot), the average PC responses suggest further abnormalities. In the case of Patient 145, the average parasympathetic activity increases abnormally from resting (A) to standing (F), indicating PE. Stand PE is confirmed in Fig. 3.7. Also from this figure, it may be argued that Patient 145’s parasympathetic response to Valsalva is borderline high, given his symptoms and a 390.8 % increase. From the PC response plot (lower right graph, Fig. 3.8), his average sympathetic activity decreases slightly over the 5 min interval, indicating (borderline) SW (associated with orthostasis). Together, the PE (indicating vagal excess) and the instantaneous stand SE (associated with syncope) indicate vasovagal syncope, with possible orthostasis, and an abnormal decrease in BP of 9/18 mmHg.

During the first posttreatment test, Patient 145 demonstrates 81 arrhythmia beats, which inflated the resting, DB, and Valsalva responses (see the top graph in Fig. 3.9). Arrhythmia invalidates the time-domain ratio measures, even though the E/I and Valsalva ratios look normal (see Table 3.3). The effects of arrhythmia on the P&S monitoring results are to also inflate the numbers. This is the reason for the “not applicable” (n/a) indications in the posttreatment row of Table 3.4. However, the P&S monitoring SB results remain readable [46]. The patient’s SB is normal (normal SB, 0.4< SB <3.0), indicating that arrhythmia does not have an autonomic component. Based on the stand baseline results (section “E” in the top graph in Fig. 3.9), SW persists.