Autonomic decline is a fact of life (see Fig. 12.1, adapted from [1]). Humans are born with as active a P and S nervous system as they will have. Ultimately, at the end of life, there is no activity in the P or S nervous systems. The normal aging process causes a gradual autonomic decline over time. Figure 12.1 shows the P (blue) and S (red) changes over time from 239 known healthy volunteers from ages 3 to 96 years old (76 females, 31.6 %). None of these subjects are diagnosed with chronic disease and all demonstrate normal responses to the clinical Autonomic Assessment study. Autonomic activity is presented on the ordinate (in bpm²) and age (in years) is presented on the abscissa. P&S activity is represented in blue and red, respectively. The broken line at the 1.0 level is the threshold for advanced autonomic dysfunction (aka DAN, if diabetic), based on Framingham Heart Study findings. These curves offer several insights to normal autonomic decline. At both ends of the age range, parasympathetic activity is normally higher than sympathetic activity (SB is in the low-normal range, 0.4< SB < 1.0). In the early years, this reflects the parasympathetic involvement in development. In the later years, the low-normal SB reflects the added parasympathetic activity that has been shown to protect the heart, reduce morbidity and mortality, and improve outcomes. This has become the recommended autonomic balance for geriatric patients [2–4]. In the middle years, the balance is approximately 1.0 (the curves overlie each other) or a little above 1.0. This may reflect the need of young adults to have the additional energy for child rearing.

The large cohort Framingham Heart Study [5] provided evidence in the general population that lack of HRV is associated with increased mortality risk. Decreased HRV is associated with a number of clinical conditions, including CAD [6–10], hypertension [11–14], altered ventricular function [15–19], and aging [20, 21]. Mortality after a myocardial infarction is more strongly associated with decreased HRV [22–25] than with poor systolic function [26]. Decreased HRV is an independent predictor of mortality in CHF [27]. Heart diseases are the focus here since many other life-threatening chronic diseases known to involve the ANS (e.g., Parkinson’s, COPD, diseases and disorders involving chronic pain, sleep apnea, depression, diabetes, obesity, kidney diseases) typically involve earlier heart disease which associates them with increased mortality risk.

The effect of chronic disease on autonomic function is to accelerate ANS decline (see Fig. 12.10, below), apparently causing earlier mortality risk, including heart diseases. Presented below are data from the four studies investigating diabetes, hypertension, coronary artery disease (CAD), and HIV/AIDS. The last study includes two patient cohorts, those diagnosed as HIV positive and those diagnosed as HIV negative. The age-matched data are plotted against the curves from the normal subjects (see Fig. 12.1). The data from the diabetic patients range from 25 to 96 years old (Fig. 12.2) [1]. The data for hypertension (Fig. 12.6) and CAD (Fig. 12.7) are plotted against the normal subject curves above, but only over the age range from 40 to 90. The HIV data includes normal subject data for the under 21-year-old subjects. The range for the HIV-positive (Fig. 12.8) and HIV-negative (Fig. 12.9) patients is 20–89 years old.

Here we present the diabetes results [1] by way of an example and as a model of chronic disease (Fig. 12.2 which is Fig. 4.​8 repeat for convenience). Serial P&S monitoring of 389 adult patients diagnosed with type 2 diabetes mellitus was administered. The average age of the cohort is 63.2 (range is from 25 to 96), with 161 females (average age 63.5). Depicted with the normal subject data (broken lines) are the resting (baseline) P&S changes (solid blue and red lines, respectively). These data are age matched.

The effects of Diabetes Mellitus on the Autonomic Nervous System may be the most studied effect of all chronic diseases.

As Diabetes effects all systems of the body (directly and indirectly via the ANS) Diabetes seems to be a model of the effects of chronic disease in general on the ANS.

As the title of this chapter indicates, the intent is to build an argument for the effects of type 2 diabetes mellitus on the autonomic nervous system as a model of chronic disease effects on the autonomic nervous system. To begin to recognize this relationship, consider that chronic diseases, like diabetes, like aging, precipitate a similar cascade of secondary symptoms: sleep and GI disturbance, dizziness or lightheadedness, secondary hypertension, and urogenital dysfunction. This is a recurring theme and may help to lend more insight to pathogenesis, identification, diagnosis, and treatment of the effects of chronic disease on the ANS.

As discussed and referenced above, poor P&S results have been correlated with poor outcomes, and normal P&S results have been correlated with healthy outcomes. For example, orthostatic hypotension (OH) is common in diabetes and perhaps the most debilitating comorbidity [30, 31]. OH is a failure of the SNS, but it could also be (partially) caused by an overdrive of the PSNS. Either way it is not an ANS structural deficit, it is a functional issue. Identifying this difference facilitates diagnosis and therapy.

In addition to dizziness or lightheadedness (often from orthostasis), the comorbidities that are associated with diabetes mellitus include:

Perhaps not in the order listed, but these comorbidities are common in chronic diseases. If they were unique to diabetes, it could be argued that the disease itself is the cause of morbidity. Since these morbidities are not unique to diabetes, there must be something else in common. The ANS is in common. Specifically, an abnormal relationship between the PSNS and the SNS, as measured by SB is in common. As has been shown, aging alone causes autonomic decline (Fig. 12.1), and these comorbidities are often demonstrated in geriatric patients. As will be shown by way of several examples below, chronic disease causes autonomic imbalance that is known to accelerate P and S decline which seems to lead to earlier onset of these comorbidities. Due to numerous and extensive investigations into the involvement of the ANS in diabetes, the relationship is characterized, more than any other disease state. As a result, diabetes is an excellent candidate for the model of the effect of chronic disease on the ANS.

The effect of autonomically active therapy (e.g., beta-blockers, antihypertensives, antidepressants) is to help establish and maintain normal SB. Normal SB is known to minimize morbidity and mortality [2–4]. By relieving the comorbidities, the patient becomes more stable and the physician may be more aggressive toward the primary disease. Examples of similar age-matched P and S deficits found in chronic diseases included next are hypertension, CAD, and HIV/AIDS.

As shown before (see “P&S monitoring versus HRV alone” Chap. 3), P&S responses to DB and Valsalva show age-matched declines similar to that at rest (Fig. 12.2). The data [32] are represented here for convenience, together with published average-normal and low-normal DB (Fig. 12.4) and Valsalva (Fig. 12.5) data [33]. Again, a benefit of the dynamic P&S monitoring responses to challenge is that they are a sensitive, and possibly earlier, indicator of systemic P and S dysfunction. Figures 12.4 and 12.5 present the age-varying PSNS (RFa) responses to DB and SNS (LFa) responses to Valsalva challenge, respectively, as thick solid lines. The average high- and low-normal data are the upper and lower thin line curves on the two plots. The insert in each graph is the same graph plotted against a logarithm scale. This is included for those familiar with the DB and Valsalva responses plots on the MPGRs.

Assuming that the effects of diabetes accelerate the aging effects on the ANS, the decline in the patient’s P&S responses to challenge (RFa to DB and LFa to Valsalva) would be faster than that of age-matched normals. While the younger patients’ results are well within the range of age-matched normal data, the parasympathetic responses to DB are near the low end of normal by age 45 and drop below the low end of normal by age 65. This early decrease in parasympathetic responsivity to challenge (Fig. 12.4) may delay the accelerated decline in the sympathetic response to Valsalva challenge (Fig. 12.5).

P&S monitoring uses the heart and lungs as a window to noninvasively quantify P&S activity, regardless of the diagnosis. The ANS is known as one of the great mediators of all of the body’s metabolic needs on a moment-by-moment basis. Since the body only has one heart and one set of lungs, the PSNS and SNS are forced into a continual compromise that requires a single HR and a single respiratory rate to suffice for all. By monitoring the compromise from the point of view of respirations and HR, an overall systemic measure is made. P&S monitoring enables clear observations of underlying physiology, proving more information for improved outcomes. For parasympathetic insufficiency to DB, sympathetic insufficiency to Valsalva, SW, or PE, P&S monitoring provides indications of dysfunction. Further, perhaps due to their sensitivity and the fact that the ANS controls organs and tissues, P&S monitoring detects functional changes earlier, changes that may lead to early clinical diagnoses and intervention.

P&S monitoring provides physicians with more sensitive, quantifiable measures of their patient’s P&S levels of activity. Evidence suggests that these measures also detect physiologic changes sooner than other measures. This is particularly useful, especially given that reversing poor P&S results leads to improved outcomes and that slowing P&S decline reduces morbidity, improving quality of life and mortality. The comorbidities secondary to diabetes within this cohort (orthostasis, BP difficulties, upper and lower GI upset, and sleep and urogenital dysfunction) are comparable to those for other chronic diseases. P and S dysfunction is common to all of these disorders.

P&S monitoring parameters have been shown to be reflective of medication effects, as well as disease and aging effects. Many common medications are known autonomic agents, e.g.:

Patient reactions to disease, therapy, medication, and dosing are directly monitored and documented and used to further guide individualized therapy.

Given the depth and scope of P and S research in diabetes, the effect of diabetes on all systems of the body, and the known effects of autonomically active medication on diabetes and the comorbidities, diabetes mellitus provides a strong model of the association between chronic diseases and the PSNS and SNS. The next three sections support these findings and present similar P and S data for hypertensives, CAD, and HIV/AIDS patients.

The data presented here (Fig. 12.6, adapted from [34]) are originally from a manuscript published in Clinical Autonomic Research entitled “Age Matched Attenuation of Autonomic Activity in Both Branches in Chronic Hypertension.” The abstract was presented as a poster at the 19th International Symposium on the Autonomic Nervous System of the American Autonomic Society, Kauai, HI, 29 October to 1 November 2008 [34]. This study will be presented in full in the “Hypertension” chapter of this compendium. The main findings of this report are presented here to compare with the “diabetes as a model of chronic disease” data. Resting autonomic changes with age in hypertensives as compared with age-matched normal subjects are presented in Fig. 12.6. The broken blue and red curves (P and S, respectively) represent age-matched normal subjects. The solid lines represent the hypertensive patients’ P&S activity. The horizontal broken line is the threshold for advanced autonomic dysfunction. CAN (resting parasympathetic activity less than 0.1 bpm²) in these cases is demonstrated around age 75.

These data are from serial P&S monitoring of 79 hypertensive patients (females = 5; age = 66.6 ± 12.2) with a history of antihypertensive medication. The common comorbidities are diabetes (45 patients) and CAD (46 patients). The data were compared with preexisting data for normal controls (ages 40–90) with no history of diabetes or cardiovascular and autonomic disorders. A Student t-test was performed given the low number of females in this cohort. The t-test finds that the females’ results are statistically similar to the males (p = 0.016).