, Rohit Arora3, 4, Nicholas L. DePace5 and Aaron I. Vinik6
(1)
Autonomic Laboratory Department of Cardiology, Drexel University College of Medicine, Philadelphia, PA, USA
(2)
ANSAR Medical Technologies, Inc., Philadelphia, PA, USA
(3)
Department of Medicine, Captain James A. Lovell Federal Health Care Center, North Chicago, IL, USA
(4)
Department of Cardiology, The Chicago Medical School, North Chicago, IL, USA
(5)
Department of Cardiology, Hahnemann Hospital Drexel University College of Medicine, Philadelphia, PA, USA
(6)
Department of Medicine, Eastern Virginia Medical School Strelitz Diabetes Research Center, Norfolk, VA, USA
From an autonomic perspective, it may be argued that diabetes is one of the most researched diseases. To this point in this book, diabetes has been involved in many discussions. Some of these discussions will be included in this chapter again. The reason for the redundancy is to enable this chapter to be stand-alone and complete.
Overview
Diabetes involves [1, 2] and degrades [3–5] the ANS, shortening a patient’s life expectancy through increased mortality risk. Diabetes also increases morbidity risk, leading to a cascade of secondary disorders that may involve virtually every organ system [6–9]. The American Association of Clinical Endocrinologists [10] and the American Diabetes Association [11, 12] recognize the increased risks associated with diabetes and autonomic neuropathy. It is indicated that risks are evident in the very early stages, for it is recommended that diabetic patients, upon first diagnosis, should have their P&S tested. In fact, in age-matched studies, the average diabetic has already lost approximately 50 % of their autonomic function by the time of the initial diagnosis of the diabetes itself (see Fig. 21.1) [1, 13]. While diabetic neuropathy, starting with diabetic peripheral neuropathy, involves the sensory, motor, and autonomic nervous systems, the P and S consequences of the disease were largely assumed to coincide with the sensory motor changes. This assumption was necessary due to the fact that noninvasive, independent, simultaneous measures of P&S measures were not available. Assuming autonomic neuropathy progresses at the same rate as diabetic peripheral neuropathy may have been the best approximation available. It is now known to be largely in error. The cost of this assumption is measured in lives lost and pain and suffering. It is true that sensory motor losses affect quality of life, but if the nerves that control the heart and vasculature are “dead” and the heart stops, what does it matter? Frequent and periodic, independent, simultaneous P&S monitoring detects the early changes in autonomic function (P&S imbalance) that lead to involvement and degradation of the other organ systems [12, 14]. Restoring P&S balance slows the progression of autonomic decline [4, 5, 7, 15–20].
Fig. 21.1
An age-matched comparison between normal subjects and patients with diabetes (Fig. 4.8 repeated for convenience)
Autonomic decline includes (in order) peripheral autonomic neuropathy (PAN), then diabetic autonomic neuropathy (DAN), and finally cardiovascular autonomic neuropathy (CAN). PAN is characterized by poor peripheral circulation [3, 11, 12, 14], including poor peripheral vascular control that may result in orthostasis. Poor peripheral circulation results in dysfunction such as poor wound healing and dry skin that facilitates wound genesis. More recently, cardiac autonomic imbalance in patients with newly diagnosed and established diabetes has been associated with markers of adipose tissue inflammation [21]. PAN does not involve sensory and motor deficits, causing paralysis and paresthesia. In fact, if the patient feels it, it is not PAN (It is a sensory or motor deficit.) DAN is characterized by resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, “brittle diabetes,” and hypoglycemic autonomic failure [3, 11, 12, 14, 22]. DAN affects many organ systems throughout the body, including the kidneys and the retina [3, 11, 12, 14, 22]. CAN is characterized by damage to the autonomic nerves, both P and S, that innervate the heart and blood vessels resulting in dysfunction in HR control and vascular dynamics [3, 11, 12, 14, 22], increasing mortality risk [5, 22]. Note that the literature often represents CAN or “autonomic neuropathy” as both the process of autonomic decline and the end point of autonomic decline. This is unfortunate as it has led to confusion and an assumption that autonomic neuropathy is not treatable. The latter is not the case, and to avoid confusion in this book, CAN is reserved solely for the end state of autonomic decline.
Sympathetic excess is associated with hypoglycemia [1]. One, early hypoglycemic event (typically asymptomatic) may cause (asymptomatic) SE [23], leading to hypertension secondary to autonomic dysfunction and the start of the cascade of secondary symptoms that characterize PAN and then DAN [23]. Establishing and maintaining normal P&S balance slows the progression of autonomic dysfunction, reducing risk of morbidity and mortality [4, 5], reducing medication load, reducing hospitalizations, improving patient outcomes, and reducing healthcare costs [18].
Ultimately, CAN (the end stage) is demonstrated. CAN is measured as very low parasympathetic activity (with P&S monitoring CAN is defined as RFa < 0.1 bpm2). CAN indicates risk of SCD or silent MI and may be normal for a geriatric patient or post-MI or post-CABG patients. It has been shown that CAN is stratified by SB (see Fig. 21.2, adapted from [24]). CAN with SE (SB > 3.0) indicates high risk of SCD. Given that autonomic dysfunction is asymptomatic until very late in the disease, independent, simultaneous P&S monitoring is required to diagnose and differentiate parasympathetic insufficiency with SE (high risk of sudden death). In fact, the leadership recommends early and frequent P&S monitoring [3, 10–12, 14] to stay autonomic neuropathy as long as possible. The leadership specifies that P&S monitoring is recommended as part of the standard of care for diabetes [3, 11, 12, 14]. That early detection and correction of P&S imbalance (dysfunction) and maintaining normal P&S balance reduces the risk of morbidity and mortality [18].
Fig. 21.2
The results from a large population of geriatric patients (Fig. 15.4 repeated for convenience), demonstrating the mortality (longevity) consequences of the four different ranges of SB
DAN and CAN places a patient at increased risk of mortality under general anesthesia. Preoperative P&S assessment is required since DAN and CAN are often asymptomatic. If undetected or unreported, the mortality risk is exacerbated [25–28].
Several studies, including the United Kingdom Prospective Diabetes Study (UKPDS) [26], the Action in the Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study [29], the Veterans Affairs Diabetes Trial (VADT) [30, 31], and, most recently, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [32], have demonstrated increased morbidity and mortality risk in diabetes associated with CAN.
The VADT study did show that there was a trend towards increased incidence of CAN with intensive versus standard glycemic therapy. The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study [33] showed that (asymptomatic) CAN had one of the highest hazard ratios associated with cardiac death and MI; stronger than (symptomatic) peripheral (non-autonomic) neuropathies. The STENO-2 study [52] showed the intensive multifactorial treatment (including glycemic control) reduced cardiovascular disease by 53 % and CAN by 63 %.
Perioperative morbidity and mortality rates are markedly increased in diabetics [22], with all-cause mortality as much as 20 times greater than for nondiabetics [34]. While diabetics have an increased prevalence of CAD [35, 36], this comorbidity does not fully explain their increased mortality rates [11, 23, 37]. Of note, longitudinal morbidity and mortality in diabetics are significantly associated with the presence of CAN [5, 22, 38–41]. Poor glycemic control plays a central role in development and progression of CAN [42, 43]. However, data from 8,135 patients followed for 3.5 years in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study revealed an all-cause mortality hazard ratio of 2.07 (95 % CI: 1.14–3.76, p = 0.02) and cardiovascular disease mortality hazard ratio of 2.95 (95 % CI: 1.33–6.53, p = 0.008) for patients with advanced CAN compared to patients without CAN – regardless of glycemic control [32]. Indeed, intensive glycemic control leading to chronic hypoglycemia may worsen ANS function [44] increasing the risk of sudden death [42]. Recent articles from Pop-Busui’s lab [32, 45] examined the effect of CAN in the aborted ACCORD trial. As suggested, individual patients with poorer glycemic control and CAN may be those at greater mortality risk. CAN is the differentiator. CAN patients are 1.55–2.14 times more likely to die as compared with those without CAN [32].
Identification of CAN is “pivotal” [32]. As shown in Fig. 21.2 [18], low-normal P&S balance, indicating more parasympathetic activity (but not PE), minimizes the morbidity and mortality risk [4, 5], minimizing medication load and hospitalizations, improving patient outcomes, and reducing healthcare costs [18, 19, 44]. Establishing and maintaining low-normal P&S balance is the treatment for CAN [46].
Numerous accounts have been documented in patients with diabetes, for which P&S monitoring documented rapid, abnormal fluctuations in P&S activity. These findings have enabled proactive intervention, preventing hospitalizations. DAN is well known as the risk indicator for cardiac disease in diabetics. However, earlier detection and treatment of P and S decline, far in advance of DAN, is also known to help preserve quality of life, extend overall survival, and reduce the demand for costly intervention procedures. In the acute (early) stages, improved nerve protected is possible through improved glucose and insulin regulation and with antioxidants. These therapies have been shown to reverse the trend of P and S decline. Early stages are characterized by functional deficits only. There is little or no structural damage at this time. Returning P&S balance and better disease management slows autonomic decline in the subacute and chronic stages and still preserve extant quality of life. This is all prior to a typical DAN diagnosis. Returning P&S balance to a DAN patient forestalls CAN and allows the physician to protect the patient’s cardiovascular system and others. The clinical and autonomic manifestations and consequences of DAN and CAN in patients with diabetes and expected outcomes are summarized in Table 21.1. Diabetes mellitus is a disease that requires customized medicine, and P&S monitoring facilitates customized medicine.
Table 21.1
Manifestations, consequences, and treatment for DAN and CAN in patients with diabetes
DAN | CAN | |
|---|---|---|
Clinical manifestations | Resting tachycardia | Heart rate control dysfunction |
Exercise intolerance | Vascular dynamics dysfunction | |
Orthostatic hypotension | Exercise intolerance | |
Constipation | Intraoperative cardiovascular lability | |
Gastroparesis | Orthostatic hypotension | |
Erectile dysfunction | Painless myocardial ischemia | |
Sudomotor dysfunction | Increased risk of mortality | |
Impaired neurovascular function | ||
“Brittle diabetes” | ||
Hypoglycemic autonomic failure | ||
Early kidney dysfunction | ||
Early retinal dysfunction | ||
Increased risk of morbidity | ||
Autonomic manifestations | Resting P&S measures between 0.5 and 0.1 bpm2 | Resting parasympathetic measure less than 0.1 bpm2 |
P and S abnormalities with PC | High risk of mortality: p < 0.1 bpm2 and SB > 3.0 | |
Damage to P and S nerves that innervate the heart and blood vessels | ||
Treatment | Exercise | Aggressive glycemic control (after controlling SB, see below) |
Weight management | Exercise | |
Glycemic control | Weight management | |
Antioxidants | Antioxidants | |
Lifestyle management | ACE-Is | |
Treat symptoms, including orthostasis (or SW if not symptomatic) and elevated BP | ARBs | |
Aldosterone blockers | ||
Calcium channel blockers | ||
Beta-blockers | ||
Metformin | ||
Autonomic consequences of treatment | Establishing and maintaining normal SB (0.4 < SB < 3.0) and normalizing the stand response (relieving PE, SW, or stand SE) minimizes risk of morbidity | Establishing and maintaining low-normal SB (0.4 < SB < 1.0) minimizes mortality risk |
Hypertension Secondary to Autonomic Dysfunction
These are excerpts from a manuscript originally accepted as an abstract entitled “Enhanced frequency domain analysis identifies early autonomic dysfunction that may lead to elevated blood pressure in diabetics” and submitted to the Diabetes Technology Conference, San Francisco, CA, 10–12 November 2005 [13]. Excerpts of this manuscript are presented here.
Diabetes (A Model of Chronic Disease) Leads to Hypertension Secondary to Autonomic Dysfunction
Introduction
P&S monitoring differentiates autonomic dysfunction before structural deficits or autonomic neuropathy (AN) presents. This differentiation facilitates diagnosis and early therapy, even before end-organ effects present. Our lab has shown that early autonomic decline in the face of a chronic progressive disease such as diabetes begins with the PSNS weakening first, followed by the SNS [47, 48]. It is well known that the SNS modulates BP by modulating baroreceptor reflex (BRR). It is hypothesized that the SNS, before it weakens, is strengthened by the initial PSNS weakness. Thus, this period of SE might upregulate BRR, which in turn may elevate BP. Then when the SNS weakens and it loses its ability to downregulate the baroreceptor reflex, the BP remains elevated.
Methods
Two or more P&S function tests were performed by 389 adult diabetic patients. The average age of the cohort is 63.2 (25–96 years), with 161 females. The cohort includes 354 patients with type 2 diabetes (average age 63.5) and 35 patients with type 1 diabetes (average age 61.1). P&S function tests are based on P&S monitoring. See Fig. 3.18 and Chap. 5 of this compendium for a complete methodology describing the Autonomic Assessment. P&S monitoring allows proper dissection of P from S to further diagnostics. For example, orthostatic hypotension is common in diabetics. Orthostatic hypotension is a failure of the SNS, but it could also be caused (indirectly) by a PE. Either way, it is not a P or S structural deficit, it is a functional issue. Identifying this difference facilitates diagnosis and therapy. Results
Dynamic challenge (DB and Valsalva) responses provide the earliest clues to disease and disorder. From the clinical exam presented to the patients in this study, the P&S (LFa and RFa) responses to DB and Valsalva challenges are the earliest indicators of autonomic decline [see Autonomic Stages, Chap. 13]. Assessing these responses over age provides a sensitive measure of autonomic dysfunction. The left-hand graph of Fig. 21.3 depicts the age-related, average, parasympathetic responses to DB for the cohort. The right-hand graph of Fig. 21.3 depicts the age-related, average, sympathetic responses to Valsalva (V) for the cohort. For reference, these data are presented together with their respective normal ranges (low and high limits) [49]. Both plots include inserts that present the same data plotted on a logarithmic scale to compare with the DB and Valsalva response plots from the Multi-Parameter Graph Report. The parasympathetic response to DB challenge demonstrates an initial decline over the first two decades, followed by a slight plateau. A decade later, the parasympathetic response curve is abnormally low. Although the average decline at this time slows, the parasympathetic response curve remains abnormally low. The sympathetic response to Valsalva challenge demonstrates an initial average decline over the first decade, followed by a more rapid decline over the second decade, and then a plateau over the next two decades. The sympathetic response to Valsalva demonstrates a second period of rapid decline over the last two decades, at the end of which it becomes abnormally low, just before age 85, on average. The early decline in the sympathetic response to Valsalva challenge is delayed relative to the DB, parasympathetic response. The following Valsalva, sympathetic decline parallels the DB, parasympathetic decline over the second decade. The Valsalva sympathetic response continues to parallel the DB, parasympathetic response through the third decade, but holds at its (relative) plateau while the DB, parasympathetic response drops in the fourth decade. Remaining above the low-normal curve, the Valsalva sympathetic response shows a second period of rapid decline during the last two decades presented. On average, the sympathetic response curve does not drop below normal until just before age 85. These relative changes are highlighted in Fig. 21.4.
