Several times throughout this book, we list the risk factors that are associated with autonomic neuropathy, specifically CAN. As we have defined, CAN is indicated when there is very low vagal or parasympathetic activity (RFa <0.1 bpm² [1]). In fact, cardiovascular diseases (CVDs, whether primary or secondary) are considered, in part, to be autonomic pathologies, specifically involving abnormal SB. Here we expound on that list. DePace et al. have submitted a review article discussing the association between CAN and risk factors [2, 3]. Heart disease is the leading cause of mortality in the United States [4–7]. Medicine has aggressively sought to determine means of assessing which individuals are most at risk and effective means of treating at-risk patients. As a result, traditional and nontraditional risk factors have been identified. Many of the treatable or modifiable risk factors, however, are lacking in standardized guidelines even though there are noninvasive tests developed to assess these risk factors.

However, the efficacy of standards, such as beta-blocker use after a myocardial infarction (MI), is unclear. Evidence for beta-blockers is derived from relatively old studies, but it has been widely extrapolated to patients with coronary artery disease (CAD) and even to patients at high risk for, but without established, CAD. It is not known if these extrapolations are justified. Moreover, the long-term efficacy of beta-blockers in patients treated with contemporary medical therapies is not known, even in patients with prior MI. Furthermore, beta-blockers are not without adverse effects, and their tolerability is not ideal. Therefore, the benefit of beta-blocker use is unclear. Recently published in JAMA [8], the Reduction of Atherothrombosis for Continued Health (REACH) registry (a longitudinal, observational study) assessed the association of beta-blocker use in stable patients with known risk for cardiovascular events. REACH cohort patients are with a prior history of MI (n = 14,043), or with CAD but no history of MI (n = 12,012), or with only risk factors for CAD (n = 18,653). The study concluded that the use of beta-blockers is not associated with a lower risk of composite cardiovascular events.

The Framingham Heart study [9] has identified numerous risk factors for the development of atherosclerotic heart disease, coronary heart disease (CHD), cerebral vascular disease (which may be manifested by stroke and transient ischemic attack), peripheral artery disease (which may be manifested by intermittent claudication and ischemia to the limbs of the lower extremity), and atherosclerosis of the aorta (which may lead to aneurysm formation). In 1998 the first Framingham Risk score was developed, which incorporated age, gender, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, BP, diabetes, and smoking to derive a calculated risk score of developing CHD, coronary death, or angina within a 10-year period of time [10]. Based on additional research, this risk score was modified in 2002, and diabetes was omitted from the equation, since at that time it was considered a CHD equivalent [11, 12]. Finally, in 2008, the Framingham General Cardiovascular Risk Score was developed, which was a more reliable predictor, not only just of CHD events, but of consequences of atherosclerosis such as stroke, transient ischemic attack, claudication, and heart failure [13–16]. More recently, the Reynolds risk score [17] was introduced as a more comprehensive scoring system and included two additional risk factors: (1) a measure of inflammation, such as high sensitive C-reactive protein (CRP), and (2) a family history of premature CAD.

There are modifiable risk factors, which are risk factors that may be treated and negated, reversed, or diminished. These include (1) diabetes or impaired glucose tolerance, (2) elevated LDL cholesterol, (3) depression of (protective) HDL cholesterol, (4) cigarette smoking, and (5) hypertension. Elevated CRP may also be considered a modifiable risk factor [18]. Treating these risk factors has been shown to reduce risk. For example, the “lipid hypothesis” was eventually resolved [19]. It was demonstrated that cholesterol lowering with pharmacological agents did reduce cardiac mortality and CHD complications [20–28]. Furthermore, it has been demonstrated that very low levels of serum LDL, down to 50 mg/dl, reduce mortality risk [29].

There are nontraditional risk factors which may be modifiable that have been identified. These include (1) psychosocial stresses, (2) clinical depression, and (3) sedentary lifestyle. Obesity, particularly of the abdominal, male type, is also considered an evolving risk factor. Other uncertain risk factors, such as (1) abnormal diet, (2) homocysteine elevation, (3) fibrinogen abnormalities, (4) lipoprotein-a, (5) other systemic inflammatory markers, (6) elevated serum insulin levels, (7) sleep abnormalities, (8) various types of infections, and (9) collagen vascular diseases, are becoming more recognized and investigated [18]. Non-modifiable risk factors include (1) advanced age, (2) gender, (3) genetic abnormalities, and (4) a family history of premature atherosclerosis [18, 30].

Attaining normotensive systolic BP is important. While treating hypertension reduces stroke, heart attack, and heart failure risk and severity, an absolute target level has not been clearly demonstrated [31]. Optimal target blood sugar (hemoglobin A1c) in diabetics is also not known. Initial hypotheses that intensive control of blood sugar would lower cardiac heart disease events have not been proven. Results from recent studies involving various subsets of patients appear to contradict the initial hypotheses [32].

Fifteen studies of 2,900 patients with CAN and without CAN showed a 230 % higher risk of mortality for the CAN diabetics [33]. These data are supported by Ewing’s findings [34]. He demonstrated a 53 % mortality risk after 5 years in patients with CAN. He also compared the mortality rate of abnormal autonomic function tests to a mortality rate of only 15 % over a 5-year period among diabetic patients with normal autonomic function tests. Half of the deaths of individuals that have abnormal autonomic function were from renal failure and 29 % from SCD. Others have utilized meta-analysis to strengthen the association of CAN with cardiac mortality [33, 35, 36]. CAN with high SB is considered high risk [37–39]. HR alone does not provide a reliable diagnostic criterion of CAN [40]. Curtis and O’Keefe [41] showed that the associations of CAN with high mortality rates were consistent across study groups, patient cohorts, testing modalities, autonomic dysfunction, and disease definitions. Subsequent studies have shown that with multivariant analysis, autonomic neuropathy still remains significantly associated with mortality [36, 42, 43]. In summary, after assessment for age, gender, cigarette smoking, diabetes, and other relevant risk factors, autonomic measurements offer significant prognostic information beyond that provided by evaluation of traditional cardiovascular risk factors [2].

Tsuji et al. found a predicted risk increase for a sudden cardiac event in 2,501 men and women who were without clinically apparent heart disease and had reduced autonomic activity [1]. A biologically feasible mechanism for this is that patients with heart disease with increased sympathetic activity, or decreased parasympathetic activity, are predisposed to ventricular fibrillation. While this has been documented by many researchers in many subpopulations of heart disease patients as reduced autonomic activity with increased mortality, increased sympathetic activity and decreased parasympathetic activity often require different treatment modalities. Tsuji noted that his patients appeared to be free of any significant underlying CHD, suggesting that reduced autonomic activity may simply reflect a subclinical cardiac disease state.

Two prospective studies, (1) the Veterans Affairs’ Survival Trial of Anti-arrhythmic Therapy in Congestive Heart Failure and (2) the Autonomic Tone and Reflexes After Myocardial Infarction sub-study, identify an association between reduced autonomic function and heart disease risk in a community-based population [44–46]. Barthel and coworkers [47] demonstrated that abnormalities of autonomic reflex function and autonomic tonic activity in diabetic patients identified those patients with very poor prognosis. Years of follow-up were used in this study and define severe autonomic failure as showing abnormalities in both reflex and tonic activity. In their risk model, autonomic dysfunction was determined to be a significant risk predictor for poor outcome status after MI. They added history of previous MI, arrhythmia on Holter monitoring, poor glucose control, and left ventricular ejection fraction less than 30 % as factors that increase predictions. This highlights the importance, even in the low risk subset of patients post-MI, of performing P&S testing to risk stratify for future cardiac events, including cardiac death. In general, abnormal cardiac autonomic activity as assessed by autonomic monitoring has been associated with post-MI mortality, sudden death, and all-cause mortality.

Liao and coworkers [48] suggest that often abnormal cardiac autonomic activity, especially lower parasympathetic activity, is associated with the risk of developing CHD. This is applicable to a much larger patient base including the general population, whereas post-MI studies are limited solely to those group of patients who have already had a cardiac complication. The study by Liao et al. shows that autonomic dysfunction may be a predictor of subsequent development of CAD. This is an extremely important finding. In this particular study, the follow-up was relatively short, spanning only 3 years, and the population was young. Nonetheless, this study highlights autonomic dysfunction as a potentially important risk factor for newly developing CAD. Therefore, not only is identifying abnormal autonomic function and CAN important for secondary prevention, it is also important for primary prevention.

Microalbuminuria has been associated with an increased risk of cardiovascular mortality independently of other known coronary artery risk factors [49]. Endothelial function and low-grade inflammation have been proposed to explain the increased risk of cardiovascular mortality in individuals with microalbuminuria [50]. The Hoorn study [51] involved 498 individuals from a population-based cohort ages 50–75 who were followed for a median period of 13.6 years. In patients with albumin to creatinine ratio greater than 2.0 mg/mmol, cardiovascular autonomic dysfunction was independently associated with cardiovascular mortality. The conclusions of this study support the fact that it may be useful to treat both microalbuminuria and cardiac autonomic dysfunction in populations at a high risk for cardiovascular mortality. Further, the results suggested that microalbuminuria and cardiac autonomic dysfunction were associated with cardiovascular mortality in an elderly Caucasian population of individuals with normal glucose tolerance.

Lastly, one cannot discuss diagnosis and treatment of CVDs without addressing sudden cardiac death (SCD) [52]. Approximately 67 % of symptoms of SCD are related to CHD [53–55]. Approximately 450,000 individuals per year have SCD in the United States [56], and this is probably an underestimate of the frequency. The risk is three times greater in men than in women based on the Framingham Study data [57]. People at high risk for SCD may be treated with implantable cardiac defibrillators or have other precipitating factors corrected. In a study of 5,713 asymptomatic men, it was concluded that HR profile during exercise and recovery was a predictor of SCD [58]. Subjects had an increase in HR during exercise that was less than 89 bpm. The relative risk was 6.18. Subjects that failed to decrease HR by 25 beats in the first minute after exercise had a relative risk that was 2.2. The risk from SCD was also increased in patients with a resting HR that was more than 75 bpm (relative risk 3.92) [58]. The recovery of HR immediately after exercise is a parasympathetic function, and poor HR recovery is associated with insufficient parasympathetic activity (e.g., CAN). Insufficient parasympathetic activity is associated with increased mortality risk [59]. Again, sufficiently sensitive testing for risk factors and specific predictors of SCD are lacking. However, it may be useful, when treating patients with normal left ventricular systolic function, to risk stratify. Abnormal HR responses, with P&S dysfunction, translate into a significant prognostic risk factor, which results in further follow-up, especially in individuals with normal left ventricular systolic function.

It is apparent that independent, simultaneous P&S testing for cardiac autonomic dysfunction may provide additional information to understand these issues, to guide therapy and treatment, and to enable improved outcomes. P&S testing allows for the risk assessment of patients for future adverse cardiac events, even when they are asymptomatic and have no clinical CAD. Subclinical CAD is associated with cardiac autonomic dysfunction. Testing for the latter may be extremely productive in identifying high-risk patients for cardiac events [60, 61].

DePace et al. conclude that it is unequivocally established, and CAN is associated with increased cardiac morbidity and mortality. Identifying and addressing CAN early, especially in a subclinical cardiac patient, will further differentiate which asymptomatic patients (e.g., those with abnormal SB) require more aggressive therapy. The results from P&S testing documenting CAN may be used as a baseline. One should view these test results as a guide toward more individualized treatment. A more specific selection of medications and dosing based on these results is possible. P&S test results represent objective data which are useful in guiding pharmacological and lifestyle changes, in addition to normalizing and improving CAN risk [62]. Independent, simultaneous P&S testing provides unambiguous measures of P and S activity levels. This may guide the physician toward the type and dosing of pharmacological agents necessary to achieve objective clinical targets or outcomes. The pharmacopeia includes adrenergic agents (beta-blockers, antihypertensives, bronchodilators, and vasopressors) and cholinergic agents (antidepressants, anxiolytics, and antipsychotics). This would eliminate arbitrarily dosing medications without a clear target outside of HR and BP. Also, the threshold for implanting of prophylactic devices such as cardiac defibrillators may be better defined by assessing and following P&S dysfunction. While further studies are indicated, the clinical and epidemiological data are too compelling not to test for, diagnose, and treat CAN aggressively to guard the patient’s well-being.

Because of the higher mortality with CAN, investigators have suggested that individuals with abnormal autonomic assessment should be candidates for closer surveillance and more aggressive pharmacological therapy aimed at targeting values that achieve autonomic balance even if the patient is asymptomatic or subclinical [33]. Using the quantitative measures of P&S activity and P&S balance, as targets for treatment decisions, pharmacological agents may be appropriately titrated and utilized with more precise selection of class and dosing for the individual patient. Identifying P or S dysfunction early and treating it aggressively (based, at least in part, on the autonomic findings) will reduce the emergence of CHD and the ancillary complications [2]. Treatment to establish and maintain proper P&S balance is known to minimize mortality risk [63]. Treatment to modulate one autonomic branch or the other, e.g., with sympatholytics [41] or anticholinergics [64], is known to reduce mortality as well as morbidity risk. This evidence indicates that treating to normalizing P&S balance normalizes CAN risk. Furthermore, Umetani et al. [63] indicate that “more” parasympathetic activity may minimize mortality risk [64]. Yet, too much parasympathetic activity is associated with depression and is known to elevate mortality risk. They indicate that some more parasympathetic activity (at rest) is cardioprotective [63]. “More” parasympathetic activity (at rest) may be titrated against the individual patient’s P&S balance, i.e., low-normal SB.

The data presented here are originally from a manuscript published in US Endocrinology, 2008, entitled “Autonomic Neuropathy Is Treatable.” [62]. CAN is associated with a high risk of SCD. In patients with diabetes, DAN is defined based on the earliest symptoms of autonomic dysfunction, but is currently diagnosed based on early symptoms of sensorimotor neuropathy and Autonomic Assessment (see Fig. 9.1). DAN indicates an increased risk of CAN. In patients without diabetes, DAN is known as advanced autonomic dysfunction and carries similar symptoms and risk. Symptoms of advanced autonomic dysfunction include orthostatic dizziness and gastrointestinal (GI) and genitourinary (GU) symptoms. In diabetics, DAN adds symptoms of hypoglycemia and unawareness, or unresponsiveness, to hypoglycemia. DAN or advanced autonomic dysfunction is only demonstrated in the advanced stages of autonomic decline with dramatic symptoms. Diagnosis of DAN, or advanced autonomic dysfunction, is made only after eliminating other causes of neuropathy. These symptoms are much too late to give anything but symptomatic treatment, and prior to P&S monitoring, autonomic neuropathy (AN) was perceived to not be treatable.

Contrary to the common misperception, AN is treatable. P&S monitoring, based on the diagnosis of chronic disease, enables positive detection, differentiation, and documentation of the progression of autonomic decline. Early detection of autonomic dysfunction (e.g., abnormal SB) enables a greater number of therapy options (see Table 6.​2). With P&S monitoring, advanced autonomic dysfunction in chronic disease patients is documented even when still asymptomatic or vaguely or mildly symptomatic (i.e., fatigue, lightheadedness, palpitations, difficult to control blood glucose or blood pressure, etc.). Therapeutic intervention to restore P&S balance improves outcomes [33, 65, 66] by slowing or halting autonomic decline and associated disease progression in the percentage of patients who, perhaps, were destined to get worse.

If only diabetes led to symptoms that disrupted quality of life, the argument could be made that it was the disease; however, many diseases involve these symptoms. The argument must be made for some underlying condition. Since P or S compromises are involved in all of these functions, it is logical that autonomic dysfunction is part of the process. Advanced autonomic dysfunction, DAN, and CAN are preceded by autonomic dysfunction, characterized by abnormal SB (see Fig. 9.1). The process of aging causes autonomic decline, which in turn leads to AN (see Fig. 9.2; advanced autonomic dysfunction is indicated by the broken horizontal line). Chronic diseases such as diabetes accelerate the aging process and cause early onset of AN (see Fig.​ 4.​8 and Chap. 21).