, 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
Overview
In the United States, more people have or have had high BP than any other disorder. It is estimated that more than 60 million patients are diagnosed with hypertension [1]. Hypertension is well known to place patients at risk for heart disease, kidney disease, vascular disease, retinal disorders, stroke, and aneurysm, to name a few [2]. Persistent hypertension increases the morbidity and mortality risk, through accelerating P and S decline and the onset of cardiovascular autonomic neuropathy (CAN, see Fig. 20.1) [3, 4]. Management of hypertension may be affected by reduction in sympathetic activity [5]. Upon first diagnosis, P&S activity is already low (see Fig. 20.1), with the sympathetics (red, solid curve) higher than the parasympathetics (blue, solid curve). The normals’ curves (broken lines) are the opposite; parasympathetic are higher than sympathetics. This P and S arrangement in the hypertensives is associated with reduced mortality and morbidity [3, 6, 7], including for patients with CAN. The horizontal, broken line indicates advanced autonomic dysfunction. CAN is demonstrated in the patients around age 75 when the resting parasympathetic activity is below 0.1 bpm2.
Fig. 20.1
An age-matched comparison between normal subjects and patients with hypertension (Fig. 12.6 repeated here for convenience)
It is well known that only the SNS innervates the vasculature, thereby controlling peripheral resistance. Both the P and S nervous systems innervate the heart and control HR (chronotropic activity) and strength of compression (inotropic activity). The SNS mediates baroreceptor reflex (BRR), which in turn mediates BP. The angiotensin–renin system controls fluid levels in the body, including blood volume. Angiotensin directly affects the SNS and the SNS indirectly affects angiotensin [8–10] (see Fig. 1.6). Conditions or activities that result in persistent or chronic increases in sympathetic activity, including emotional and psychological, as well as physiological, stress, may lead to chronic increases in BP and ultimately hypertension [2]. Conversely, prior to organ damage (e.g., heart or vasculature), conditions or activities that reduce sympathetic activity, including stress management programs as well as beta-blockers and antihypertensives, decrease sympathetic activity and thereby decrease BP and relieve hypertension.
SE such as measured during a stress challenge (e.g., a series of short Valsalva maneuvers, see section “Valsalva challenge” in Chap. 5) is a positive risk indicator for hypertension, even prior to an increase in BP [11]. Resting SE is well correlated with hypertension and may be present prior to the diagnosis of hypertension. SE may persist after therapy suggesting persistent risk for hypertension. Sympathetic blockade (e.g., beta-blockers and antihypertensives) relieves SE, relieving high BP and ultimately hypertension. Elevating parasympathetic activity, such as through stress management, may also relieve SE, as long as the parasympathetics are not elevated too far, causing depression, which may increase risk of mortality, as well as fatigue and exercise intolerance [12, 13].
Other factors that may contribute to hypertension include vascular or (alpha-) sympathetic insufficiency or sympathetic withdrawal (SW, see “Hypertension secondary to autonomic dysfunction”) [14]. SW may be induced by antihypertensive therapy, including diuretics. SW, causing vascular insufficiency, causes increased cardiac workload while the patient assumes an upright posture. Increased BP, underlying hypertension, is a measure of the increased cardiac workload. Only independent, simultaneous P&S monitoring detects SE (a beta-adrenergic response) with SW (an alpha-adrenergic response). Normalizing SW reduces resting BP [14].
Independent, simultaneous P&S monitoring is required to differentiate P from S activity to differentiate the various forms of hypertension. Primary SE causes frank hypertension. If SE is induced by chronic diseases such as diabetes, COPD, sleep apnea, or chronic pain, the SE leads to hypertension secondary to autonomic dysfunction [11]. Maintaining normal P&S balance, including normalized SE, for the individual patient, prevents high BP and thereby hypertension [2]. Difficult to control hypertension is associated with SE that is secondary to a hidden PE. The PE is demonstrated either during the Valsalva or the PC challenge [13]. PE causes the reactionary sympathetics to overexert, causing a SE leading to hypertension. Treating the symptoms essentially treats the SE, further enabling the underlying PE, further destabilizing the patient [15]. Relieving PE stabilizes the patient and in some cases even relieves the hypertension. Valsalva PE or stand PE cannot be measured through symptoms or by monitoring BP, HR, or cardiac output. This form of PE is only measured with P&S monitoring. Treating PE with SE reduces the patient’s medication load and eliminates inefficiencies in treating the patient, including trying different medications until finding the one that “works” [15].
Treating PE with hypertension or SE must consider the PE as the primary first and then, if hypertension or SE persists, follow with primary hypertensive therapy as above. To treat PE, consider (1) amitriptyline or nortriptyline (10–12.5 mg QD dinner titrated up to 25 mg bid) or duloxetine (20–30 mg QD dinner) to reduce the cholinergic excess. These are useful if the patient also reports with fatigue, exercise intolerance, sleep disturbances, pain, anxiety, depression, or frequent headache or migraine. Alternatively, for cardiac or geriatric patients, consider carvedilol (3.125 mg titrated higher as needed).
Independent, simultaneous P&S monitoring is required to detect early SE in at-risk patients and differentiate patients with frank SE from those with PE and secondary SE. HRV-alone methods cannot differentiate PE from SE [15]. Continued P&S monitoring, two to four times per year depending on intervention, is required to (1) titrate sympathetic blockade to normalize the individual patient’s resting P&S balance and sympathetic challenge responses, (2) prevent over medication and secondary symptoms, (3) document patient response to disease and therapy, (4) document patient’s compliance with therapy, (5) maintain P&S balance long term to prevent recurrence of hypertension, and (6) document recovery and guide weaning from antihypertensive therapy when possible or establishing maintenance therapy.
Independent, simultaneous P&S monitoring helps to stabilize and manage difficult to control hypertension. Detecting SE early, or detecting PE with SE, guides therapy; enables short-term, low-dose therapy; enables lifestyle management rather medication (if detected prior to end-organ effects); and reduces medication load, morbidity and mortality risk, hospitalizations, and healthcare costs [12, 13].
Attenuation of P&S Activity in Chronic Hypertension
This manuscript was first published as an abstract entitled “Age matched attenuation of autonomic activity in both branches in chronic hypertension.” The manuscript was accepted at the American Autonomic Society, 17th International Symposium, Kauai, HI, November 2008, and presented as a poster presentation [4]. Excerpts of this manuscript are presented here.
Background
With independent, simultaneous measures of P&S activity, a causal relationship between hypertension and SNS activity may be possible. Furthermore, a potential relationship between parasympathetic activity and hypertension may also be possible. This study considers the relationship between the resting sympathetic activity (relative to parasympathetic activity) and hypertension.
Methods
Serial P&S monitoring was performed on 79 hypertensive patients (females = 5; age = 66.6 ± 12.2) with a history of antihypertensive medication (beta-blockers, ACE-Is, or ARBs) and with and without comorbidities (diabetes = 45; coronary artery disease = 46). See Fig. 3.18 and Chap. 5 of this compendium for a complete methodology describing the Autonomic Assessment. The data were compared with preexisting data for normal controls (ages 40–90) with no history of diabetes or cardiovascular and autonomic disorders.
Results
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). Resting P&S levels were found to be significantly (p < 0.001) reduced in chronic hypertensive patients compared to normal controls. An age-distributed investigation (see Fig. 20.1) revealed that the P&S activity normally decreases with age. However, these differences between normal controls and hypertensives are much more marked in the younger population and gradually decrease with age. These trends were observed regardless of any comorbidities or medications. P&S values for 45-year-old hypertensive patients were similar in magnitude to those of 85-year-old normal controls. SE relative to parasympathetic activity at rest (high SB) is associated with high BP and hypertension. Even with a history of antihypertensive medication, and their BPs controlled (average BP for the cohort was less than 133/84), the hypertensives at ages 45 and 55 demonstrate average SBs nearly double that for the normals. In hypertensive patients (Fig. 20.1), there is an average increase in P&S levels from ages 45 to 55, before they decrease again by age 65. It may be that this increase is due to the greater presence of antihypertensive therapy in the patients in their fifth decade as compared to their fourth. The ensuing decrease is presumably due to the continuing aging effect and presence of the disease. Another feature of these data (Fig. 20.1) is the difference between the P&S levels in the two groups by age 85. For the normals, parasympathetic activity is greater than sympathetic activity, which has been shown to be associated with reduced morbidity and mortality [6]. For the hypertensives, the opposite is the case.
Conclusions
Early resting SE relative to resting parasympathetic level (high SB) is the autonomic condition associated with hypertensive patients. Between these two cohorts, both P&S activities appear to be significantly decreased in chronic hypertensives compared with age-matched normal controls. Whether these observations suggest autonomic decline as the effect of hypertension, or as the cause of hypertension, still remains to be established. P&S activity in this (hypertension) cohort is significantly depleted upon first diagnosis and the cohort demonstrates greater morbidity, which is known to lead to poorer outcomes. Establishing and maintaining low-normal SB (0.4< SB <1.0, see Table 6.2) is recommended in the cardiology literature [6] and has been shown to reduce morbidity and mortality, improving outcomes [7, 16].
Hypertension Secondary to Autonomic Dysfunction
Hypertension Secondary to Sympathetic Withdrawal
Hypertension is possible as secondary to the SW (e.g., preclinical orthostatic dysfunction). In fact, the hypertension seems to be a compensatory mechanism. By way of explanation, consider the following example. Assume for a given patient, 140 mmHg pressure systolic is needed for proper brain perfusion upon standing. Assume that the patient’s pressure drops 7 mmHg upon standing. Therefore, to maintain proper brain perfusion, a minimum of 147 mmHg of resting pressure is required by that patient. At 147 mmHg pressure, resting, this patient’s physician would diagnose hypertension and prescribe an agent to reduce pressure. In this example, let us assume that the resting pressure is reduced to 5–142 mmHg. Now the standing pressure is below 147 mmHg again, and the patient complains of dizziness. Without knowing about SW the physician may reduce the dose to reduce the symptoms of dizziness. This is often the case and many patients live with reduced symptoms of both hypertension and orthostasis. Whereas with SW documented by P&S monitoring, a low-dose vasopressor may also be prescribed. This is possible in this case due to low resting BP, assuming no supine hypertension. By prescribing both an antihypertensive and a vasopressor (or volume builder), the heart is protected by the antihypertensive and the vasculature is being treated. Assuming no vascular end-organ issues (“lazy walls,” bad valves, etc.) the vasopressor “retrains” the alpha-adrenergic system to promote vasoconstriction, which reintegrates the vasculature with the heart and in many (especially “physiologically” younger) patients, both symptoms are relieved and both agents may be discontinued once the autonomic dysfunction(s), dizziness, and high BP symptoms are relieved, corrected, and stabilized.
If resting BP is greater than 160/90, consider a mineralocorticoid (e.g., fludrocortisone) with an antihypertensive to build volume and lower BP first. Once BP is under 160/90, if SW persists, then consider switching to the vasopressor, history dependent. Remember, SW may (in part) contribute to elevated, or high, resting BP as a compensatory mechanism to prevent dizziness upon standing. As your patient’s BP is treated, she/he may become dizzy (again). Reassure your patient that this is a good sign. It shows that their ANS is being treated. Treat the dizziness as needed, history dependent.
Diabetes (A Model of Chronic Disease) Leads to Hypertension Secondary to Autonomic Dysfunction
See “Hypertension secondary to autonomic dysfunction” in Chap. 21.
Hypertension Secondary to Autonomic Dysfunction in HIV/AIDS
The HIV/AIDS cohort included in the “Progression of Autonomic Dysfunction” section provides another example of a disease that involves hypertension secondary to autonomic dysfunction. Since HIV/AIDS is not as closely associated with heart disease or hypertension as diabetes, it seems to offer a counterpoint. The cohort of HIV/AIDS patients [17, 18] was further studied to determine their breathing challenge (Fig. 20.2) and resting BP responses (Fig. 20.3) to challenges [17]. The earlier decrease in parasympathetic response to DB ((Fig. 20.2), blue, solid curve) creates a P&S imbalance that results in sympathetic dominance, as indicated by the hashed area. The corresponding, resting BPs are shown in the black curves of Fig. 20.3. Note the higher BPs for the HIV/AIDS patients (Fig. 20.3, solid, black curves) as compared with age-matched normals (Fig. 20.3, dashed, black curves). Comparing these results with those for diabetes (see Fig. 12.10), the early imbalance between the parasympathetic, DB response and the sympathetic, Valsalva response is also demonstrated. This seems to be the root of hypertension secondary to autonomic dysfunction in HIV/AIDS patients. Again, establishing and maintaining P&S balance prevents this imbalance and reduces the risk for hypertension, minimizing morbidity and mortality risk.
Fig. 20.2
Normalized HIV patients’ P&S responses to deep breathing and Valsalva (solid blue and red lines, respectively). The broken lines represent the average normal subjects’ responses
Fig. 20.3
Age-matched resting BP responses for HIV/AIDS patients and normal subjects. (SYS systolic, DIAS diastolic, B×1 = resting, baseline challenge)
Early Autonomic Dysfunction Is Associated with Hypertension in HIV/AIDS Patients
This manuscript was first published as an abstract and was accepted at the American Autonomic Society, St. Thomas, Virgin Islands, 31 October to 3 November 2009, and presented as a poster presentation [17]. Excerpts of this manuscript are presented here.
Introduction
Chronic disease, including HIV/AIDS, leads to early autonomic dysfunction (AD) [10]. AD is defined as an abnormal SB (normal = 0.4 < SB < 3.0). AD presents prior to autonomic neuropathy (AN) and is asymptomatic. AD is associated with greater morbidity (gastrointestinal upset, urogenital disorders, dizziness and lightheadedness, and hypertension secondary to autonomic dysfunction) [19] and mortality [20]. Early intervention restores balance between P & S and reduces comorbidities [19]. We hypothesize that HIV/AIDS-induced autonomic imbalance leads to hypertension secondary to autonomic dysfunction.
To detect early AD, both P&S need to be measured independently and simultaneously. Autonomic decline or AD tends to begin before AN. AD may begin up to two decades prior to AN in some cases. In adults, autonomic decline (Stage 1) begins with weakness in the PSNS response to DB [21]. Stage 2 follows with SNS weakness to Valsalva with or without PSNS weakness to DB. AD continues with Stage 3, which is defined as an abnormal SNS response to standing. Stage 3 may be associated with peripheral autonomic neuropathy (PAN) and onset of comorbidities that affect quality of life (e.g., dizziness, GI upset, sleep disturbances, and urogenital dysfunction). Stage 4 presents when resting autonomic (P or S) response(s) becomes abnormally low. Stage 4 is known as advanced autonomic decline or, if a diabetic patient, DAN. Stage 5 presents when the resting PSNS response becomes very low (resting RFa < 0.1 bpm2). Stage 5 is associated with CAN. CAN indicates high risk of sudden cardiac death. CAN risk follows the Framingham Heart Study [22] time course in post-acute patients. Comparing stages of AD with symptoms, AD may be present up to two decades prior to symptoms associated with AN [19].
Logic suggests that one form of hypertension secondary to autonomic dysfunction hypothesized in this study has its roots in the earliest stages of AD. With the first weakness in the PSNS, as indicated by a weak PSNS response to DB, the dynamic balance between the two autonomic branches is shifted to the SNS, establishing a (relative) sympathetic dominance. Since it is the SNS that uniquely drive BRR and thereby directly control BP, this time of sympathetic dominance could perhaps force BP high. Further, as the SNS weakens in latter stages of AD, due to persistent disease and autonomic imbalance, perhaps the resulting absolute sympathetic weakness prevents sustained BP correction, permitting the rise in BP to persist, leading to hypertension secondary to autonomic dysfunction and perhaps lifelong therapy.
Methods
Autonomic profiling of 232 consecutive HIV-positive patients (47 females) was performed by P&S monitoring at an ambulatory clinic in Missouri (see Table 20.1). During the same time frame, 81 consecutive, HIV-negative patients (34 females) were also assessed by autonomic profiling (see Table 20.1). See Fig. 3.18 and Chap. 5 of this compendium for a description of the methodology.
Table 20.1
Patient cohort demographics, including average stage of autonomic decline
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