, 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
Sudden Cardiac Death
Several times throughout this book, we have listed the risk factors that are associated with autonomic neuropathy, specifically CAN. Here we expound on that list. As we have defined, CAN is indicated when there is very low vagal or parasympathetic activity (RFa < 0.01 bpm2). In fact, cardiovascular diseases (whether primary or secondary) are considered to be associated with autonomic pathologies, specifically abnormal SB. Autonomic responses during acute MI are a major determinant of the outcome (i.e., occurrence of ventricular fibrillation or survival). Specifically, sympathetic activation can trigger malignant arrhythmias, whereas vagal activity may exert a protective effect. Several experimental observations have provided new insights on the relation between sympathovagal interactions and the likelihood for the occurrence of ventricular fibrillation. The antifibrillatory effect of vagal activation (such as with vagal nerve stimulators [1]) is confirmed by the prevention of ventricular fibrillation. Prospective studies show a higher cardiac mortality in patients who after an MI have a depressed baroreflex sensitivity or a decreased HRV [2].
It is known that, as a general rule, parasympathetic stimulation in the atrium is profibrillatory but antifibrillatory in the ventricles, while sympathetic stimulation appears to be profibrillatory for both chambers. From a clinical standpoint, it is interesting that many studies have demonstrated that increased vagal activity at the level of the sinus node, measured by HRV, BRS, HR turbulence, and sinus rate during and after exercise [3, 4] augment reduced risk of SCD, while decreased vagal activity identifies patients at increased risk [5, 6].
A finding of the MADIT-II trial is that in patients with prior MI and ejection fraction (EF) ≤30 %, prolonged QRS duration does not predict sudden cardiac death (SCD), ventricular tachycardia (VT), or ventricular fibrillation (VF) in implantable cardioverter–defibrillator (ICD)-treated patients. However, prior MI and low EF does predict SCD in medically treated patients [7].
Zipes [8] finds that the ANS has an important role in the genesis, maintenance, and interruption of ventricular arrhythmias and SCD [9]. In most instances, sympathetic activation precipitates or enhances ventricular arrhythmias. Evidence is substantial for a neural component in SCD. Sympathetic nerve sprouting and regional myocardial hyperinnervation following myocardial injury promote cardiac arrhythmia and SCD through several potential mechanisms. Modulating autonomic tone is a method to reduce the risk of ventricular arrhythmias. Specifically, vagal tone suppresses their occurrence [10, 11]. Therefore, modulating autonomic tone has been proposed as a method to potentially suppress ventricular arrhythmias [6]. An important mechanism underlying the development of ventricular arrhythmias is electrophysiologic heterogeneity. Electrical heterogeneity predisposes to the development of reentrant arrhythmias and other types of arrhythmias [12].
CAN Indicates SCD Risk
DePace et al. have submitted review articles associating CAN risk with SCD and other cardiovascular risk factors [13, 14]. Coronary heart disease (CHD) is a major health concern among the Western population, affecting nearly half the middle-aged population at some time in their life. CHD is responsible for nearly one-third of all deaths of those over the age of 35. Today, clinicians have several major responsibilities beyond diagnosing which patients have CHD, as they must risk stratify which patients are predisposed for an adverse cardiac event. Studies, such as the Framingham Heart Study, have been performed in order to identify risk factors for the development of CHD. These factors have been effective in targeting high-risk patients, but there are still a large number of individuals who will develop complications from heart disease who are not identified by current scoring systems. Many patients with heart conditions, who appear to be well-managed by traditional therapies, will experience an adverse cardiac event in the future. In order to identify these patients, other possible risk factors, including carotid intimal thickening and arterial brachial index, have been explored. Autonomic function testing, specifically independent measurement of P&S activity, may further aid doctors in risk assessment. Advanced autonomic dysfunction and its more severe form, CAN, have been strongly associated with an elevated risk of cardiac mortality and are diagnosable through P&S testing. Not only will physicians be able to identify a greater number of high-risk patients, but autonomic testing will allow physicians to titrate therapies in order to minimize risk of cardiac mortality and morbidity.
Diabetes, a Model of CAN-Induced SCD Risk
CAN is indicated when there is very low vagal or parasympathetic activity. In fact, cardiovascular diseases (CVD, whether primary or secondary) are considered to be associated with autonomic pathologies, specifically abnormal SB [15, 16].
For example, consider patients diagnosed with diabetes. Diabetes is known to be a risk factor for CVD. They demonstrate a nearly threefold increase in the occurrence of silent MI ([17], see Fig. 19.1, adapted from [18]). P&S testing of these patients prior to the MI could have detected CAN.
Fig. 19.1
Prevalence rate ratios and 95 % confidence intervals for association between CAN and silent myocardial ischemia in 12 studies (Adapted with permission from Vinik and Ziegler [18])
CAN may be induced by a single hypoglycemic event, predisposing patients to sudden death from a second such event [19, 20]. CAN is associated with impending or early ischemia, indicating stenting, enabling a reduction in the occurrence of MIs. Once diagnosed, physicians are encouraged to test patients at least every 6 months [21]. This will also help to detect patients at risk of sudden death due to hypoglycemic or ischemic events or for restenosis.
The risk associated with CAN is confirmed by Ducla-Soares et al. [19]. The authors state:
… the ultimate outcome of increased risk of mortality is clearly associated with the presence of autonomic dysfunction. Results from the ACCORD trial again confirmed the association of CAN and mortality. These investigators showed that the individuals in this trial with baseline CAN were 1.55 – 2.14 times as likely to die as individual without CAN. Furthermore, CAN in the presence of peripheral neuropathy was the highest predictor of CVD [cardiovascular disease] mortality (i.e., hazard ratio 2.95, P = 0.008).
In other words, combining the two articles (consider Fig. 19.2 in light of Fig. 19.1), half (50 %) of the diabetic patients with CAN who suffered ischemic attacks die from CVD, including MI.
Fig. 19.2
Relative risks and 95 % confidence intervals for association between cardiovascular autonomic neuropathy and mortality in 15 studies (Adapted with permission from Vinik and Ziegler [18])
In clinical medicine, it is less than desirable to identify a problem without a solution. Parasympathetic insufficiency (CAN) is known to lead to poor outcomes, regardless of the cause [22–27]. Further it has been shown that CAN is treatable [28]. Beta-blockers and antihypertensives reduce sympathetic activity to the heart, in the hopes of increasing absolute levels of parasympathetic activity. At least in most cases the relative levels of parasympathetic insufficiency are reduced.
Increasing vagal or parasympathetic tone is known to be protective of the heart and is associated with improved outcomes [29–33]. While there are no good, chronic, and cholinergic means of directly increasing vagal tone to the heart without significant and, at times, deleterious side effects, vagal nerve stimulation (VNS) has been explored [1, 34]. VNS has the advantage of not being systemic, thereby reducing side effects of the therapy. VNS has the disadvantage of stimulating both vagal efferents and afferents; it requires surgery and intense management, and it lacks standardized protocols.
However, for the purposes of our illustration, the advantage of VNS demonstrates the benefits of enhanced or preserved vagal or parasympathetic activity. VNS has been shown to prevent cardiac remodeling after MI [34]. Human data show only small differences after a 3-day stimulation protocol but significant differences between controls (non-VNS, post-MI patients) and VNS post-MI patients after 8 weeks [34]. In rodent heart failure models [35], VNS produced no change in mice without induced heart failure and significant, positive changes in mice with heart failure. These positive changes lead to a 40 % increased survival rate after 20 weeks. Zhang [36] showed similar results in dog. In humans, Schwartz and Ferrari [37, 38] showed that long-term VNS improved ejection fraction and end-diastolic diameter. When beta-blockers are added to VNS, a further increase in the human survival rate was demonstrated over that of beta-blockers or VNS alone. It seems as if the effects are additive. VNS improves outcomes by reducing MI, VF, and heart failure [39].
Although the exact mechanism by which sympatholytics or VNS helps to prevent remodeling and improve outcomes is not known, clues may be based on the combined benefits by improving resting parasympathetic activity, with respect to sympathetic activity [40]. Figure 19.3 summarizes the progression of cardiovascular risk with worsening autonomic dysfunction, including CAN. While these data are from patients diagnosed with diabetes, other major chronic diseases seem to follow the same progression of autonomic dysfunction leading to increased morbidity and mortality risk.
Fig. 19.3
The natural history of autonomic balance, based on diabetes as a model of the affect of chronic disease on the autonomic nervous system. IL-6 interleukin-6, an inflammatory marker, HMWA/L high-molecular weight adiponectin-to-leptin ratio, an inflammatory marker, LFa low-frequency area, a pure measure of sympathetic activity (based on concurrent spectral analyses of continuous measures of both respiratory activity and HRV), RFa respiratory-frequency area, a pure measure of parasympathetic activity (based on concurrent spectral analyses of continuous measures of both respiratory activity and HRV), E/I ratio the ratio of the peak exhalation R-R interval to the peak inhalation R-R interval (R-R interval is the interval between two consecutive heart beats and is a qualitative measure of more or less parasympathetic activity), rmsSD root mean square of standard deviation, a statistical measure of heart rate variability (HRV) and is a qualitative measure of more or less parasympathetic activity, PAI-1 plasminogen activator inhibitor 1, an inflammatory marker, TA/L ratio total adiponectin/leptin ratio, an inflammatory marker, Valsalva ratio the ratio of the longest to shortest R-R interval during a 15 s Valsalva maneuver, a qualitative measure of more or less parasympathetic activity, TSP total spectral power, a measure of gross autonomic activity (parasympathetic plus sympathetic activity), sdNN standard deviation of the beat-to-beat (R-R) intervals, a measure of gross autonomic activity (parasympathetic plus sympathetic activity), RFa respiratory-frequency area, a pure measure of parasympathetic activity (based on concurrent spectral analyses of continuous measures of both respiratory activity and HRV), SB sympathovagal balance = ratio of resting sympathetic activity to resting parasympathetic activity. Very low RFa is a definition of cardiovascular autonomic neuropathy (CAN), increased indicating mortality risk. CAN with high SB is associated with high mortality risk (see text) (Adapted with permission from Vinik and Ziegler [18])
Heart Diseases
Overview
All muscles in the body are controlled by nerves. The heart is no exception. The heart is controlled by both the PSNS and the SNS. Heart muscle, of course, is unique. When considering heart muscle function, there is the mechanical activity of the heart (i.e., muscles, valves) such as measured in echocardiograms and the electrical activity of the heart muscle such as measured by EKG. Neither of these directly considers the influence of the ANS. Historically, due to a lack of reliable P&S measures, the ANS input to the heart has largely been assumed as represented in HR, BP, and cardiac output levels and changes. However, this is often misleading, since both P and S branches are involved in the control of all three.
Generally, in healthy, normal individuals, the parasympathetic input to the heart results in respiratory sinus arrhythmia, which causes higher HR variability (HRV). Parasympathetic input also causes lower mean HR and reduces contractility which reduces average BP. The SNS input to the heart results in the opposite: reduced HRV, higher HR, and higher BP. P&S monitoring, together with cardiac monitoring (EKGs, stress testing, imaging, tilt-studies, etc.), differentiates muscle from nerve dysfunction, providing more information to improve the differential diagnosis, quantify individual patient’s responses to disease and therapy, and improve outcomes.
Effects of abnormal SB have been reported by physicians [personal communication from a contributing editor]. Example effects include unexplained arrhythmia (reports of palpitations with negative 12-lead EKG) and mitral valve prolapse syndrome (symptoms of mitral valve prolapse with negative auscultation).
Heart diseases, including congestive heart failure (CHF) [41], coronary artery disease (CAD, see Fig. 19.4 [42]), arrhythmias [43], and sudden cardiac death syndrome, involve P and S dysfunction (imbalance), including CAN [18, 44]. CAN begins as asymptomatic and progresses. Oftentimes when symptoms of heart disease are present, it is too late, or lifelong maintenance therapy is required. Symptoms may include sudden death, MI, or ischemia. Simply normalizing HR, BP, and cardiac output is often not sufficient. Normalizing these measures is tantamount to normalizing only sympathetic activity. Advanced autonomic dysfunction is indicated below the horizontal broken line in Fig. 19.4. CAN is defined as severely low parasympathetic activity as demonstrated around age 65 (parasympathetic activity, RFa, less than 0.1 bpm2) and is not directly or primarily associated with HR, BP, and cardiac output.
Fig. 19.4
An age-matched comparison between normal subjects and patients with coronary artery diseases (CAD). Figure 12.7 repeated here for convenience
CAN is characterized by structural neurological deficits due to loss of P or S neurons that innervate the heart and blood vessels, resulting in abnormalities in HR control and vascular dynamics [18]. CAN is associated with risk factors, including low ejection fraction [45, 46]; poor cardiac output [47]; arrhythmias [43, 48, 49]; cardiomyopathies [50, 51], including chronic heart failure [52]; poor circulation [53], including poor cardiac circulation; angina or CAD [54]; greater mortality [18]; and greater morbidity [44], including silent myocardial infarction and early cardiac death [44, 55]. CAN leads to sudden death, sometimes before patients demonstrate symptoms [24]. Establishing and maintaining autonomic balance slows the progression of autonomic dysfunction and autonomic neuropathy, reducing morbidity and mortality and improving outcomes [18, 44, 56].
Direct or indirect sympathetic blockade (e.g., beta-adrenergic blockers and antihypertensives, respectively) is known to change autonomic balance. They decrease sympathetic activity, including sympathetic activity to the heart [57], and may also increase parasympathetic activity at the heart [58]. Increased parasympathetic activity is associated with greater longevity in geriatric and heart disease patients [18, 56, 59].
With heart disease, there are known cases where resolving P&S imbalance relieves the cardiac symptoms (e.g., tachycardia, bradycardia, arrhythmia [43]). Likewise, there are known cases where chronic heart disease causes P&S imbalance. Most of the time, it is a combination of cardiac and autonomic dysfunction. Regardless of which came first, the two exacerbate each other, accelerating the progression of cardiac and autonomic dysfunction. Relieving P&S imbalance slows the progression, reducing morbidity and mortality, improving patient outcomes, and reducing healthcare costs [59, 60].
Relieving P&S imbalance typically depends on prescribing sympathetic blockade. However, as documented in the Framingham Heart Study, too much sympathetic blockade may induce PE [41, 61]. PE is associated with depression [62]. Depression is also known as a risk factor for increased mortality in heart disease patients [63]. Even if the depression is not induced by therapy, it still places a heart disease patient at greater mortality risk. Establishing a proper P&S balance for the patient, as documented by P&S monitoring, minimizes mortality risk, reduces medication load and hospitalizations, improves outcomes, and reduces healthcare costs.
As reported [personal communications], there are numerous cases where CAN with SE has been documented in younger patients without diagnosed heart disease, hypertension, or diabetes. These patients report chronic headache, palpitations or unexplained arrhythmia, dizziness or lightheadedness, thyroid disease, or depression or fatigue. Upon independent, simultaneous P&S monitoring, CAN with SE (as measured by high SB) is documented. Then, upon cardiac work-up, a positive stress test is documented. The majority of these patients are referred for cardiac catheterization. In all cases, interventions are required, including some to prevent catastrophic cardiac events from blocked coronary arteries or malignant, asymptomatic arrhythmias. Similar cases were found in patients with CHF, for which P&S monitoring documented rapid, abnormal fluctuations in P&S activity, enabling proactive intervention and preventing hospitalizations.
Coronary Artery Disease
This manuscript was first published as an abstract entitled “Altered sympathetic and parasympathetic activity is associated in patients with chronic coronary artery disease.” The manuscript was accepted at the American Autonomic Society, 17th International Symposium, Kauai, HI, October 2008, and presented as a poster [42]. Excerpts of this manuscript are presented here.
Background
Chronic CAD may lead to a reduction in both the low- and high-frequency power (LF and HF, respectively) of baseline HRV [64, 65]. The additional information provided by P&S monitoring helps to gain a deeper understanding of the cumulative effect of patients’ history and responses to therapy, disease state, and lifestyle. Establishing and maintaining a normal P&S balance has been shown to improve outcomes through reduced morbidity and mortality [59].
Methods
Serial ANS testing was performed on 55 CAD patients (females = 5; age = 65.5 ± 13.3) with and without comorbidities (hypertension = 42; diabetes = 25). The data was compared with preexisting data for normal controls (age range = 40–90) with no history of diabetes or cardiovascular and autonomic disorders. See Fig. 3.18 and Chap. 5 of this compendium for a complete methodology describing the Autonomic Assessment. ANS profiling was based on patient responses to a standard clinical study that includes a 5 min resting baseline. Patients with arrhythmia were excluded.
Results
The results are presented in Fig. 19.4. Baseline (Bx or resting) P and S changes with age in CAD patients are represented by the solid blue and red lines, respectively. The broken blue and red lines represent age-matched normals (P and S, respectively). The horizontal, broken line indicates advanced autonomic dysfunction. CAN is demonstrated around age 65 when the resting parasympathetic activity is below 0.1 bpm2.
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 = 0.051). Resting sympathetic as well as parasympathetic levels were found to be significantly reduced in chronic CAD patients as compared to normal controls (see Fig. 19.4). An age-distributed investigation revealed that P&S activity decreases with age, a trend similar to that of normal controls. However, these differences between normal controls and CAD patients are much more marked in the younger population and gradually decrease with age. These trends were observed regardless of any comorbidities or medications. The P&S values for 45-year-old CAD patients were similar in magnitude (or lower) than those of 85-year-old normal controls (see Table 19.1). The fact that the difference between the CAD patients and normals decreases seems to be due to the aging effect of the normals. The CAD patients’ average P&S levels remain much the same across the ages studied.
Table 19.1
P&S results for normal and CAD patients’ age by decade
CAD | Normal | |||||
|---|---|---|---|---|---|---|
Mean age | S | P | N | S | P | N |
42.0 | 1.10 | 0.65 | 5 | 3.58 | 3.64 | 28 |
54.2 | 0.87 | 0.59 | 18 | 2.73 | 2.68 | 18 |
63.0 | 0.91 | 0.35 | 13 | 1.94 | 1.92 | 15 |
74.7 | 0.52 | 0.35 | 10 | 1.21 | 1.39 | 8 |
83.6 | 0.49 | 0.46 | 9 | 0.54 | 1.00 | 3 |
Excess sympathetic activity relative to parasympathetic activity at rest (high SB) is associated with CAD and heart disease. Even with a history of cardiac medication, and their BPs controlled (average BP for the cohort was less than 153/89), the CAD patients present at ages 45 and 55 with SB, on average nearly double than for the normals. Throughout most of the CAD population, resting sympathetic activity is nearly doubled that of the resting parasympathetic activity. High sympathetic activity relative to parasympathetic is also known to be a risk factor for mortality [59]. The geriatric cardiology literature indicates that more parasympathetic activity relative to sympathetic activity is associated with improved outcomes and lower morbidity and mortality [18, 44, 59]. From these data, this is represented by the relative parasympathetic dominance (over sympathetic) in the normals at ages 75 and 85. This relation between P and S is reversed in the CAD population throughout the decades. This higher SB may be associated with the increased morbidity and mortality in CAD patients leading to poorer outcomes.
Conclusions
Overall, autonomic activity appears to be significantly decreased in CAD patients compared with age-matched normal controls, suggesting that CAD may affect an acceleration in the (physiologic) aging process of patients as compared to age-matched controls. A significant, relative sympathetic dominance in these patients may be associated with the greater morbidity and mortality associated with CAD.
Congestive Heart Failure
The following quotes are from the Journal of the American Medical Association [57]: “…[For] patients with heart failure, [beta]-blockers have been shown to reduce morbidity and mortality and are strongly supported by consensus recommendations and clinical guidelines.” “Enthusiasm for the use of [beta]-blockers as a treatment for heart failure emerged slowly. Conventional wisdom held that heart failure was solely due to a decline in systolic function and was an absolute contraindication for the prescription of any medication with negative inotropic action.” However, “…the heart-rate–lowering properties of [beta]-blockers could provide benefit to patients with heart failure….” “…[Beta]-blockers were well tolerated by patients with heart failure…,” and there are “clinical benefits of [beta]-blockers in patients with heart failure…”
“…[Heart] failure [is] a complex disorder characterized not only by declines in systolic function, but also by a maladaptive increase in adrenergic drive… The pathophysiology of heart failure was related to activation of the adrenergic nervous system. Early in heart failure, drops in cardiac output lead to decreased organ perfusion, a compensatory increase in adrenergic drive, and the subsequent release of neurohormones such as norepinephrine. In turn, norepinephrine stimulates ventricular contraction and increases vascular resistance, thereby increasing cardiac output and BP. This increase in the cardiac adrenergic drive, initially a compensatory mechanism for the failing heart, is one of the earliest measurable responses in heart failure occurring while patients are still asymptomatic…” “This chronic activation of the adrenergic nervous system leads to several potentially deleterious effects on the heart. Sustained adrenergic activation and norepinephrine release raise cardiac output and HR, which then increase myocardial oxygen demand, ischemia, and oxidative stress. At the same time, peripheral vasoconstriction increases, both preload and post-load, causing additional stress on the failing ventricle. This long-term mechanical stress in conjunction with cardiac fibrosis and necrosis promoted by norepinephrine contributes to cardiac remodeling and a dilated, less contractile cardiac chamber. Norepinephrine downregulates the beta-1 adrenergic receptor and uncouples the beta-2 adrenergic receptor, leaving the myocyte less responsive to adrenergic stimuli, and further decreases contractile function. Thus, prolonged activation of the adrenergic system may be maladaptive, causing progressive deterioration of myocardial function and portending a poor prognosis [57].
As the neurohormonal hypothesis emerged, so too did a new understanding of the potential role of beta-blockers in heart failure. Although acute treatment with beta-blockers decreases BP and cardiac index, long-term administration of beta-blockers is associated with significant increases in ejection fraction and cardiac index and a decrease in left ventricular end diastolic pressure. Beta-blockers reverse the deleterious changes associated with left ventricular remodeling and decrease myocardial mass and left ventricular volume, leading to improved hemodynamics. Finally, beta-blockers may also mediate benefit via regulating HR and decreasing cardiac arrhythmias. These direct cardiac effects led to the hypothesis that beta-blockers would provide substantial clinical benefits in patients with heart failure [57].
Therefore, CHF (like other cardiovascular diseases) is associated with SE. SE is known to be associated with high mortality rates. Currently, combinations of beta-blockers and antihypertensives (both block or reduce sympathetic activity) are part of the therapy plan to protect the patient’s heart by reducing SE. P&S monitoring documents the patient’s response to disease, and subsequently therapy, to help titrate therapy to normalize the patient’s SB as well as HR and BP. Without P&S monitoring, the average therapy CHF plan tends toward high doses of sympathetic blockade.
It is also known that depression is associated with high mortality rates in heart disease patients. Depression is associated with PE (see Chap. 16). To this end, the American Heart Association has established the standard of care for CHF to include triple adrenergic (sympathetic) blockade and an antidepressant (i.e., anticholinergic). According to the ValHeft study [61, 66], 35 % of CHF patients (NYHA Classes I–III) are over blocked. This was determined without the use of P&S monitoring. The study showed that for these 35 %, upon removal of one of the sympathetic blockers, the patients reported feeling better. A repeat of the ValHeft study was performed with P&S monitoring at the Albert Einstein College of Medicine under Dr. Ed Sonnenblick [41]. The study showed that the patients qualifying under the ValHeft criterion had resting PE as compared to the nonqualifiers, with normal to low resting sympathetic levels. By removing an adrenergic blocker (the ARB in this case), the patient’s resting parasympathetic levels dropped significantly. The resting sympathetic levels were still low and remained blocked even in the face of a Valsalva challenge (see the Chap. 5). Furthermore, the patients reported being able to climb a flight of stairs without pausing or were able to spend an hour with the grandchildren without fatiguing quickly. The details of the study follow.
The ValHeFT Trial Revisited
This manuscript was first published as an abstract entitled “Withdrawal of angiotensine receptor blocker from triple neurohormonal therapy partially restores sympathetic activity in chronic heart failure.” The manuscript was accepted at the American Heart Association, Scientific Sessions, Anaheim, CA, 11–14 November 2001, and presented as a platform speech [41]. Excerpts of this manuscript are presented here.
Background
Congestive heart failure (CHF) is a syndrome in which the cardiac output is reduced, with subsequent compensatory activation of the renin–angiotensin and adrenergic systems secondary to hypoperfusion of the renal system. Therapies that have proven to reduce morbidity and mortality in patients with CHF have targeted the inhibition of the renin–angiotensin system (see Fig. 19.5) and include sympathetic blockers such as ACE-Is, ARBs, and beta-blockers.
Fig. 19.5
Inhibition of the angiotensin–renin system by sympathetic blockers, including beta-blockers, ACE-Is, ARBs, aldosterone blockers, and renin blockers
The Valsartan in Heart Failure Trial (ValHeFT) examined more than 5,000 patients with mild-to-moderate heart failure. The study results showed that compared to placebo, Valsartan (an ARB) when added to an ACE-I reduced heart failure hospitalizations by 28 %, but had no effect on mortality. Subset analysis of the ValHeFT trial defined a group of patients on triple neurohormonal blockade (beta-blocker, ACE-I, and ARB) and observed a trend toward poorer outcomes in these patients. See ValHeFT results in Fig. 19.6. The figure presents relative risks and 95 % confidence intervals for the combined end point (death from any cause, cardiac arrest with resuscitation, hospitalization for worsening heart failure, or therapy with intravenous inotropes or vasodilators) according to demographic and clinical characteristics [66].
Subset analysis of ValHeFT suggests that triple neurohormonal blockade increases mortality secondary to abnormally low SB. The low SB indicates resting PE. PE is associated with depression, which is known to be associated with risk of increased mortality in HF patients [63]. Normalizing SB may relieve this risk, but independent, simultaneous measures of P&S are required to document the baseline imbalance and follow up normalized SB.
Hypothesis
Withdrawal of ARB from triple neurohormonal blockade restores sympathetic activity as measured quantitatively with P&S monitoring.
Methods
Patients diagnosed with heart failure were encountered in an outpatient heart failure setting and were receiving triple neurohormonal blockade at the time of enrollment. Ten patients (age 64 ± 11 years, including five women) were enrolled. Five patients were ischemic, five were hypertensive, five were diabetic, and five were diagnosed with CAD, NYHA Class I–III. The average left ventricular ejection fraction (normal 50–70 %) for the cohort was 39 ± 7.3 %, and the left ventricular internal dimension, diastole (normal 35–60 mm), was 61 ± 5.5 mm. Patients were studied and baseline P&S assessment was performed, including resting SB and sympathetic response to PC challenge (standing). See Fig. 3.18 and Chap. 5 of this compendium for a complete methodology describing the Autonomic Assessment. Patients were excluded if they presented with AFib or high-quality arrhythmia. ARBs were then discontinued as suggested by the ValHeFT study. P&S monitoring was repeated after an average 1-month washout period. Resting SB balance and sympathetic response to standard physiologic stress (PC) were compared before and after discontinuation of the ARB. Patients on beta-blocker and ACE-I served as controls. Patients had a history of one of two ACE-Is: fosinopril (31 mg, QD) or enalapril (20 mg, bid). Patients had a history of one of three beta-blockers: carvedilol (19.4 mg bid), atenolol (93.8 mg QD), or metoprolol (75 mg bid).
Results
Upon initial assessment, all patients presented with abnormally low (resting) SB (cohort average = 0.06; normal SB: 0.4 < SB < 3.0), indicating PE, and an abnormal response to standing was observed consistently in patients prescribed triple neurohormonal blockade. After the ARB was discontinued, all patients were retested, those now on dual neurohormonal blockade, as well as those who remained on triple neurohormonal blockade. The results are presented in Table 19.2. Patients who remained on triple neurohormonal blockade persisted with abnormally low SB (subpopulation average = 0.04). Patients who were now on dual neurohormonal blockade presented with normal SB (subpopulation average = 0.51). Improvement in resting balance was accompanied by improvements in patients’ sympathetic responses to standing. Patients who remained on triple neurohormonal blockade presented with a 12-fold average increase in their standing sympathetic response. This is considered excessive. Patients who were now on dual neurohormonal blockade presented with a more normal standing sympathetic response, a cohort average 11 % increase.
Table 19.2
Comparison of P&S parameters by dosing population
NHB | Sympathetic | Parasympathetic | ||
|---|---|---|---|---|
Rest | Standing | Rest | Standing | |
Triple | 0.01* | 0.13* | 0.24 | 0.18 |
Dual | 0.19* | 0.21* | 0.37 | 0.20 |
Control | 5.33 | 18.85 | 2.70 | 10.46 |
Conclusion
Triple neurohormonal blockade may result in profound blockade of the adrenergic system, producing significant loss of sympathetic tone and disruption of normal SB. This may explain the observed adverse outcome of such patients in the ValHeft trial. Discontinuation of the ARB results in normalization of SB in heart failure patients on triple neurohormonal blockade. Depression is a known mortality risk factor in heart failure patients. PE is associated with depression. PE may be induced in some patients by excessive neurohormonal blockade. Reducing sympathetic blockade, such as by discontinuing the ARB, reduces PE, normalizing SB, and may result in reducing morbidity and improving outcomes.
The next two sections present two outcome studies for therapies that are typically considered to be a part of therapy plans for heart disease patients. The two medications are ranolazine and carvedilol. The outcome studies also focus on the effect of these agents on the P and S nervous systems and consider the role of the P and S nervous system in the outcomes.
Ranolazine Therapy
These are excerpts from an original submission entitled “Changes in autonomic balance in aggressively treated heart failure patients associated with Ranolazine therapy [67].”
Background
Adverse neurohumoral activation in CHF contributes to progressive left ventricular failure and sudden death. In CHF, there is an increase in the myocardial late sodium current (INa), leading to an intracellular Ca++ overload that causes diastolic dysfunction, microvascular ischemia, and after depolarizations increasing the risk of sudden death [68]. In therapeutic concentrations, ranolazine decreases the late INa by 50 %, thereby improving this Ca++-related mechanical and electrical dysfunction [68]. Additionally, like lidocaine, ranolazine is an inactive-state Na channel blocker, causing selective atrial Na channel blockade [69]. Since nervous system Na channel (Nav) types 1, 2, 3, and 6 are found in the heart [70], it is possible that ranolazine may directly alter ANS Nav function. The effects of ranolazine on cardiac SB in CHF are studied.
Methods
Seventeen aggressively managed CHF patients (six females) were treated with ranolazine at 500–1,000 mg bid after baseline noninvasive assessment of hemodynamic (impedance cardiogram) and P and S function. P and S function is based on P&S monitoring (see Table 19.3 detailing patient demographics). See Fig. 3.18 and Chap. 5 of this compendium for a complete methodology describing the Autonomic Assessment.
Table 19.3
Ranolazine study patient cohort demographics and therapy description
Demographics | Therapy | ||
|---|---|---|---|
Totals (n) | 17 | ||
Age (mean) | 65 years old | Beta-blocker | 17 (100 %) |
Sex | 6 females (35 %) | ACE-I/ARB | 12 (71 %) |
AODM | 11 (65 %) | Statin | 11 (65 %) |
CAD | 10 (59 %) | Aldo. antag. | 8 (47 %) |
Hypertension | 9 (53 %) | biV pcd | 6 (35 %) |
CRD | 5 (29 %) | pcd | 2 (12 %) |
Average electrocardiographic findings | ||
|---|---|---|
Patients | Systolic CHF | Diastolic CHF |
Totals (n) | 9 | 8 |
LVEF (%) | 28 | 58 |
LVEDD (mm) | 62 | 46 |
LAD (mm) | 45 | 46 |
Nine patients were diagnosed with systolic CHF, and eight with diastolic CHF. All (100 %) of those studied were prescribed beta-blocker therapy, 71 % were prescribed ACE-I/ARB therapy, 21 % were diagnosed with chronic renal disease, 65 % had a history of a statin, 59 % were prescribed an aldosterone antagonist, and 47 % had an implanted defibrillator. Baseline studies were repeated in 1 week to 3 months.
Results
Changes in P&S Measures in CHF
Nine of the 17 patients (53 %, 5 with systolic CHF, 4 with diastolic CHF) presented with abnormal ANS assessment. Five of the nine (56 %) presented with high SB (SB >3.0), indicating a relative resting SE, and four of the nine (44 %) presented with CAN, indicating risk of SCD. All nine showed improvement on ranolazine. Patients’ SB decreased on average 94 % and normalized in four of five (80 %) patients. CAN was relieved in all four (100 %) patients originally presenting with CAN. Table 19.4 presents changes in CHF patients’ P&S and hemodynamic responses.
Table 19.4
Changes in P&S and hemodynamic responses in patients diagnosed with CHF with high SB or CAN
(n = 9) | Pre-ranolazine | Post-ranolazine | Significance |
|---|---|---|---|
Average resting results | |||
Sympathetic modulation (LFa) | 8.75 bpm2 | 0.76 bpm2 | p = 0.089 |
Parasympathetic modulation (RFa) | 0.79 bpm2 | 0.63 bpm2 | p = 0.381 |
SB (LFa/RFa) | 23.1 | 1.46 | p = 0.125 |
Average deep breathing results | |||
Parasympathetic modulation (RFa) | ×6.85 | ×4.65 | p = 0.076 |
Average Valsalva results | |||
Sympathetic modulation (LFa) | ×16.73 | ×14.20 | p = 0.422 |
Average standing results | |||
Sympathetic modulation (LFa) | 6.45 bpm2 | 0.33 bpm2 | p = 0.164 |
Parasympathetic modulation (RFa) | 2.73 bpm2 | 0.13 bpm2 | p = 0.166 |
Systolic BP change | +1.3 mmHg | −5.0 mmHg | p = 0.128 |
Hemodynamics | |||
Cardiac index | 2.37 l/min/m2 | 2.78 l/min/m2 | p = 0.164 |
Stroke index | 34 ml/m2 | 40 ml/m2 | p = 0.125 |
Changes in Hemodynamic Responses
Resting hemodynamic responses were worse in the nine CHF patients with abnormal P&S assessment as compared with CHF patients with normal P&S assessment (mean cardiac index 2.37 l/min/m2 vs.3.08 l/min/m2, respectively, and stroke index 34 ml/m2 vs. 46 ml/m2, respectively; p = 0.077).
Ranolazine increased cardiac and stroke indices 17–18 %, even though four of the nine (44 %) had no hemodynamic changes. Five of the nine (56 %) CHF patients with initially abnormal P&S measures who were considered to have had hemodynamic improvement had increases in cardiac and stroke indices of 33 and 38 %, respectively, and decreases in B-type natriuretic peptide (BNP) of 45 %. Patients with improved hemodynamic responses were taking 1,600 mg ranolazine daily versus 1,250 mg in patients without improvement (see Tables 19.4 and 19.5).
Table 19.5
Changes in P and S and hemodynamic responses in patients diagnosed with CHF with normal SB and no CAN
(n = 6*) | Pre-ranolazine | Post-ranolazine | Significance |
|---|---|---|---|
Average resting results | |||
Sympathetic modulation (LFa) | 1.33 bpm2
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