Joseph Colombo

Autonomic Mechanisms and Therapeutic Implications of Postural Diabetic Cardiovascular Abnormalities

Background: Cardiovascular autonomic neuropathy (CAN) is a disorder of progressive autonomic dysfunction (AD) associated with diabetes and other chronic diseases. Orthostatic hypotension (OH) is one of the most incapacitating symptoms of CAN and AD. AD in OH can include sympathetic withdrawal (SW). To detect and diagnose SW, parasympathetic and sympathetic changes must be clearly differentiated from each other. This is accomplished by means of the novel autonomic nervous system (ANS) method based on the simultaneous spectral analyses of respiratory activity (RA) and heart rate variability (HRV). Methods: We performed autonomic profiling of 184 (142 females) consecutive, arrhythmia-free patients with type 2 diabetes using the ANX-3.0 autonomic monitoring system. The patient cohort included 86 (64 female) patients for whom an a1-agonist was the only drug changed and increased from one test to the next; 37 (33 female) for whom the a1-agonist was discontinued; and 61 (45 female) who were on an a1-agonist, but for whom no drug changes were made. The tests averaged 3.1 ± 1.4 months apart; midodrine (ProAmatine) was the a1-agonist prescribed. Of the group, 99 patients also had hypertension and 47 also had cardiovascular disease. No patient had supine hypertension. Results: Changes in parameters from the HRV (without respiration) and ANS methods were compared with changes in heart rate and blood pressure (BP) as measured from one test (test N) to the next (test N + 1). SW with a BP drop of less than the clinical definition may be a trend that can be an early indicator of orthostasis. In this study, patients were treated with low-dose, short-term α1-agonist (vasopressor) therapy, which tended to correct the abnormal trend of SW with a drop in BP. Included in the findings was a systolic BP trend in response to vasopressor therapy of an (expected) initial increase in BP followed by an eventual decrease in systolic BP as SW was reversed. Conclusions: The ANS method enables quantitative assessment of CAN by independently and simultaneously quantifying the two branches of the ANS, sympathetic and parasympathetic. The ANS method modifies standard spectral analysis of HRV (without RA analysis) by incorporating spectral analysis of RA. The ANS method appears to model the normal and abnormal responses to upright posture and changes in vasopressor therapy with greater fidelity than the HRV method. Independent, simultaneous assessment of progressive parasympathetic and sympathetic dysfunction, autonomic imbalance, and responses of the two ANS branches to therapy seems to enable early detection and early intervention. Orthostasis, by way of example, illustrates that frequent, sensitive assessments of both ANS branches can improve the negative outcomes associated with CAN.

Cardiac autonomic testing and treating heart disease. "A clinical perspective".

Background Coronary heart disease (CHD) is a major health concern, affecting nearly half the middle-age population and responsible for nearly one-third of all deaths. Clinicians have several major responsibilities beyond diagnosing CHD, such as risk stratification of patients for major adverse cardiac events (MACE) and treating risks, as well as the patient. This second of a two-part review series discusses treating risk factors, including autonomic dysfunction, and expected outcomes. Methods Therapies for treating cardiac mortality risks including cardiovascular autonomic neuropathy (CAN), are discussed. Results While risk factors effectively target high-risk patients, a large number of individuals who will develop complications from heart disease are not identified by current scoring systems. Many patients with heart conditions, who appear to be well-managed by traditional therapies, experience MACE. Parasympathetic and Sympathetic (P&S) function testing provides more information and has the potential to further aid doctors in individualizing and titrating therapy to minimize risk. Advanced autonomic dysfunction (AAD) and its more severe form cardiovascular autonomic neuropathy have been strongly associated with an elevated risk of cardiac mortality and are diagnosable through autonomic testing. This additional information includes patient-specific physiologic measures, such as sympathovagal balance (SB). Studies have shown that establishing and maintaining proper SB minimizes morbidity and mortality risk. Conclusions P&S testing promotes primary prevention, treating subclinical disease states, as well as secondary prevention, thereby improving patient outcomes through (1) maintaining wellness, (2) preventing symptoms and disorder and (3) treating subclinical manifestations (autonomic dysfunction), as well as (4) disease and symptoms (autonomic neuropathy).

Ranolazine preserves and improves left ventricular ejection fraction and autonomic measures when added to guideline-driven therapy in chronic heart failure

Background Ranolazine (RAN) reduces cardiac sodium channel 1.5’s late sodium current in congestive heart failure (CHF), reducing myocardial calcium overload, potentially improving left ventricular (LV) function. RAN blocks neuronal sodium channel 1.7, potentially altering parasympathetic and sympathetic (P&S) activity. The effects of RAN on LV ejection fraction (LVEF) and P&S function in CHF were studied. Methods Matched CHF patients were given open-label RAN (1000 mg po-bid) added to guideline-driven therapy (RANCHF, 41 systolic, 13 diastolic) or no adjuvant therapy (control, NORANCHF, 43 systolic, 12 diastolic). Echocardiographic LVEF and P&S measures were obtained at baseline and follow-up (mean 23.7 months). Results LVEF increased in 70% of RANCHF patients, an average of 11.3 units. Mean LVEF remained unchanged in NORANCHF patients. P&S measures indicated cardiovascular autonomic neuropathy (P≤0.1 bpm2) in 20% of NORANCHF patients at baseline and in 29% at follow-up (increasing in both groups). At baseline, 28% of patients had high sympathovagal balance (SB), RAN normalized SB over 50% of these; in contrast, the NORANCHF group had a 20% increase in patients with high SB. Conclusions RAN preserves or improves LVEF and decreases high SB in CHF.

Ranolazine Therapy Reduces Non-ST-Segment-Elevation Myocardial Infarction and Unstable Angina in Coronary Disease Patients with Angina.

High sympathetic tone and cardiac autonomic neuropathy (CAN) are associated with major adverse cardiac events (MACE). We have shown ranolazine (RAN) improves autonomic function. RAN was introduced to 51 successive anginal CD patients (RANCD). A control group of 54 successive nonanginal CD patients (NORANCD) continued baseline therapy. Mean study duration was 6.1 years, which included semi-annual autonomic function measures (ANX 3.0, ANSAR Medical Technologies, Inc., Philadelphia, PA) and yearly myocardial perfusion SPECT studies (MPI). MACE were experienced by 29% RANCD patients versus 46% NORANCD patients (p = 0.0105). The patients from both groups with abnormal parasympathetic and sympathetic (P&S) measures and MACE totaled 52 of those patients with MACE versus 17% of those patients without MACE (p = 0.0274). Abnormal MPI was demonstrated in 35% of those with abnormal (P&S) measures and MACE versus 12% without MACE. Sympathovagal balance (SB) was lower, indicating higher, relative parasympathetic tone (known to be cardioprotective) in the RANCD group. Acute coronary syndromes occurred 4.5 times as often in NORANCD patients. High SB occur more frequently than abnormal MPI in CD patients experiencing MACE. In addition to increased myocardial blood flow as its proposed mechanism of angina relief, RAN improves P&S measures, a potentially new mechanism whereby RAN improves outcomes.

The Progression of Autonomic Dysfunction in Chronic Disease

Normally, when we are born, we are born with as healthy an ANS as we will have: our resting response is in the middle of the gray area on the baseline response plot. When we are no longer breathing, there is no power in either ANS branch: our resting response is at the bottom left corner of the baseline response plot. The middle diagonal line connecting the two points, the perfect balance line, turns out to be the slowest path from birth to death. This means that the ANS will decline, even if we live a “perfectly healthy life.” As will be demonstrated, chronic disease accelerates this decline. Fortunately, as has been demonstrated in the previous chapter, establishing and maintaining proper balance for the individual can return the patient to a “normal” decline, slowing the progression of autonomic dysfunction as much as possible, minimizing morbidity and mortality risk. Note that the progression plots are not from numbers of patients followed from birth; they are composite plots from large populations of subjects covering the ages. Albeit balance has become the key to promoting and maintaining health and minimizing morbidity and mortality risk. These plots demonstrate the difference between normal aging balance and disease balance.

Clinical Autonomic Dysfunction

Clinical autonomic dysfunction : , Clinical autonomic dysfunction : , کتابخانه دیجیتال جندی شاپور اهواز

Autonomic Dysfunction Versus Neuropathy

Unfortunately the “autonomic neuropathy” has inherited the misperception that it is not treatable. While this may be true due to a lack of sufficient information, it is no longer the case. This then begs the question, when does autonomic dysfunction become autonomic neuropathy. While neuropathy may now be treatable, given more information, it still leaves the physician with few therapy options. Autonomic dysfunction has more therapy options but is asymptomatic. In this chapter, we will discuss a recent study to highlight the difference between autonomic neuropathy and dysfunction, and provide another approach to differentiating stages of autonomic decline. There is actually two schools of thought: five stages of decline or six. The six stages of decline include a brief second stage which is early in the progression. It is not often observed. However, it may provide the insight needed to understand the etiology of high BP or hypertension secondary to many chronic diseases.

Medical Specialties’ View of Autonomic System Measurements

This short chapter presents the seminal articles that provide the basis for the patients for whom Autonomic Assessment is recommended. The articles are from the medical leadership, including the American Academy of Family Practitioners, American Academy of Neurology, American Diabetes Association, and American Heart Association. The articles identify which diseases or disorders lead to autonomic neuropathy. We know that autonomic neuropathy is late in the progression and leaves few therapy options. We know that autonomic dysfunction is treatable, but is asymptomatic. Therefore, the leadership articles lead to the conclusion that the disease or disorder itself is the “symptom” indicating the need for autonomic assessment. This avoids the issue of screening. So, as long as the patient has been diagnosed with a chronic condition that is identified in the literature as leading to autonomic neuropathy, then they are recommended for periodic Autonomic Assessment.

Introduction to Parasympathetic and Sympathetic Monitoring

This introductory section starts with a review of the “Old School” information commonly taught in medical school, including the anatomy of the autonomic nervous system (ANS) and its two branches, the parasympathetic and sympathetic nervous systems; the biochemistry of the ANS; general physiology associated with the two ANS branches; and methods of measuring the ANS. Measuring the ANS includes older noninvasive measures and the newer method to be the basis of this book. This section concludes by answering the “So What?” question behind the development of a newer method of measuring the ANS, specifically, a general introduction to why it is important to specifically measure the parasympathetic and sympathetic nervous systems, independently (in a mathematical sense) and simultaneously. The newer method removes many of the assumptions and approximations required by the older methods, improving specificity, sensitivity, reliability, and repeatability and thereby improving patient outcomes.

General Autonomic Disorders

This chapter discusses “general” autonomic disorders. These are autonomic disorders that may be present regardless of the primary disease or disorder or age or stage. Included is the association between autonomic dysfunction and inflammation. Recent evidence indicates that the two are linked and that treating one helps to relieve the other. The etiology of inflammation may provide additional insight into the processes contributing to the progression of autonomic dysfunction.