RM- 3A Full Report Review How to Use the 8 Risk Factors

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1 RM- 3A Full Report Review How to Use the 8 Risk Factors RM- 3A Cardiovascular and ANS Medical Device The RM- 3A medical device is a powerful analytic tool in managing your patients health. Scientifically validated and FDA cleared, this medical device performs a range of tests covered and reimbursed by most insurance companies. This system is fast, non- invasive and takes less than 5 minutes to complete an assessment. The one- page Physician Dashboard provides a comprehensive overview of a patient s health at- a- glance. The analytic system provides patient insights covering 8 key risk factors that are described in the pages that follow. Depending on the risk score for each factor, you will be able to determine the best course of action to resolve the patient s condition as well as motivate your patient to immediate action. RISK FACTORS: AUTONOMIC NERVOUS SYSTEM DYSFUNCTION SUDOMOTOR DYSFUNCTION ENDOTHELIAL DYSFUCNCTION INSULIN RESISTANCE CARDIOMETABOLIC RISK The health information provided by UHSpro and Renua Medical is solely for informational purposes as a public service to promote consumer health. It is not meant to provide medical advic tailored in any SMALL way. It does FIBER not constitute NEUROPATHY medical advice and is not intended to be a substitute for proper medical care provided by a physician. UHSpro and Renua Medical assume no responsibility for any circumstances arising out of the use, misuse, interpretation or application of any information supplied. It is the responsibility of the physician or medical provider to diagnose, and provide CARDIAC the appropriate AUTONOMIC examinations, NEUROPATHY treatment, testing, and care recommendations. CARDIOVASCULAR DISEASE VIA PLETHYSMOGRAPHY

2 8 risk factors How the RM- 3A helps you better assess and manage your patient s cardiovascular and autonomic nervous system health. 1 ANSD: AUTONOMIC NERVOUS SYSTEM DYSFUNCTION RISK Problems with the ANS can range from mild to life threatening. Sometimes only one part of the nervous system is affected. In other cases, the entire ANS is affected. Some conditions are temporary and can be reversed, while others are chronic and will continue to worsen over time. Diseases such as Diabetes or Parkinson s disease can cause irregularities with the ANS. Problems with ANS regulation often involve organ failure, or the failure of the nerves to transmit a necessary signal. 2 SudoD: SUDOMOTOR DYSFUNCTION RISK Sudomotor dysfunction testing may indicate to physicians of a patient s peripheral nerve and cardiac sympathetic dysfunction. Neuropathy is a common complication in diabetes mellitus (DM), with 60% 70% of patients affected over lifetime. Symptoms of neuropathy are very common, and subclinical neuropathy is more common than clinical neuropathy. Neuropathy may remain undetected, and progress over time leading to serious complications. The most common associated clinical condition is peripheral neuropathy, affecting the feet. Autonomic nerve involvement is common but probably the most undiagnosed. Low scores in the sudomotor may lead a medical provider to look at clinical neuropathy. 3 EndoD: ENDOTHELIAL DYSFUNCTION RISK Current evidence suggests that endothelial function is an integrative marker of the net effects of damage from traditional and emerging risk factors on the arterial wall and its intrinsic capacity for repair. Endothelial dysfunction, detected as the presence of reduced vasodilating response to endothelial stimuli, has been observed to be associated with major cardiovascular risk factors, such as aging, hyperhomocysteinemia, post menopause state, smoking, diabetes, hypercholesterolemia, and hypertension. 4 IR: INSULIN REISTANCE RISK Insulin resistance is defined clinically as the inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and utilization in an individual as much as it does in a normal population. Insulin resistance occurs as part of a cluster of cardiovascular- metabolic abnormalities commonly referred to as "The Insulin Resistance Syndrome" or "The Metabolic Syndrome". This cluster of abnormalities may lead to the development of type 2 diabetes, accelerated atherosclerosis, hypertension or polycystic ovarian syndrome depending on the genetic background of the individual developing the insulin resistance. 5 CMR: CARDIOMETABOLIC RISK The specific factors that can cause this increased risk include: obesity (particularly central), hyperglycemia, hypertension, insulin resistance and dyslipoproteinemia. When patients have one or more risk factors and are physically inactive or smoke, the cardiometabolic risk is increased even more. Medical conditions that often share the above characteristics, such as type 2 diabetes, can also increase cardiometabolic risk. The primary focus of cardiometabolic risk treatment is management of each high risk factor, including dyslipoproteinemia, hypertension, and diabetes. The management of these subjects is based principally on lifestyle measures, but various antihypertensive, lipid- lowering, insulin sensitizing, anti- obesity and antiplatelet drugs could be helpful in reducing cardiometabolic risk. 6 SFN: SMALL FIBER NEUROPATHY RISK A small fiber neuropathy occurs when damage to the peripheral nerves predominantly or entirely affects the small myelinated fibers or unmyelinated C fibers. The specific fiber types involved in this process include both small somatic and autonomic fibers. The sensory functions of these fibers include thermal perception and nociception. These fibers are involved in many autonomic and enteric functions. 7 CAN: CARDIAC AUTONOMIC NEUROPATHY RISK High blood glucose levels over a period of years may cause a condition called autonomic neuropathy. This is damage to the nerves that control the regulation of involuntary function. When the nerve damage affects the heart, it is called cardiac autonomic neuropathy (CAN). CAN encompasses damage to the autonomic nerve fibers that innervate the heart and blood vessels, resulting in abnormalities in heart rate control, vascular dynamics and the body s ability to adjust blood pressure. CAN is a significant cause of morbidity and mortality associated with a high risk of cardiac arrhythmias and sudden death. 8 PTG CVD: PLETHYSMOGRAPY CARDIOVASCULAR DISEASE RISK The PTG CVD risk factor is the combined total of the other seven risk factors assessments. It takes into consideration the cardiovascular, as well as, the autonomic nervous system (ANS) measurements. provide medical advice tailored in any way. It does not constitute medical advice and is not intended to be a substitute for proper medical care provided by a physician. Renua Medical assumes no responsibility for any circumstances arising out of the use, misuse, interpretation or application of any information supplied. It is the responsibility of the physician or medical provider to diagnose, and provide the appropriate examinations, treatment, testing, and care recommendations.

3 RM- 3A DASHBOARD A Review of the 8 Key Risk Factors (Bar Graphs) Please note: the information contained within this document is designed as a guide to help the qualified medical provider identify levels of risk for each of the health issues contained herein. Only a qualified medical provider may utilize this analytical data to diagnose and provide specific treatment regimens for any health issue. Many options for additional testing are provided. However, Renua Medical does not in any way claim: these are the only tests available, these are applicable for all patients, and where these should be performed. All decisions remain the responsibility of a qualified medical provider. The interpretation of all RM-3A reports is entirely left up to the qualified medical provider. RISK FACTOR NOTE: Be advised that indicator levels for interpretation of either normal or elevated are as follows: Green Normal range, Yellow Elevated, Orange Abnormal.

4 Autonomic Nervous System Dysfunction (ANSD) 1 st Risk Factor or Bar The autonomic nervous system (ANS) controls several basic bodily functions. These include heart rate, body temperature, breathing rate, digestion, and many other systems. You don t have to consciously think about these systems in order for them to work. The ANS provides the connection between your brain and your internal organs. For instance, it connects to the heart, liver, sweat glands, and even the interior muscles of your eye. The ANS is made up of two subsystems: the sympathetic autonomic nervous system (SANS) and the parasympathetic autonomic nervous system (PANS). Most organs have nerves from both the sympathetic and parasympathetic systems. The SANS usually stimulates organs. For instance, it increases heart rate and blood pressure when necessary. The PANS, on the other hand usually slows down bodily processes. For example, it reduces heart rate and blood pressure. There are certainly exceptions. Digestion and urination, for instance are stimulated by the PANS and slowed by the SANS. The general responsibility of the SANS is to trigger emergency responses when required. These fight or flight responses get you ready to respond to stressful situations. The PANS, on the other hand, conserves your energy and restores tissues for ordinary functions. When they affect your breathing or heart function, these disorders can be life-threatening. Patients with ANS disorder often receive complete physical skin exam performed (ml), hemoglobin A1C measurement, other diagnostic procedures (interview; evaluation; consultation), lipid panel, ultrasonography, wound-care management, physical therapy exercises and echocardiography. Nausea Elevated blood sugar Vomiting Frequent urination Extreme thirst Blurred vision Increased hunger Numbness & tingling in the hands or feet Fatigue Diabetes, Cardiovascular Disease (CVD), & Metabolic disorders Supplemental Data: (Physician s Full Report Summary, Page 3) PTGTP: Helps identify the risk of insulin resistance and therefore prediabetes, as well as, possible heart disease and metabolic disorders, high number may be associated with fatty liver and atherosclerosis. Possibly the need to modify diet and increase exercise. Problems with the ANS can range from mild to life threatening. Sometimes only one part of the nervous system is affected. In other cases, the entire ANS is affected. Some conditions are temporary and can be reversed, while others are chronic and will continue to worsen over time. Diseases such as diabetes or Parkinson s disease can cause irregularities with the ANS. Problems with ANS regulation often involve organ failure, or the failure of the nerves to transmit a necessary signal. PTG R: Provides 3 homeostatic markers (see Full Physician s Report page 6). The sum of the amplitudes of all peaks is the PTG index. This is used to evaluate CVD; A score of 0 = normal, 1 = borderline and 2 = abnormal. PTGVLFi: This is a marker for impaired glucose testing (IGT) and microcirculation complications. High numbers indicate a risk of diabetes. Your autonomic nervous system is the part of your nervous system that controls involuntary actions, such as the beating of your heart and the widening or narrowing of your blood vessels. When something goes wrong in this system, it can cause serious problems, including blood pressure problems, heart problems, and trouble with breathing and swallowing, and erectile dysfunction in men. Autonomic nervous system disorders can occur alone or as the result of another disease, such as Parkinson s disease, alcoholism and diabetes. Problems can affect either part of the system, as in complex regional pain syndromes or all of the system. Some types are temporary, but many worsen over time. STRESS 1: Correlated to C reactive Protein is a marker for sympathetic failure. High numbers indicate a risk for heart disease. Hemoglobin A1C Lipid Profile Complete Blood Count Additional testing for Cardio Vascular disease Insulin resistance CMP (Complete metabolic profile) Ultrasound

5 Sudomotor Dysfunction (SudoD) 2 nd Risk Factor or Bar The Sudomotor Dysfunction is a common feature of diabetic autonomic neuropathy. This generally manifests as anhidrosis of the extremities, which may be accompanied by hyperhidrosis in the trunk. Initially, patients display a loss of thermoregulatory sweating in a glove and stocking distribution that, with progression of autonomic neuropathy, extends from the lower to the upper extremities and to the anterior abdomen, conforming to the length dependency of diabetic neuropathy. This process ultimately may result in global anhidrosis. Hyperhidrosis may also accompany diabetic autonomic neuropathy. Excessive sweating may occur as a compensatory phenomenon involving proximal regions such as the head and trunk that are spared in a dyingback neuropathy. Gustatory sweating is the abnormal production of sweat that appears over the face, head, neck, shoulders, and chest after eating (even non-spicy foods). Lower ESC is suggestive of sudomotor dysfunction. Lower ESC Diabetes at feet is significantly associated both with increasing symptoms Cardiovascular Disease (MNSI A) and increasing score on physical abnormalities (MNSI Peripheral & Distal neuropathies B). Lower ESC at feet was also significantly associated with increasing VPT by biothesiometry (P < ), and with higher number of abnormal CAN results (P < ). ESC was associated with postural fall in blood pressure (sympathetic abnormality) (P < ), but not with heart rate variability (HRV) tests (parasympathetic abnormalities). The Sudomotor dysfunction testing may indicate to physicians of a patients peripheral nerve and cardiac sympathetic dysfunction, Neuropathy is a common complication in diabetes mellitus (DM), with 60% 70% of patients affected over lifetime. Symptoms of neuropathy are very common, and subclinical neuropathy is more common than clinical neuropathy. Neuropathy may remain undetected, and progress over time leading to serious complications. The most common clinical affection is peripheral neuropathy, affecting the feet. Autonomic nerve involvement is common but probably the most undiagnosed. Low scores in the sudomotor may lead one to look at clinical neuropathy. Some of the autonomic neuropathies are amenable to treatment of the underlying disease. For example, early detection and treatment of the underlying cancer is the primary treatment for paraneoplastic autonomic neuropathy. In other cases, drug treatment is required. Some patients with autoimmune autonomic neuropathy have been found to be responsive to intravenous gammaglobulin (Heafield et al 1996; Smit et al 1997). Occasionally, multiple therapies may be required; there is evidence that patients may respond with combined therapy even if they had not responded with either treatment alone (Gibbons et al 2008). Lifestyle Adjustments. In some acute autonomic neuropathies, only symptomatic treatment is required (see the MedLink Neurology article titled Chronic autonomic neuropathies). Some nonpharmacologic interventions for symptomatic orthostatic hypotension include raising the head of the bed, physical counter-maneuvers (crossing the legs, squatting, tensing muscles of the lower extremities, etc.), physical activity, elastic stockings, abdominal binders, and adequate hydration. Dizziness or fainting Urinary Problems Sexual difficulties Difficulties in digesting food Sweat abnormalities Exercise intolerance Sluggish pupil reaction Possible Microcirculation issues Burning sensation Tingling hands and feet Supplemental Data: (Physician s Full Report Summary, Page 7) ESR NO: Is a marker of electrical skin response to nitric oxide (NO) production and vasodilation. This marker reflects microcirculation blood flow. Decreased ESR NO indicates microcirculation. A low number indicates signs of poor micro vascularization and increased risk of distal neuropathy. ESR L: Is a marker of sweat gland nerve density. This marker reflects post sympathetic nerve density. The peak reflects C- fiber density. Low number is an early detection of Peripheral distal neuropathy. Peak C: Is a marker of sweat gland function and reflects maximum number of water and chlorine released on the electrode plate after stimulation. Decreased Peak C is either due to nerve damage or hypohidrosis (low sweat). An abnormal number (high or low) can be attributed to hyperhidrosis (Excessive Sweat): A low number found with nerve damage. Breathing Test Gastrointestinal testing (Gastric emptying), QSART Urodynamic testing (Bladder/Urinary Tract) Ultrasound

6 Endothelial Dysfunction (EndoD) 3 rd Risk Factor or Bar In vascular diseases, endothelial dysfunction is a systemic pathological state of the endothelium (the inner lining of blood vessels) and can be broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium. Current evidence suggests that endothelial function is an integrative marker of the net effects of damage from traditional and emerging risk factors on the arterial wall and its intrinsic capacity for repair. This endothelial-dependent vascular biology is critical, not only in the initiation and progression of atherosclerosis, but also in the transition from a stable to an unstable disease state with attendant risks. As a result, study of endothelial function in clinical research has emerged as an important end point that complements measurement of circulating risk factors, imaging techniques for structural arterial diseases burden (such as carotid intima media thickness, intravascular ultrasound, computed tomography), and traditional cardiovascular clinical outcomes. Endothelial dysfunction, detected as the presence of reduced vasodilating response to endothelial stimuli, has been observed to be associated with major cardiovascular risk factors, such as aging, hyperhomocysteinemia, post menopause state, smoking, diabetes, hypercholesterolemia, and hypertension. Endothelial dysfunction responds favorably to a healthful diet and exercise. Exercising to maintain a healthy weight decreases a person's risk of developing certain diseases, including type 2 diabetes and high blood pressure. Aerobic Exercise: The heart is a muscle and needs a good workout. Aerobic exercise gets the heart pumping and quickens breathing, resulting in a more efficient delivery of oxygen-carrying blood cells. Strength and flexibility training are of benefit too. Pharmacologic interventions may include: ACE inhibitors used for treating high blood pressure and heart failure Nitrate therapy Lipid-lowering pharmaceuticals used for managing blood cholesterol levels Alpha-beta blockers for blood pressure management Novel therapies that include ranolazine, aminophylline and experimental therapies. External counter pulsation (ECP) therapy is another treatment option. Lying on a table or bed, pressure cuffs are fitted to the patient's thighs, hips and calves. The cuffs inflate and deflate in sync with the patient's heart rhythm, supplying the heart with extra oxygen-rich blood in the resting phase. The extra blood supply stimulates growth of the surrounding blood vessels, improving the supply of blood to the heart. Angina Chest Pain that goes away with rest TIA Stroke Pain in calves Cardio Vascular Disease Endothelial dysfunction (ANS Biomarker of Atherosclerosis) Supplemental Data: (Physician s Full Report Summary, Page 6) PTGTP: helps identify risk of insulin resistance and therefore pre diabetes as well as possible heart disease and metabolic disorders, high number may be associated with fatty liver and atherosclerosis. Possibly need to modify diet and increase exercise. PTG R: analysis provides 3 homeostatic markers. The sum of the amplitudes of all peaks is the PTG index. This is used to evaluate PTG CVD score. 0 = normal, 1 = borderline and 2 = abnormal to calculate CVD possibilities. PTGVLFi: is a marker for impaired glucose testing (IGT) and microcirculation complications. High numbers indicate a risk of diabetes. RI: (reflection index) Small and medium arterial stiffness. Marker for atherosclerosis SD Da: is an indicator that correlates with angiotensin system level activity. High numbers are associated with increased angiotensin activity. C-reactive protein (CRP) Stress Test Ultrasound Angiograph

7 Insulin Resistance (IR) - 4 th Risk Factor or Bar IR is the diminished ability of cells to respond to the action of insulin in transporting glucose (sugar) from the bloodstream into muscle and other tissues. Insulin resistance typically develops with obesity and heralds the onset of type 2 diabetes. It is as if insulin is "knocking" on the door of muscle. The muscle hears the knock, opens up, and lets glucose in. But with insulin resistance, the muscle cannot hear the knocking of the insulin (the muscle is "resistant"). The pancreas makes more insulin, which increases insulin levels in the blood and causes a louder "knock." Eventually, the pancreas produces far more insulin than normal and the muscles continue to be resistant to the knock. As long as one can produce enough insulin to overcome this resistance, blood glucose levels remain normal. Once the pancreas is no longer able to keep up, blood glucose starts to rise, initially after meals, eventually even in the fasting state. Type 2 diabetes is now overt. Insulin resistance is defined clinically as the inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and utilization in an individual as much as it does in a normal population. Insulin action is the consequence of insulin binding to its plasma membrane receptor and is transmitted through the cell by a series of protein-protein interactions. Two major cascades of protein-protein interactions mediate intracellular insulin action: one pathway is involved in regulating intermediary metabolism and the other plays a role in controlling growth processes and mitoses. The regulation of these two distinct pathways can be dissociated. Several mechanisms have been proposed as possible causes underlying the development of insulin resistance and the insulin resistance syndrome. These include: (1) genetic abnormalities of one or more proteins of the insulin action cascade (2) fetal malnutrition (3) increases in visceral adiposity. Insulin resistance occurs as part of a cluster of cardiovascular-metabolic abnormalities commonly referred to as "The Insulin Resistance Syndrome" or "The Metabolic Syndrome". In addition to the A1C test, other blood tests can check your blood glucose levels. A fasting blood glucose test repeat if needed after first test. Certain foods can help a patient to lose weight and even manage their blood sugar. For instance, vegetables are low in calories and carbohydrates, making them an ideal food for people who are trying to manage their blood sugar and lose weight. Skip whole milk and full-fat yogurts since insulin resistance can worsen when you consume foods high in saturated fat Exercise can help prevent diabetes by lowering blood sugar and reducing weight. It also helps the cells become more sensitive to insulin. There are none that can tell you that you have insulin resistance by the way you feel. Likewise, you won t know if you have most of the other conditions that are a part of insulin resistance syndrome (high pressure, low good cholesterol levels and high triglycerides) without seeing your doctor. Insulin Resistance Supplemental Data: (Physician s Full Report Summary, Page 3) IR (insulin resistance): High numbers indicate need of weight management, optimization /diet modification, increase risk of heart and metabolic disease. A1C Blood Glucose Testing This cluster of abnormalities may lead to the development of type 2 diabetes, accelerated atherosclerosis, hypertension or polycystic ovarian syndrome depending on the genetic background of the individual developing the insulin resistance.

8 Cardiometabolic Risk (CMR) 5 th Risk Factor or Bar Cardiometabolic Risk refers to a condition in which the possibilities of developing atherosclerotic cardiovascular (CV) disease and diabetes mellitus are significantly enhanced as a consequence of the presence of insulin resistance and atherogenic dyslipidemia, the latter being characterized by the presence of low high-density lipoprotein (HDL)-cholesterol and high triglyceride levels. CMR is particularly prevalent in the hypertensive populations and those patients diagnosed as having metabolic syndrome. The specific factors that can cause this increased risk include: obesity (particularly central), hyperglycemia, hypertension, insulin resistance and dyslipoproteinemia. When patients have one or more risk factors and are physically inactive or smoke, the cardiometabolic risk is increased even more. In addition, when these risk factors occur in clusters, they can greatly increase the risk of CVD. Medical conditions that often share the above characteristics, such as type 2 diabetes, can also increase cardiometabolic risk. As such, the term can be used to persons already diagnosed with chronic disease. The primary focus of cardiometabolic risk treatment is management of each high risk factor, including dyslipoproteinemia, hypertension, and diabetes. The management of these subjects is based principally on lifestyle measures, but various antihypertensive, lipid-lowering, insulin sensitising, anti-obesity and antiplatelet drugs could be helpful in reducing cardiometabolic risk. Lifestyle modifications may counteract the effect of the underlying risk factors. Moreover, hypertensives also require a tight BP control, a choice of antihypertensive treatment not producing other metabolic disturbances, and, quite often, parallel drug treatment for associated metabolic risk factors (dyslipidemia, insulin resistance, and prothrombotic and proinflammatory states). In addition, a diet rich in fruits, vegetables & low-fat dairy products (DASH diet) substantially lower BP in comparison to the standard American diet. A key feature of metabolic syndrome that explains the increased cardiometabolic risk is an enhanced prothrombotic state, especially in the presence of insulin resistance. Postprandial hyperglycemia, increased free fatty acids and elevated triglyceride levels may all have adverse effects on platelets, coagulation and fibrinolysis. Pharmacological interventions targeting these abnormalities have the potential to reduce thrombosis. Antiplatelet drugs represent an option in the management of hypertensives with cardiometabolic risk. Myocardial Infarction Dizziness Headaches Swelling of ankles High Cholesterol Heart Disease High Blood Pressure Diabetes Supplemental Data: (Physician s Full Report Summary, Page 3) ELEVATED PTGTP: Helps identify risk of insulin resistance and therefore pre diabetes as well as possible heart disease and metabolic disorders, high number may be associated with fatty liver and atherosclerosis. Possibly need to modify diet and increase exercise. STRESS 1: Correlated to C reactive Protein is a marker for sympathetic failure. High numbers indicate a risk for heart disease. ESR NO: Is a maker of electrical skin response to nitric oxide (NO) production and vasodilation. This marker reflects microcirculation blood flow. Decreased ESR NO indicates microcirculation. A low number indicates signs of poor micro vascularization and increased risk of distal neuropathy. LF/HF: Indicates ANS balance. If the value is high (greater than 2), it indicates sympathetic system predominance and possibility of mental stress or anxiety. If the value is low (less than 0.5), it indicates parasympathetic system predominance and possibility of fatigue or depression. RI (REFLECTION INDEX): If elevated, this indicates possible small and medium arterial stiffness. Marker for atherosclerosis. BMI (BODY MASS INDEX): Is a measure of body fat based on your weight in relation to your height, and applies to most adult men and women aged 20 and over. According to the Affordable Healthcare Act, if a patient is over a 27 BMI with at least 2 comorbidities or 30 BMI regardless of Co-Morbidities, the Physician must offer Obesity Counseling (which is Medicare and private insurance reimbursable). If they do not and they are on Electronic Medical Records, according to the Meaningful Use Act, their Medicare reimbursements may be reduced up to 2%. TP: Is the main indicator of ANS activity. Low numbers may indicate a sedimentary lifestyle and may indicate the need to increase activity. TP may also define the variability, or degree of fluctuation in the length of the intervals between beats. A low HRV score is associated with poor prognosis for patients who are post Myocardial Infarction (MI) and increased risk of autonomic neuropathy in diabetes population. Cholesterol Blood pressure checks Hemoglobin A1C Glucose testing (BG, OGTT, etc) ABI CBC (Complete Blood Count) Carotid Ultrasound CMP (Complete Metabolic Profile)

9 Small Fiber Sensory Neuropathy (SFN) 6 th Risk Factor or Bar A small fiber neuropathy occurs when damage to the peripheral nerves predominantly or entirely affects the small myelinated fibers or unmyelinated C fibers. The specific fiber types involved in this process include both small somatic and autonomic fibers. The sensory functions of these fibers include thermal perception and nociception. These fibers are involved in a number of autonomic and enteric functions. Most small fiber neuropathies occur in a length-dependent fashion, resulting in loss of function in a stocking distribution in the lower extremities. When the condition is more advanced, a glove-like loss in the upper extremities also may occur. Anatomically, the small nerve fibers may be damaged or destroyed in these conditions, resulting in a loss of small nerve fibers and/or abnormal nerve fiber morphology. However, the pathogenesis of injury to small nerve fibers is not well understood. Small nerve fiber neuropathies can occur without large nerve fiber involvement, but in some cases they occur concomitantly or progress to involve large nerve fibers. Symptoms of small fiber neuropathy can vary widely in severity. Many individuals report the gradual onset of distal symptoms that include vague disturbances of sensation in the feet. These symptoms may include the feeling of a wrinkle in a sock that cannot be removed or of small pebbles or sand in the shoe. Others may report a cold-like pain, tingling or a pins and needles sensation. More severe symptoms of small fiber neuropathy may include burning pain that often is persistent, although it may vary in intensity throughout the day. There are several different classes of medications and lifestyle changes commonly used to treat neuropathic pain. Treatments should be based on evidence of safety, efficacy in other neuropathic conditions, tolerability, drug interactions, comorbid conditions, and cost. These include antidepressants, anticonvulsants, opioids, and topical treatments. Tricyclic antidepressants (TCAs) consistently are recommended as first tier drugs across all guidelines. Serotonin norepinephrine reuptake inhibitors (SNRIs) are another class of antidepressants commonly used for the treatment of neuropathic pain. In addition to antidepressants, anticonvulsants also are routinely recommended for the treatment of neuropathic pain. Non-pharmacologic agents: Some patients may benefit from cool or warm soaks, soft socks, and foot tents. Other treatments include transcutaneous electrical nerve stimulation, acupuncture, physical therapy and massage. Pins and needles sensation in feet Burning sensations Stabbing or electrical shock sensation Painful contact with socks or bed sheets Pebble or sand like sensation in shoes Small Fiber Neuropathy Supplemental Data: (Physician s Full Report Summary, Page 7) ESR NO: Is a marker of electrical skin response to nitric oxide (NO) production and vasodilation. This marker reflects microcirculation blood flow. Decreased ESR NO indicates microcirculation. A low number indicates signs of poor micro vascularization and increased risk of small fiber neuropathy. ESR L: Is a marker of sweat gland nerve density. This marker reflects post sympathetic nerve density. The peak reflects C- fiber density. Low number is an early detection of Peripheral distal neuropathy. Peak C: Is a marker of sweat gland function and reflects maximum number of water and chlorine released on the electrode plate after stimulation. Decreased Peak C is either due to nerve damage or hypohidrosis (low sweat). An abnormal number (high or low) can be attributed to hyperhidrosis (Excessive Sweat): A low number found with nerve damage. Skin Biopsy Nerve Conduction Testing Other Pain Management Testing

10 Cardiac Autonomic Neuropathy (CAN) 7 th Risk Factor or Bar High blood glucose levels over a period of years may cause a condition called autonomic neuropathy. This is damage to the nerves that control the regulation of involuntary function. When the nerve damage affects the heart, it is called cardiac autonomic neuropathy (CAN). CAN includes damage to the autonomic nerve fibers that innervate the heart and blood vessels, resulting in abnormalities in vascular dynamics, heart rate control, and the body s ability to adjust blood pressure. CAN is a significant cause of morbidity and mortality associated with many cardiac arrhythmias and sudden death. One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy. There is now clear evidence that suggests activation of inflammatory cytokines in diabetic patients and that these correlate with abnormalities in sympathovagal balance. Dysfunction of the autonomic system predicts cardiovascular risk and sudden death in patients with type 2 diabetes. It also occurs in prediabetes, providing opportunities for early intervention. The window of opportunity for aggressive control of all the traditional risk factors for cardiovascular events or sudden death with intensification of therapy is with short duration diabetes, the absence of cardiovascular disease and a history of severe hypoglycemic events. To this list we can now add autonomic dysfunction and neuropathy, which are the most powerful predictors of risk for mortality. Normally, our heart rate increases when we sit up and stand up, as well as, when we start to exercise. It slows down when we are resting. If the heart rate and blood pressure do not adjust quickly to our need for increased blood flow, we can become dizzy, lose our balance and in some cases faint. This is called orthostatic hypotension. CAN is not a disease of the heart it is a problem with the nerves that control the heart rate. The nerves that signal the heart to beat faster are called cardiac autonomic nerves. Damage to these nerves may cause a heart rate that stays high, even at rest, instead of rising and falling in response to the body s needs and activities. One effect is that blood pressure may drop when you stand up. Another danger is that people with CAN may have heart attacks without feeling the pain and symptoms that signal a problem. There are a number of possible pharmaceutical solutions for helping keep blood pressure from dropping too low. In addition, several agents have become available for the correction of functional defects in the autonomic nervous system. Restoration of autonomic balance is possible and has been shown with therapeutic lifestyle changes, increased physical activity, diabetes treatment, b-adrenergic blockers and potent anti-oxidants, such as a-lipoic acid. There are several steps one can take to make living with CAN easier and safer. Move slowly when moving from a lying down to a seated position or from a sitting to standing position. Avoid lying down for long periods of time (other than for sleep). Exercise is strongly encouraged. When exercising, include gradual, prolonged warm-up and cool-down periods so that your heart rate can adjust to your muscles need for more oxygen. Keep the pace of your workout at a comfortable level. Water exercise may be ideal because the pressure exerted by water helps return blood to the heart. Fainting (syncope) Dizziness or lightheadedness Nausea Lack of concentration Blurred vision Cold, clammy, pale skin Fatigue Rapid, shallow breathing Depression Thirst Hypotension Supplemental Data: (Physician s Full Report Summary, Page 5) SPRV2: is correlated with norepinephrine response. Low number may indicate orthostatic hypotension; high numbers indicate increased sympathetic response and release of norepinephrine (often associated with increased vascular constriction). DPRS: reflects the sympathetic adrenergic response. High number may indicate orthostatic hypotension. Low numbers are considered normal. Vals.R: reflects parasympathetic response. High score may indicate dysautonomia and/or vagal syndrome. K30:15: reflects parasympathetic response to change in posture. High score may indicate problems with autonomic nerve disorders (dysautonomic). E/I R: reflects the parasympathetic response to a challenge. High number may indicate problem with autonomic nerve (dysautonomia). Blood Glucose EKG Echocardiogram Cardiac Ultrasound Holter Monitor Additional cardiac testing

11 Plethysmography Cardiovascular Disease (PTG CVD) 8 th Risk Factor or Bar The PTG CVD risk factor is the combined total of the other seven risk factors assessments. This is done by collecting information on both systems using time-domain, geometric, frequencydomain and non-linear methods and algorithms. The information is then applied to the cardiovascular health of the patient. Supplemental Data: (Physician s Full Report Summary, Page 3) Plethysmography (PTG) is used to detect blood volume changes ELEVATED PTGTP: Helps identify risk of insulin resistance and in the microvascular bed of tissue. The PTG waveform comprises therefore pre diabetes as well as possible heart disease and a pulsatile ('AC') physiological waveform attributed to cardiac metabolic disorders, high number may be associated with fatty synchronous changes in the blood volume with each heartbeat, liver and atherosclerosis. Possibly need to modify diet and and is superimposed on a slowly varying ('DC') baseline with increase exercise. various lower frequency components attributed to respiration, sympathetic nervous system activity and thermoregulation. PTG provides valuable information about the cardiovascular system such as measuring oxygen saturation, blood pressure and cardiac output, assessing autonomic function, detecting peripheral vascular disease and heart rate variability (HRV). HRV is the physiological variation in the time interval between heartbeats. It is measured by the variation in the beat-to-beat interval. Reduced HRV has been shown to be a predictor of mortality after myocardial infarction. A range of other outcomes/conditions may also be associated with lower HRV, including congestive heart failure, diabetic neuropathy, depression, and post-cardiac transplant. It is important to note that HRV measures fluctuations in autonomic inputs to the heart rather than the mean level of autonomic inputs. Thus, both withdrawal and saturating high levels of autonomic input to the heart can lead to diminished HRV. Heart rate and rhythm are largely under the control of the autonomic nervous system. The parasympathetic influence on heart rate is mediated via release of acetylcholine by the vagus nerve. The sympathetic influence on heart rate is mediated by release of epinephrine and norepinephrine. Because peripheral arterial disease is associated with the two other major atherosclerotic conditions, coronary artery disease (heart disease) and cerebrovascular disease (stroke), treatment may range from management of risk factors to surgical procedures. There are two main goals for treatment of peripheral artery/vascular disease: control the symptoms and halt the progression of the disease to lower the risk of heart attack, stroke, and other complications. Specific treatment may include lifestyle modifications to control risk factors, including regular exercise, proper nutrition, and smoking cessation. Aggressive treatment of existing conditions that may aggravate PVD, such as diabetes, hypertension, and hyperlipidemia (elevated blood cholesterol) and medications for improving blood flow, such as antiplatelet agents (blood thinners) and medications that relax the blood vessel walls. Possible Symptoms & Condition(s): Stroke Heart Attack Cardiomyopathy Atrial Fibrillation Endocarditis Aortic aneurysms Venous thrombosis STRESS 1: Correlated to C reactive Protein is a marker for sympathetic failure. High numbers indicate a risk for heart disease. ESR NO: Is a maker of electrical skin response to nitric oxide (NO) production and vasodilation. This marker reflects microcirculation blood flow. Decreased ESR NO indicates microcirculation. A low number indicates signs of poor micro vascularization and increased risk of distal neuropathy. LF/HF: Indicates ANS balance. If the value is high (greater than 2), it indicates sympathetic system predominance and possibility of mental stress or anxiety. If the value is low (less than 0.5), it indicates parasympathetic system predominance and possibility of fatigue or depression. RI (REFLECTION INDEX): If elevated, this indicates possible small and medium arterial stiffness. Marker for atherosclerosis. BMI (BODY MASS INDEX): Is a measure of body fat based on your weight in relation to your height, and applies to most adult men and women aged 20 and over. According to the Affordable Healthcare Act, if a patient is over a 27 BMI with at least 2 comorbidities or 30 BMI regardless of Co-Morbidities, the Physician must offer Obesity Counseling (which is Medicare and private insurance reimbursable). If they do not and they are on Electronic Medical Records, according to the Meaningful Use Act, their Medicare reimbursements may be reduced up to 2%. TP: Is the main indicator of ANS activity. Low numbers may indicate a sedimentary lifestyle and may indicate the need to increase activity. TP may also define the variability, or degree of fluctuation in the length of the intervals between beats. A low HRV score is associated with poor prognosis for patients who are post Myocardial Infarction (MI) and increased risk of autonomic neuropathy in diabetes population. Coronary artery testing Cardiometabolic Profile lab tests BNP (Brain Natriauretic Peptide) Carotid total plaque area, LDL-P