1. Introduction:

Cardiovascular autonomic neuropathy (CAN) is defined as the impairment of autonomic control of the cardiovascular system. It may be associated with several abnormalities in cardiovascular function.

2. Abbreviations:

CAN: Cardiovascular Autonomic Neuropathy
DM: Diabetes Mellitus
HRV: Heart Rate Variability
BP: Blood Pressure
ANS: Autonomic Nervous System
POTS: Postural Orthostatic Tachycardia Syndrome
OH: Orthostatic Hypotension
ECG: Electrocardiogram
HbA1c: Hemoglobin A1c
SNS: Sympathetic Nervous System
PNS: Parasympathetic Nervous System
QTc: Corrected QT Interval
Valsalva: Valsalva Maneuver
CVR: Cardiovascular Reflexes
R-R Interval: The interval between two successive R-waves of the QRS signal on the electrocardiogram

3. Clinical manifestations

CAN may be associated with overt clinical symptoms such as palpitations at rest, exercise intolerance, orthostatic hypotension, syncope, intraoperative cardiovascular instability, and silent myocardial infarction and ischemia. In addition, CAN may be identified by cardiovascular reflex testing performed on screening evaluation of asymptomatic individuals.

3.1 Resting tachycardia:

The earliest clinical manifestation of CAN may be a resting tachycardia. The increased resting heart rate is due to unopposed cardiac sympathetic nerve activity.

A resting heart rate consistently above 100 beats per minute (bpm) is generally considered tachycardia.

3.2 Exercise intolerance:

is usually due to impaired augmentation of cardiac output resulting from inadequate sympathetic modulation.

3.3 Persistent sinus tachycardia:

can occur and may be associated with minimal or absent variation in heart rate during activities that normally increase heart rate variability, such as deep breathing and the Valsalva maneuver.

As autonomic neuropathy progresses, the resting heart rate gradually slows.

3.4 Cardiac denervation

can occur in diabetic patients with advanced autonomic neuropathy. It is characterized by a fixed heart rate, in the range of 80 to 90 beats per minute, and is associated with an elevated risk of painless myocardial infarction, arrhythmias, and sudden death.

3.5 Orthostatic (postural) symptoms

Clinical features of CAN may be related to posture, provoked by standing and relieved by sitting. Tachycardia or hypotension may occur, causing palpitations, lightheadedness, dizziness, or syncope.

3.6 Postural tachycardia

A posture-induced tachycardia without a fall in blood pressure can result in significant postural symptoms of lightheadedness, dizziness, and presyncope. Postural tachycardia is typically seen in patients with diabetes who have a high resting heart rate due to vagal cardiac neuropathy with an unopposed cardiac sympathetic nerve activity.

Although postural tachycardia may occur both with diabetes and postural tachycardia syndrome (POTS), patients with postural tachycardia and diabetes should be diagnosed with DAN. While both conditions can be due to an underlying neuropathy, treatments may differ, and the role of glycemic control and vascular risk factor management is an additional component of the treatment of DAN.

3.7 Orthostatic hypotension

Orthostatic hypotension is defined as a fall in blood pressure of ≥20 mmHg systolic or ≥10 mmHg diastolic following a change from a supine to a standing (or upright tilt table test) position. Orthostatic hypotension results from a combination of central and peripheral cardiovascular sympathetic denervation. It reflects failure of vasoconstriction in both the splanchnic and peripheral vascular beds.

3.8 Other symptoms and presentations may include:

3.8.1 Intermittent dizziness

Dizziness or lightheadedness may occur spontaneously or may be provoked by dehydration. Symptoms are typically intermittent.

Day-to-day variability of symptoms may also be provoked by insulin therapy, which has provoked hypotension in both diabetic and nondiabetic patients with autonomic failure, although the clinical relevance of this to most patients with diabetes is not known.

3.8.2 Supine hypertension

A loss of the diurnal variation in blood pressure may lead to supine hypertension occurring at night. This may also occur to a lesser degree in diabetic patients without neuropathy. In addition, ambulatory 24-hour blood pressure monitoring has detected hypertension in over 50 percent of subjects with type 2 diabetes and CAN, despite normal office blood pressure measurements. Medications used to treat orthostatic hypotension may also cause supine hypertension.

3.8.3 Postprandial hypotension

Supine and standing systolic blood pressures may fall profoundly after meals. The mechanism of postprandial hypotension in DAN is unclear. Both inadequate sympathetic compensation to meal-induced pooling of blood in the splanchnic circulation and vasodilatory gut peptides may contribute to this phenomenon.

3.8.4 Syncope

In its most severe form, orthostatic hypotension can cause significant drops in blood pressure resulting in syncope. This severe form of orthostasis is rare, with most patients having milder symptoms that are amenable to therapeutic interventions.

Retrospective data suggest that the presence of orthostatic hypotension is associated with microvascular and macrovascular complications of diabetes. The presence of orthostatic hypotension in diabetes is associated with a significant increase in 10-year mortality.

3.8.5 Adverse cardiovascular events

The presence of CAN is associated with the risk of silent myocardial ischemia.

CAN is also associated with other adverse cardiac outcomes such as cardiac arrhythmia, heart failure, and need for coronary revascularization. A study of 120 patients with type 1 or type 2 diabetes and no history of myocardial infarction or angina but at least two additional cardiovascular risk factors followed for an average of 4.5 years found that a major cardiac event was significantly more common in patients with CAN than in those without CAN (24 versus 7 percent).

CAN is also associated with an increased mortality risk.

3.8.6 Other vascular complications

The presence of CAN may also be associated with kidney disease and cerebrovascular events.

3.8.7 Kidney disease

CAN has been associated with the development of chronic kidney disease.

3.8.8 Cerebrovascular disease

CAN may be associated with an increased stroke risk. In patients with type 2 diabetes enrolled in the longitudinal Appropriate Blood Pressure Control in Diabetes trial, CAN was an independent risk factor for the occurrence of stroke.

4. Diagnostic testing

CAN may be diagnosed with cardiovascular reflex testing in both symptomatic patients and asymptomatic patients.

Some experts believe that a confident diagnosis of CAN requires abnormalities in two or more cardiac autonomic functions.

There is no evidence that any one test has diagnostic superiority , although it is rare that a single test would be administered.

4.1 Tests of predominantly parasympathetic function:

4.1.1 Heart rate variability to deep breathing

(ie, supine position with the subject breathing at a fixed rate of six breaths per minute during a six-minute period): Analyzed by the heart rate variability and the expiratory to inspiratory ratio

4.1.2 Heart rate response to standing (the 30:15 ratio)

4.1.3 Heart rate response to Valsalva maneuver (the Valsalva ratio)

4.2 Tests of predominantly sympathetic adrenergic function:

4.2.1 The beat-to-beat blood pressure response to a Valsalva maneuver

(drop in phase 2, the phase 4 overshoot)

4.2.2 The systolic and diastolic blood pressure change in response to tilt table testing or active standing

4.3 Tests of sympathetic cholinergic function

4.3.1 Quantitative sudomotor axon reflex testing (QSART)

4.3.2 Thermoregulatory sweat testing (TST)

4.3.3 Sympathetic skin response (SSR)

4.4 Other Investigational tests

Other tests using radiolabeled analogues of norepinephrine can provide direct assessments of the pattern of cardiac sympathetic innervation and help establish the diagnosis of CAN. However, these have limited clinical utility because they are expensive and not widely available. These include :

4.4.1 123-I-metaiodobenzylguanidine (MIBG; iobenguane I-123)

4.4.2 11-C-hydroxyephedrine scintigraphy

5. Criteria for the diagnosis and staging of CAN:

5.1 Possible or early CAN

One abnormal cardiovascular reflex test.

5.2 Definite or confirmed CAN

Two abnormal cardiovascular reflex tests.

5.3 Severe or advanced CAN

definite CAN and the additional presence of orthostatic hypotension.

Stage of CAN	Description
Possible or early CAN	One abnormal cardiovascular reflex test.
Definite or confirmed CAN	Two abnormal cardiovascular reflex tests.
Severe or advanced CAN	Definite CAN and the additional presence of orthostatic hypotension.

6. Treatment

The management of CAN involves glycemic control and risk factor reduction in an attempt to reduce disease progression and associated morbidity as well as symptomatic strategies to alleviate symptoms. Symptomatic therapy is administered in a step-wise fashion, to minimize adverse treatment effects.

6.1 General treatment measures for all patients

Glycemic control and risk factor management strategies for all patients with CAN should also incorporate interventions to increase overall cardiovascular fitness and weight control since there is evidence that an exercise program can improve surrogate measures of both early and more advanced CAN. In individuals with type 2 diabetes, there is a beneficial effect of weight loss on autonomic function, although it is unclear if this translates into a clinically meaningful outcome. However, the clinical benefits of weight loss across all functional outcomes in type 2 diabetes support this clinical recommendation.

6.2 Nonpharmacologic symptomatic treatment

The initial step in managing CAN symptoms involves several nonpharmacologic strategies that are used for patients with orthostatic hypotension. For some patients with mild symptoms, these measures may be sufficient to achieve symptom control without pharmacologic interventions. Strategies include:

6.2.1 Simple lifestyle and supportive measures include:

Avoiding sudden changes in body posture to the head-up position.
Avoiding medications that aggravate hypotension.
Eating small, frequent meals; avoiding a low-salt diet; adequate fluid intake.
Partaking in physical activity and exercise to avoid deconditioning. However, activities that involve straining should be avoided.
Elevating the head of the bed 45 cm (18 inches) at night. This improved symptoms in a small series of patients with orthostatic hypotension from various causes.
Using a compressive garment over the legs and abdomen. Case reports suggest that this approach may be of benefit.
Using an inflatable abdominal band. This was effective in a study of 6 patients with orthostatic hypotension.
Using a low portable chair, as needed for symptoms. This was effective in one study.
Several physical counter-manoeuvres, such as leg crossing, squatting, and muscle pumping, can help maintain blood pressure (BP).

6.2.2 Detailed review and removal of any medications that may worsen orthostatic

Examples of medications that may cause or exacerbate orthostatic hypotension

Druggroup	Mechanismofhypotensionandcomments
Diuretics Loop diuretics (eg, furosemide, torsemide) or thiazides	Extracellular fluid volume depletion.
Adrenergicantagonists
Alpha-1-adrenergic blockers (eg, alfuzosin, tamsulosin, terazosin)	Alpha-1-adrenergic blockers produce vasodilation via direct effect in vascular smooth muscle.
Beta-adrenergic blockers (eg, propranolol)	Beta-adrenergic blockers reduce cardiac output and renin release. May also reduce vascular peripheral resistance.
Alpha-2-adrenergicagonists (eg, tizanidine, clonidine)	Vasodilation via central inhibition of sympathetic efferent activity.
Nitricoxide-mediatedvasodilators Nitroglycerin, hydralazine Phosphodiesterase-5-inhibitors (eg, sildenafil)	Vasodilation via direct effect in vascular smooth muscle.
Renin-angiotensinsystem(RAS)inhibitors (eg, lisinopril, valsartan)	Vasodilation via RAS inhibition.
Calcium-channelblockers (eg, verapamil, diltiazem)	Reduction of cardiac output, vasodilation via direct effect in vascular smooth muscle.
Dopamineantagonists Phenothiazines (eg, chlorpromazine) Atypical antipsychotics (eg, olanzapine, risperidone, quetiapine)	Vasodilation via central inhibition of sympathetic efferent activity.
Antidepressants (eg, trazodone, amitriptyline)	Vasodilation via central and peripheral inhibition of sympathetic efferent activity through stimulation of adrenergic receptors.
Selectiveserotoninreceptorreuptakeinhibitors (eg, paroxetine)	Unknown mechanism, possibly via central and peripheral inhibition of sympathetic efferent activity through stimulation of alpha-2-adrenergic receptors.
Sodium-glucoseco-transporter2inhibitors (eg, empagliflozin, canagliflozin)	Volume depletion via osmotic diuresis.

6.2.3 Increase in fluid intake and liberalize salt intake.

6.2.4 Modify daily activities

(eg, stand upright slowly, elevate head of bed, flex hands and/or feet before standing).

However, we typically avoid measures aimed at increasing peripheral vascular tone (such as body stockings and gravity suits) that may be used for other patients with orthostatic hypotension. They often prove ineffective for patients with CAN since blood pooling probably occurs in the large splanchnic vascular bed. Furthermore, in individuals with diabetic peripheral neuropathy, pressure sores can occur with compression stockings and should be avoided.

6.3 Pharmacologic symptomatic treatment

For patients with CAN whose symptoms do not resolve with nonpharmacologic treatment options, medications used for treatment of orthostatic hypotension may provide additional relief. The selection of agent depends on symptom severity and patient risk factors. Options for patients with CAN include:

6.3.1 Selected drugs for orthostatic hypotension

Drug	Dose	Pharmacokineticconsiderations	Mechanismofaction	Majorsideeffectsandprecautions
Approvedfororthostatichypotension
Midodrine	2.5 to 10 mg up to 3 times daily. Administer in the morning, midday, and/or 3 to 4 hours before bedtime; individualize to patient need.	Short acting (peak effect 1 hour; duration 2 to 3 hours).	Alpha-1-adrenergic receptor agonist	Supine hypertension, piloerection (“goose flesh”), scalp itching, urinary retention Use with caution in patients with congestive heart failure and chronic kidney disease.
Droxidopa	100 to 600 mg up to 3 times daily. Administer in the morning, midday, and/or 3 to 4 hours before bedtime; individualize to patient need.	Short acting (peak effect 3.5 hours; duration 5 to 6 hours).	Synthetic norepinephrine precursor	Supine hypertension, headache, nausea, fatigue. Use with caution in patients with congestive heart failure and chronic kidney disease.
Notspecificallyapprovedfororthostatichypotension
Atomoxetine	10 to 18 mg 2 times daily.	Short acting. Most effective for patients with central autonomic dysfunction.	Norepinephrine reuptake inhibitor	Supine hypertension, insomnia, irritability, decreased appetite.
Fludrocortisone	0.05 to 0.2 mg once daily in the morning. Doses >0.2 mg/day are not more effective	Long acting. Clinical effect is observed after ≥7 days of treatment.	Synthetic mineralocorticoid, volume expander that increases sodium and water reabsorption	Short-termuse: Supine hypertension, hypokalemia *, edema.
Pyridostigmine	and have greater adverse effects.			Long-termuse: Hypertension and target organ damage (eg, left ventricular hypertrophy), kidney failure. Use with caution in patients with congestive heart failure.
Erythropoietin				Improves standing BP in patients with orthostatic hypotension.
Octreotide			May attenuate the postprandial BP fall and reduce orthostatic hypotension in patients with autonomic failure.
Pseudoephedrine			Mixed alpha-adrenoreceptor agonists, which act directly on the alpha-adrenoreceptor and release noradrenaline from the post-ganglionic sympathetic neuron