Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment

Table 1 Cardiac autonomic neuropathy in type 1 and type 2 diabetes mellitus: Differences in relation to risk factors and natural history[21]

Risk factors	Type 1 DM	Type 2 DM
Age	+	+
Gender (female)	+	-
Obesity	-	+
Hyperinsulinemia	NA	+
Duration of DM	++	++
Smoking	+	+
HbA1c	++	++
Hypertension	++	+
Retinopathy	++	+
Hypertriglyceridemia	+	+
Classical DPN	++	++
Microalbuminuria	++	++
Dyslipoproteinemia (> LDL and < HDL	+	(+)
Prevalence at diagnosis of DM	7.70%	5%
Prevalence after 10 yr	38%	65%
Prevalence (random)	25%	34%

++: Strong association; +: Moderate association; -: Not found; (+): Controversial; NA: Not applicable; DM: Diabetes mellitus; LDL: Low-density lipoprotein; HDL: High-density lipoprotein.

Table 2 Abnormalities associated with cardiovascular autonomic neuropathy at the level of cardiovascular system and peripheral vascular function[5,45,46]

Cardiovascular system	Peripheral vascular function
Perioperative unstability	↑ Peripheral blood flow and warm skin
Resting tachycardia	↑ Arteriovenous shunting and swollen veins
Loss of reflex heart rate variations	↑ Venous pressure
Hypertension	Leg and foot oedema
Exercise intolerance	Loss of protective cutaneous vasomotor reflexes
Orthostatic hypotension	Loss of venoarteriolar reflex with microvascular damage
Postprandial hypotension	↑ Transcapillary leakage of macromolecules
Silent myocardial ischaemia	↑ Medial arterial calcification
Left ventricular dysfunction and hypertrophy	-
QT interval prolongation	-
Impaired baroreflex sensitivity	-
Non-dipping, reverse dipping	-
Sympathovagal imbalance	-
Dysregulation of cerebral circulation	-
↓ Sympathetically mediated vasodilation of coronary vessels	-
↑ Arterial stiffness	-

Table 3 Symptoms and signs associated with diabetic cardiovascular autonomic neuropathy[39]

Cardiovascular autonomic neuropathy
Resting tachycardia
Abnormal blood pressure regulation	Nondipping
	Reverse dipping
Orthostatic hypotension (all with standing)	Light-headedness
	Weakness
	Faintness
	Visual impairment
	Syncope
Orthostatic tachycardia or bradycardia and chronotropic incompetence (all with standing)	Light-headedness
	Weakness
	Faintness
	Dizziness
	Visual impairment
	Syncope
Exercise intolerance

Table 4 Cardiovascular autonomic reflex tests[29,42]

Test	Technique	Normal response and values
Beat-to-beat HRV	With the patient at rest and supine, heart rate is monitored by ECG while the patient breathes in and out at 6 breaths per minute, paced by a metronome or similar device	A difference in HR of > 15 beats per minute is normal and < 10 beats per minute is abnormal. The lowest normal value for the expiration-to inspiration ratio of the R-R interval decreases with age: age 20-24 yr, 1.17; 25-29, 1.15; 30-34, 1.13; 35-39, 1.12; 40-44, 1.10; 45-49, 1.08; 50-54, 1.07; 55-59, 1.06; 60-64, 1.04; 65-69, 1.03; and 70-75, 1.02
Heart rate response to standing	During continuous ECG monitoring, the R-R interval is measured at beats 15 and 30 after standing	Normally, a tachycardia is followed by reflex bradycardia. The 30:15 ratio should be > 1.03, borderline 1.01-1.03
Heart rate response to the valsalva maneuver	The subject forcibly exhales into the mouthpiece of a manometer to 40 mmHg for 15 s during ECG monitoring	Healthy subjects develop tachycardia and peripheral vasoconstriction during strain and an overshoot bradycardia and rise in BP with release. The normal ratio of longest R-R to shortest R-R is > 1.2, borderline 1.11-1.2
Systolic blood pressure response to standing	Systolic BP is measured in the supine subject. The patient stands and the systolic BP is measured after 2 min	Normal response is a fall of < 10 mmHg, borderline fall is a fall of 10-29 mmHg and abnormal fall is a decrease of > 30 mmHg
Diastolic blood pressure response to isometric exercise	The subject squeezes a handgrip dynamometer to establish a maximum. Grip is then squeezed at 30% maximum for 5 min	The normal response for diastolic BP is a rise of > 16 mmHg in the other arm, borderline 11-15 mmHg

HRV: Heart rate variability; ECG: Electrocardiography; BP: Blood pressure; HR: Heart rate.

Table 5 Normal, borderline and abnormal values in tests of cardiovascular autonomic function[27]

	Normal	Borderline	Abnormal
Tests reflecting mainly parasympathetic function
Heart rate response to Valsalva Manoeuvre (Valsalva ratio)	≥ 1.21	1.11–1.20	≤ 1.10
Heart rate (R-R interval) variation	≥ 15 beats/min	11–14 beats/min	≤ 10 beats/min
During deep breathing (maximum-minimum heart rate) immediate heart rate response to standing (30:15 ratio)	≥ 1.04	1.01-1.03	≤ 1.00
Tests reflecting mainly sympathetic function
Blood pressure response to standing (fall in systolic blood mmHg mmHg mmHg pressure)	≤ 10	11–29	≥ 30
Blood pressure response to sustained handgrip (increase in diastolic blood pressure	≥ 16 mmHg	11–15 mmHg	≤ 10 mmHg

Table 6 Diagnostic algorithm for diabetic cardiac autonomic neuropathy[3,39]

	Symptoms	Signs/diagnostic tests	Differential workup
Resting tachycardia	Palpitations could be asymptomatic	Clinical exam: Resting heart rate > 100 bpm	Anemia hyperthyroidism fever
			CVD (atrial fibrillation,
			flutter, other)
			Dehydration
			Adrenal insufficiency
			Some medications
			Smoking, alcohol, caffeine
			Recreational drugs (cocaine, amphetamines, methamphetamine, mephedrone)
Orthostatic hypotension	Light-headedness	Clinical exam: A reduction of > 20 mmHg in the systolic blood pressure or > 10 mmHg in diastolic blood pressure	Adrenal insufficiency
	Weakness		Intravascular volume depletion
	Faintness		Blood loss/acute anemia
	Visual impairment		Dehydration
	Syncope		Pregnancy/postpartum
			CVD
			Alcohol
			Medication
			Antiadrenergics
			Antianginals
			Antiarrhythmics
			Anticholinergics
			Diuretics
			ACE inhibitors/angiotensin receptor blocker
			Narcotics
			Neuroleptics
			Sedatives

CAD: Coronary artery disease; CVD: Cardiovascular disease.

Table 7 Differential diagnosis of diabetic neuropathies[39]

Metabolic disease	Thyroid disease (common)
	Renal disease
Systemic disease	Systemic vasculitis
	Nonsystemic vasculitis
	Paraproteinemia (common)
	Amyloidosis
Infectious	Human immunodeficiency virus
	Hepatitis B
	Lyme
Inflammatory	Chronic inflammatory demyelinating polyradiculoneuropathy
Nutritional	B12
	Postgastroplasty
	Pyridoxine
	Thiamine
	Tocopherol
	Industrial agents, drugs, and metals
	Industrial agents
	Acrylamide
	Organophosphorous agents
Drugs	Alcohol
	Amiodarone
	Colchicine
	Dapsone
	Vinka alkaloids
Metals	Platinum
	Taxol
	Arsenic
	Mercury
Hereditary	Hereditary motor, sensory, and autonomic neuropathies