Focus on Diabetic Cardiac Autonomic Neuropathy

February is American Heart Month, and there’s no better time to focus on diabetic cardiac autonomic neuropathy (DCAN). While heart disease and diabetes often seem to go hand in hand, DCAN remains overlooked as an important risk factor for cardiac morbidity and mortality in diabetes. 

The prevalence of confirmed DCAN, however, runs up to 20%, and rises to 65% in longstanding diabetes.¹ Yet silent cardiac ischemia and atypical signs of cardiac ischemia – acute onset dyspnea, severe fatigue, acute onset nausea and vomiting – should raise a high suspicion for cardiac ischemia and prompt immediate evaluation and treatment. All too often, though, these signs result in delayed diagnosis and treatment.

Studies have confirmed the link between DCAN and increased risk of cardiac death. The landmark Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which included over 10,000 participants followed for 3.5 years, found that all-cause mortality was up to two times higher and death from cardiovascular disease was up to three times higher in participants with DCAN at baseline compared to those without.² Post hoc analyses of ACCORD and other trials found that the presence of DCAN may predispose to cardiovascular events.³

More recently, the DIAD (Detection of Ischemia in Asymptomatic Diabetics) study looked at 1119 patients with type 2 diabetes mellitus (T2DM) who were initially asymptomatic. It found that 8.4% of patients developed symptomatic cardiac disease over five years, and identified DCAN as an independent predictor of worse cardiovascular outcomes in asymptomatic patients.⁴

Studies have also linked DCAN to early diastolic dysfunction, left ventricular hypertrophy, and increased risk of stroke, as well as increased progression and decreased survival in chronic kidney disease.^1,5

DCAN results from an autonomic imbalance in which sympathetic tone predominates over parasympathetic activity. The incidence of DCAN rises with increased duration of diabetes, though signs of autonomic dysfunction can sometimes be detected early in the course of the disease. Some evidence suggests that DCAN may precede left ventricular hypertrophy and diastolic dysfunction in patients with T2DM and normal blood pressure, pointing to autonomic dysfunction as an early marker of preclinical cardiac abnormalities.⁶

Some studies have also suggested that DCAN may precede insulin resistance in metabolic syndrome.⁵ For example, the Framingham Heart Study found that patients with prediabetes already had sympathetic predominance and reduced heart rate variability.⁷

Symptoms

Clinical symptoms of DCAN include exercise intolerance, resting tachycardia often around 100-130 beats per minute, intraoperative cardiac lability, reversal of normal nocturnal parasympathetic predominance resulting in hypertension during sleep, orthostatic hypotension, QT-interval prolongation, silent myocardial ischemia, and diabetic cardiomyopathy.⁸

Some studies have found that the development of nocturnal hypertension may precede the development of microalbuminuria, suggesting that the presence of microalbuminuria may indicate the development of myocardial abnormalities. Given the long, asymptomatic course of DCAN, some advise early evaluation for DCAN, ambulatory blood pressure monitoring, echocardiography, and early treatment in all patients with T2DM, especially those who already have microalbuminuria.⁶

Evaluation

Heart rate variability (HRV) represents the earliest clinical sign of DCAN, and is often asymptomatic. In fact, changes in cardiovascular reflex testing have been found within one year of diagnosis in T2DM and two years of diagnosis in type 1 diabetes (T1DM).⁵

Several tests can be used for clinical evaluation of DCAN, including measurements of cardiovascular reflex testing and HRV, 24-hour blood pressure profiles, and orthostatic hypotension. A recent Toronto Consensus Panel on Diabetic Neuropathy recommended cardiovascular autonomic reflex testing as the gold standard for clinical assessment of DCAN.¹ These tests measure heart rate and blood pressure responses to several different maneuvers, including deep breathing, response to standing, Valsalva ratio, and orthostatic hypotension. HRV with deep breathing is frequently used and has a specificity of about 80%.⁵

Treatment

In terms of treatment, prevention remains the best medicine. Experts advise multivariable lifestyle modification including smoking cessation, exercise, and early therapy targeting strict glycemic control and cardiovascular risk factors like hypertension and abnormal lipids.⁹ Exercise, in particular, may be cardioprotective by restoring autonomic balance in patients with DCAN, especially for those who are obese.¹⁰ Due to blunted HRV in patients who already have DCAN, stress testing before embarking on a new exercise program may be advisable in some patients.⁵

Intensive glycemic control remains controversial. The Diabetes Control and Complications Trial (DCCT) found that intensive insulin therapy in T1DM decreased the incidence of DCAN by 53%.¹¹ Long-term follow-up over 14 years documented the persistent benefits of intensive early glycemic control on DCAN in T1DM.¹²

The benefits of intensive glycemic control in T2DM, however, are less conclusive.⁵ Results from the ACCORD trial suggested that intensive therapy increases the risk of hypoglycemia and may actually increase the risk of all-cause and cardiovascular death, which prompted early cessation of the trial.¹³

Medical treatment for DCAN is limited. Some studies have suggested that antioxidants, especially α-lipoic acid, and aldose reductase inhibitors may increase HRV.⁸ ACE inhibitors, angiotensin II type 1 receptor blockers, cardioselective β blockers (like metoprolol, nebivolol, and bisoprolol), digoxin, and verapamil have also been shown to increase HRV. The results are controversial, though, and have failed to prove any clear efficacy in DCAN.⁵

On the other hand, a number of drugs often used in diabetes can aggravate DCAN, including vasodilators, diuretics, insulin, and tricyclic antidepressants.⁵

DCAN highlights the early systemic effects of diabetes. Given its progressive course and few treatment options, DCAN underscores the importance of prevention. As Benjamin Franklin is thought to have said, “An ounce of prevention is worth a pound of cure.”

Take-home Points

• Diabetic cardiac autonomic neuropathy is common but often overlooked in diabetes, and can result in delayed diagnosis and treatment for cardiac ischemia.

• DCAN has been linked to increased risk for all-cause mortality, cardiac morbidity and mortality, and stroke, as well as increased progression and decreased survival in chronic kidney disease.

• Decreased HRV represents the earliest clinical sign of DCAN.

• Experts advise multivariable lifestyle modification including smoking cessation, exercise, and early therapy targeting strict glycemic control and cardiovascular risk factors.

• Overly intensive glycemic control can increase the risk of hypoglycemia and has been linked to increased all-cause and cardiovascular death in T2DM.

References:

1. Spallone V, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. 2011 Oct; 27(7):639-653.

2. Pop-Busui R, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care. 2010 Jul; 33(7):1578-1584.

3. Paty BW. The role of hypoglycemia in cardiovascular outcomes in diabetes. Can J Diabetes. 2015 Dec;39 Suppl 5:S155-S159.

4. Chyun DA, et al. Autonomic dysfunction independently predicts poor cardiovascular outcomes in asymptomatic individuals with type 2 diabetes in the DIAD study. SAGE Open Med. 2015 Feb 24; 3:2050312114568476.

5. Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. J Cardiovasc Transl Res. 2012 Aug;5(4):463-478.

6. Felício JS, et al. Present insights on cardiomyopathy in diabetic patients. Curr Diabetes Rev. 2015 Sep 14.

7. Singh JP, et al. Association of hyperglycemia with reduced heart rate variability (The Framingham Heart Study). Am J Cardiol. 2000 Aug 1; 86(3):309-312.

8. Karayannis G, et al. Diabetic cardiovascular autonomic neuropathy: clinical implications. Expert Rev Cardiovasc Ther. 2012 Jun;10(6):747-765.

9. Gaede P, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003 Jan 30; 348(5):383-393.

10. Voulgari C, et al. Exercise improves cardiac autonomic function in obesity and diabetes. Metabolism. 2013 May;62(5):609-621.

11. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia. 1998 Apr; 41(4):416-423.

12. Pop-Busui R, et al. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). Circulation. 2009 Jun 9;119(22):2886-2893.

13. Ismail-Beigi F, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010 Aug 7;376(9739):419-30.