Cardiovascular Autonomic Dysfunction Predicts Outcomes in Diabetes

Marlene Busko

August 27, 2013

OULU, FINLAND AND GYEONGGI-DO, SOUTH KOREA — Among patients with stable CAD and type 2 diabetes, measures of autonomic function--such as heart-rate recovery after exercise--may help predict the risk of short-term adverse cardiovascular events, a new study hints[1]. A second study reports that autonomic dysfunction is strongly linked with a greater risk of severe hypoglycemia in patients with type 2 diabetes[2].

Autonomic dysfunction, which develops over many years of poor glycemic control, can produce "devastating" symptoms such as severe orthostatic hypotension, which can hamper day-to-day functioning, Dr George Bakris (University of Chicago School of Medicine, IL), who was not involved with these studies, told heartwire.

However, "it is a problem that can be avoided," he said. "The best way to avoid it is to have intensive glucose control with hemoglobin A1cs that are definitely below 7.5 and ideally below 7. . . . On the other hand, if you have [HbA1c] levels above 8, certainly above 9, you have a very high likelihood of having the problem [within] 10 or more years." According to Bakris, "It's something that only the patients can really control."

The two studies were published online August 19, 2013 in Diabetes Care.

Autonomic Dysfunction and Risk of a CV Event

In the first study, Dr Mikko P Tulppo (Oulu University Hospital, Finland) and colleagues write that among patients with CAD and type 2 diabetes, autonomic dysfunction is common, but its prognostic value is unknown.

To evaluate this, they analyzed data from a substudy of patients enrolled in the ARTEMIS trial, 530 patients with CAD and diabetes matched with 530 patients with CAD without diabetes. The patients had a mean age of 67, and 69% were males.

The patients performed a test on an exercise bicycle, which allowed the researchers to determine their heart-rate recovery, defined as the drop in heart rate from the rate at maximal exercise to the rate one minute after stopping the exercise. The patients also wore digital Holter recorders, which provided 24-hour ambulatory ECG readings, which allowed the researchers to measure heart-rate variability and heart-rate turbulence.

During a two-year follow-up, 127 patients (13%) reached the composite end point of a cardiovascular event, which included cardiovascular death (2%), acute coronary event (8%), stroke (3%), or hospitalization for heart failure (2%).

In univariate analysis, among patients with CAD and type 2 diabetes, those who had a blunted heart-rate recovery after exercise--defined as a drop in heart rate of less than 21 beats per minute--had a 1.69-fold greater risk having a cardiovascular event than their peers.

Similarly, those with blunted heart-rate turbulence (<3.4 ms/R-R interval) had a 2.08-fold increased risk of an event, and those with low heart-rate variability (<110 ms) had a 1.96-fold greater risk of having a cardiovascular event.

After multivariate analysis, C-reactive protein (CRP), but none of the three measures of autonomic function, still predicted an increased risk of having a cardiovascular event during this short follow-up.

The measures of autonomic function did not predict the risk of events among patients who had CAD but no diabetes.

"The finding that if you have diabetes and your heart-rate recovery [after stopping exercise] is less than 21 beats per minute then you have the highest risk of dying is not a huge surprise," Bakris said. What's interesting is that in this "soup" of risk factors "a marker of inflammation, specifically CRP, was more predictive of who's going to have an event," he noted.

Autonomic Dysfunction and Risk of Severe Hypoglycemia

In the second study, Dr Seung-Hyun Ko (Catholic University of Korea, Gyeonggi-do, South Korea) and colleagues probed the relationship between autonomic dysfunction and severe hypoglycemia.

They enrolled 894 consecutive patients with type 2 diabetes, aged 25 to 75, who were seen at their center.

To determine autonomic function, the researchers measured the patients' heart-rate variability at three times: during a Valsalva maneuver, deep breathing, and going from lying down to standing. These can be easily measured at a patient's bedside or in an outpatient setting, the researchers note.

A total of 252 men and 372 women completed the study.

During close to 10 years of  follow-up, 77 episodes of severe hypoglycemia occurred among 62 patients (9.9%). About 16% of patients were diagnosed with early autonomic dysfunction and another 15% were diagnosed with definite autonomic dysfunction.

Patients with early autonomic dysfunction were not at increased risk of severe hypoglycemia.

However, patients with type 2 diabetes and definite autonomic dysfunction were more than twice as likely to have an episode of severe hypoglycemia as those with normal autonomic function (HR 2.43).

"Screening and regular follow-up of cardiac autonomic neuropathy and careful clinical attention to patient education concerning hypoglycemia is essential for patients with definite [cardiovascular autonomic neuropathy] to prevent [severe hypoglycemia] and related mortality," Ko and colleagues conclude.

The authors have no conflict of interest. Bakris receives grant/research support from Takeda, Medtronic, and CVRx.

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