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The Association Between Cardiac Autonomic Dysfunction and Impaired Myocardial Blood Flow Regulation — ADA

Jun 25, 2019
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Emma Kammerer, L|E|C|O|M Bradenton School of Pharmacy, PharmD Candidate

Myocardial blood flow reserve plays a significant role as a predictor of cardiac death in patients with diabetes.

Cardiac autonomic neuropathy (CAN) is a complication of diabetes that increases the risk of mortality and silent myocardial ischemia. Previous studies have determined the association between impaired cardiac autonomic function and reduced myocardial flow reserve (MFR) in patients with type 2 diabetes, but lacked information on whether the association is also seen in patients with type 1 diabetes.

 The study was a cross-sectional study designed to determine the association between cardiac autonomic function and cardiac vascular function assessed as the MFR. 60 patients with type 1 diabetes were stratified based on their albuminuria status, 30 with normoalbuminuria and 30 with, or with previous history of, macroalbuminuria. 30 healthy patients without diabetes were included as a control group. The investigators measured HbA1c, plasma creatinine, eGFR, urinary albumin creatinine rate, 24-h blood pressure, and height and weight, then used to calculate BMI. Medical history was taken, and physical activity was questioned via questionnaires. Cardiac PET/CT was performed at rest and during stress and myocardial blood flow was calculated. All 60 patients with diabetes, and 14 patients from the control group, had cardiac 123I-MIBG scintigraphy, in which images were taken and used to calculate the myocardial washout rate. Heart rate variability was measured via the Vagus device to determine cardiac autonomic function. HRV indices were calculated using fast Fourier transformation and the ratio of LF-to-HF power were calculated. Cardiovascular autonomic reflex tests (CARTs) included 3 tests, response to standing (30-to-15 ratio), deep breathing test for 1 min (expiration-to-inspiration [E-to-I] ratio), and the Valsalva test ratio. CAN was defined as 2 things: the first, when no pathological CARTs were detected or if only 1 abnormal CART was detected, was called “no CAN.” The second: if 2 or 3 abnormal CARTs were detected it was called definite CAN. Lastly, in patients with diabetes, sudomotor function tests were performed on the hands and feet.

Analyses were performed and continuous data with normal distribution were given as the mean and SD and categorical variables presented as total numbers and percentages. When comparing differences between the 2 groups to determine differences between continuous variables, independent-samples t tests were used and the Chi square or Fisher exact test for categorical variables. Linear regression analyses were applied in stepwise adjustment for covariates. CARTs were not adjusted for as stated by the researchers due to heart rate being an influencer on the tests. To determine associations of the measures of cardiac autonomic function with each other, Pearson correlations were used. Sensitivity analyses, ANCOVA was used to determine if correlations stayed after adjustment.

CAN was determined based on CARTs, where 14 participants had definite CAN and 63 had no CAN. The late heart-to-mediastinum ratio was 2.9 + 0.39 in the control group and 2.5 + 0.45 in the participants with diabetes. Further looking at correlations between the measures of cardiac autonomic function and MFR, data showed all measures to be positively correlated to MFR in the unadjusted analysis (P < 0.004), except for LF-to-HF ratio and the Valsalva test ratio. The significance remained after adjustment for age (P < 0.01). With further adjustment for heart rate, the HRV indices were no longer significant, however, the late heart-to-mediastinum ratio stayed positively associated with MFR. After the final adjustment, both the late heart-to-mediastinum ratio and the 30-to-15 ratio persisted as positively associated with MFR (P = 0.01, P = 0.01). Pearson correlation coefficients showed that the HRV indices and CARTs had a strong positive correlation. 

Analyses were then run excluding patients with known coronary artery disease or ischemia. Results were confirmatory to the previous results stated, where the late heart-to-mediastinum ratio and the 30-to-15 ratio were positively associated with MFR (P = 0.0002). Both stayed positively associated with MFR until adjustment for risk factors, when the 30-to-15 ratio lost significance (P = 0.08). Pearson correlation coefficients were similar, except that the late heart-to-mediastinum ratio is no longer correlated with the 30-to-15 ratio. Also, HF power was not found to be correlated with SDNN or LF-to-HF ratio. Lastly analyses were run including only patients with diabetes. Again, the results were similar in that MFR was found to be positively correlated with late heart-to-mediastinum ratio (P = 0.01), total power (P < 0.001), and 30-to-35 ratio (P < 0.001). With adjustment for risk factors, the 30-to-15 ratio stayed statistically significant.

The authors wanted to examine if there is a link between cardiac autonomic function and impaired cardiac vascular function. They were able to determine a positive association between MRF and a variety of tested cardiac autonomic function measures. The strongest associations seen were between the late heart-to-mediastinum ratio, as well as, between the 30-to-15 ratio and MRF. Furthermore, after adjustment for cardiovascular risk factors and patients without coronary artery disease, the investigators were still able to determine a positive association between the late heart-to-mediastinum ratio and MFR. They believe this shows cardiac autonomic dysfunction may be associated with impaired MFR in patients with type 1 diabetes. Future studies are necessary to confirm the observed association found.

Practice Pearls:

  • A decrease in myocardial blood flow reserve makes patients with type 1 diabetes more vulnerable to ischemia.
  • While CT scans and imaging is not a typical lab at a physician visit, in patients with type 1 diabetes, scans like the ones performed in this study might offer an insight to a patient’s myocardial perfusion.
  •  Focusing on reducing other cardiovascular risk factors with diet and proper medication therapy should be discussed with every patient as they are already at an increased risk.


Zobel, Emilie, et al. Cardiac Autonomic Function Is Associated With Myocardial Flow Reserve in Type 1 Diabetes. Diabetes. 2019 June 1. 

Emma Kammerer, L|E|C|O|M Bradenton School of Pharmacy, PharmD Candidate