**Author details**

pressure change, diastolic blood pressure response to handgrip test) it was apparent that the relative risk of all-cause mortality associated with cardiac autonomic neuropathy was 2.85, 1.75-4.65; Valsalva ratio, heart rate response to standing up (30;15 ratio), and handgrip had an independent predictive value with regard to long-term all cause mortality [73]. When consid‐ ering separately time and frequency domain parameters of heart rate variability calculated on the basis of a 24-hour ECG recording, the power in the low frequency band was the only heart rate variability parameter with an independent predictive value on all-cause mortality [74]. When considering long-term predictive power of heart rate variability together with a battery of five autonomic function tests, the latter ones were superior to the former ones; particularly,

Several studies have evaluated the predictive value of various cardiac autonomic neuropa‐ thy parameters for all cause mortality and/or cardiovascular mortality and morbidity. They almost all agree that cardiac autonomic dysfunction is associated with a high-risk excess mortality/morbidity in diabetic patients. Toward a general consensus, however, many chal‐ lenges remain to be addressed by the research community. Drawbacks and limitations main‐

**1.** Establishing appropriate study design for evaluating the particular association. Pro‐ spective cohort studies are considered less vulnerable to bias than retrospective studies, because the outcomes have not occurred when the cohort is assembled and the expo‐ sures are assessed. In cohort studies the population may be fixed or open: undoubtedly, in long-term follow ups, the prevalence of cardiac autonomic neuropathy progressively increases in a direct proportion to age, duration of diabetes, and poor glycaemic control.

**2.** Defining clear health outcomes that should require confirmation by masked investiga‐

**3.** Establishing the length of follow up interval, which depends on the particular outcome under study. It has been shown that the longer the follow up, the higher the likelihood

**4.** Calculating the required sample size on the basis of anticipated differences between the groups, the background rate of the outcome, and the probability of making some statis‐

**5.** Using suitable cardiovascular autonomic reflex tests to diagnose cardiac autonomic neuropathy taking into account that a) the diagnostic definition of cardiac autonomic neuropathy based on several tests (of both vagal and sympathetic functions) reduces the probability of false positives, b) the gold standard for clinical autonomic testing in‐ cludes heart rate response to deep breathing, standing, and Valsalva manoeuvre, and

Valsalva, 30:15 ratio, and handgrip were independent predictors of death [75].

ly concern the following features that deserve attention and discussion [76]:

tors in order to guarantee their accuracy.

blood pressure response to standing [12].

**6. Concluding remarks**

378 Type 1 Diabetes

of attrition.

tical errors.

Elena Matteucci\* and Ottavio Giampietro\*

\*Address all correspondence to: elena.matteucci@med.unipi.it

Department of Clinical and Experimental Medicine, Italy
