David J. Ewing

Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications.

Cardiovascular effects of diabetic autonomic neuropathy include postural hypotension, resting tachycardia, and, possibly, painless myocardial infarction. Involvement of cardiovascular reflexes in diabetes can be assessed using simple noninvasive tests: the Valsalva maneuver, beat-to-beat heart rate variation, the heart rate response to standing, postural fall in blood pressure, and the sustained handgrip test. Tests of parasympathetic function appear to be abnormal more frequently and earlier in cardiac autonomic involvement, whereas sympathetic damage usually occurs later and is associated with clinical symptoms. When test results are abnormal, in association with symptoms suggestive of autonomic neuropathy, the prognosis is grave. Some sudden deaths that occur may be due to abnormal autonomic reflexes.

Diabetic autonomic neuropathy.

SummaryThis review attempts to outline the present understanding of diabetic autonomic neuropathy. The clinical features have been increasingly recognised but knowledge of the localization and morphology of the lesions and their pathogenesis remains fragmentary. A metabolic causation as postulated in somatic nerves accords best with clinical observations. Most bodily systems, particularly the cardiovascular, gastrointestinal and urogenital, are involved with added disturbances of thermoregulatory function and pupillary reflexes. Possible effects on neuroendocrine and peptidergic secretion and respiratory control await definition. Current interest centres around the development of a new generation of tests of autonomic nerve function that are simple, non-invasive, reproducible and allow precision in diagnosis and accurate quantitation. Most are based on cardiovascular reflexes and abnormality in them is assumed to reflect autonomic damage elsewhere. Probably no single test suffices and a battery of tests reflecting both parasympathetic and sympathetic function is preferable. Little is known of the natural history. The prevalence may be greater than previously suspected and although symptoms are mild in the majority, a few develop florid features. The relation of control and duration of diabetes to the onset and progression of autonomic neuropathy is not clearly established. Once tests of autonomic function become abnormal they usually remain abnormal. Symptomatic autonomic neuropathy carries a greatly increased mortality rate possibly due to indirect mechanisms such as renal failure and direct mechanisms such as cardio-respiratory arrest. Improved treatment of some of the more disabling symptoms has been possible in recent years.

Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients

SummaryQT intervals were measured over RR intervals ranging from 500 ms to 1000 ms in 13 normal male subjects, 13 male diabetic subjects without and 13 with autonomic neuropathy. There was a close linear relationship between QT and RR in all subjects. The slope of the regression line was significantly greater in the autonomic neuropathy group than the normal group. Thirty-two male diabetic subjects with varying degrees of autonomic dysfunction had repeat QT measurements 3 (range 2–6) years later. QT and QTC lengthened significantly at the second visit, unrelated to age or time between recordings, but which corresponded with changes in autonomic function. Of 71 male diabetic subjects under 60 years followed for 3 years, 13 had died, 8 unexpectedly. Of those with autonomic neuropathy, QT and QTC were significantly longer in those who subsequently died, despite similar ages and duration of diabetes. We conclude that QT/RR interval relationships are altered in diabetic autonomic neuropathy, and that changes in QT length with time parallel changese in autonomic function. There may be an association between QT interval prolongation and the risk of dying unexpectedly in diabetic autonomic neuropathy.

Cardiac autonomic neuropathy in diabetes: Comparison of measures of R-R interval variation

SummaryFive different methods of analysing R-R interval (heart rate) variation were compared, using a computer technique, in 61 diabetics with a wide range of responses to autonomic function testing. Two methods differentiated best between the diabetics with and without autonomic damage: (1) the standard deviation of the mean R-R interval recorded for 5 min during quiet breathing with the subject either sitting or standing; (2) the difference between the maximum and minimum heart rates recorded over 1 min during deep breathing at six breaths per minute, again with the subject either sitting or standing. For routine cHnical usage we conclude that recording the heart rate for 1 min on an ECG, while the subject sits and breaths deeply at six breaths per minute, and then measuring the difference between the maximum and minimum heart rate, is the most practical method currently available. For research purposes either this method or the standard deviation method during quiet breathing for 5 min, should be used.

VASCULAR REFLEXES IN DIABETIC AUTONOMIC NEUROPATHY

Abstract The vascular responses to the Valsalva manœuvre and sustained handgrip were measured in thirty-seven diabetics with signs and symptoms suggestive of autonomic neuropathy. The Valsalva manœuvre was abnormal in twenty-three (62%) and the handgrip was abnormal in fifteen (41%) of the patients. There was a significant correlation between the results of the two tests. The responses to the two tests were less abnormal in the fifteen patients with impotence alone, and only when this symptom was associated with other clinical features of diabetic autonomic neuropathy could it be reliably attributed to this disorder. Of the fourteen patients with postural hypotension, all had abnormal Valsalva responses, and eight had reduced handgrip responses. Motor-nerve-conduction studies showed that patients with these abnormal vascular reflexes had evidence of greater peripheral-nerve damage in their legs than those patients with normal responses. It is concluded that both the Valsalva and handgrip tests are useful in providing an objective assessment of the integrity of the autonomic nervous system in diabetes mellitus.

HEART RATE CHANGES IN DIABETES MELLITUS

Resting heart rates were measured lying, sitting, and standing in 61 diabetics with varying degrees of cardiovascular reflex abnormalities. Those with parasympathetic abnormalities alone had the highest heart rates, while those with both parasympathetic and sympathetic involvement had slightly less rapid heart rates, which were still faster than those in diabetics with normal cardiovascular reflexes. 38 other diabetics in whom autonomic function tests had been done at least three times had a similar pattern of resting heart rate. 25 had unchanged tests: those with parasympathetic involvement alone had the highest heart rates. The other 13 subjects whose autonomic function changed from normal to abnormal showed a sequential increase in heart rate as cardiac parasympathetic damage developed, followed by a fall in heart rate, but not back to normal, as sympathetic damage developed as well. The increased resting heart rates in diabetics may be due in some patients to cardiac parasympathetic damage alone and in others to combined parasympathetic and cardiac sympathetic damage. The sequential heart rate changes support the view that the vagus nerve is affected before the cardiac sympathetic nerves.

A Controlled Trial of Sorbinil, an Aldose Reductase Inhibitor, in Chronic Painful Diabetic Neuropathy

A double-blind, randomized, placebo-controlled crossover trial of the aldose reductase inhibitor sorbinil was undertaken in 15 patients (age 35–68 yr) with chronic painful diabetic neuropathy. Treatment was evaluated by subjective pain responses, clinical examination, vibration perception threshold, motor and sensory nerve electrophysiology, and cardiovascular reflex tests of autonomie nerve function. Among the many measurements, only pain, tendon reflex scores, and sural sensory potential amplitude improved significantly during sorbinil administration, while scores of clinical sensory examination deteriorated. Four patients experienced an idiosyncratic reaction that rapidly recovered on discontinuing the drug. This study suggests that aldose reductase inhibitor treatment with sorbinil may have an effect on symptomatic diabetic neuropathy in man.

Variable Relationship Between Peripheral Somatic and Autonomic Neuropathy in Patients with Different Syndromes of Diabetic Polyneuropathy

The relationship between abnormal peripheral nerve electrophysiology and abnormal cardiovascular autonomie function has been studied in four groups of diabetic subjects, comparable with regard to age, duration, and type of diabetes. Thirty-three had no symptoms of neuropathy, 28 had newly developed painful neuropathy, 24 had chronic painful neuropathy, and 21 had painless neuropathy with associated recurrent foot ulcers. In all three symptomatic groups, electrophysiology and autonomie function were more abnormal than in asymptomatic diabetic subjects. There was a significant overall relationship between peripheral nerve (electrophysiologic) and autonomie (cardiovascular reflex) dysfunction. However, when considered by groups, the degree of cardiovascular reflex abnormality was similar in the three symptomatic groups, whereas electrophysiology was appreciably worse in the foot ulcer group than in patients with painful neuropathy. Thus, patients with painful neuropathy had a higher ratio of autonomie (small fiber) abnormality to electrophysiologic (large fiber) abnormality. By contrast, foot ulceration was associated with the worst electrophysiologic (large fiber) abnormality. Heavier alcohol consumption and more severe retinopathy were also related to foot ulceration. In diabetic subjects with symmetrical sensory neuropathy, the relationship between large fiber and small fiber damage is not uniform. We conclude that there may be different etiologie influences on large and small fiber neuropathy in diabetic subjects and that the predominant type of fiber damage may determine the form of the presenting Clinical syndrome.

Nerve Function and Metabolic Control in Teenage Diabetics

Peripheral somatic and autonomic nerve function have been studied in 79 teenage (16–19 yr) diabetics and 20 age- and sex-matched normal controls. Almost three-quarters of the diabetics (72%) had abnormal peripheral somatic nerve function tests, and one-third (31%) had abnormal cardiac parasympathetic tests. Both motor and sensory peripheral somatic nerve abnormalities were related to poor prevalling glycemic control (HbA1) and duration of diabetes. Thus, the 27 patients with three or more (maximum six) peripheral nerve abnormalities had significantly higher HbA1 levels (P < 0.001) and longer duration of diabetes (P < 0.01) than the 22 with no abnormalities. Individual peripheral somatic nerve tests almost invariably correlated only with HbA1 (median motor, P < 0.05; peroneal motor, P < 0.001; sural sensory, P < 0.001) or duration of diabetes (median sensory, P < 0.001). Sensory potential amplitude, as well as conduction velocity, was frequently reduced, implying axonal involvement. These findings suggest that abnormal peripheral and autonomic nerve function are common in young insulin-dependent diabetics and that poor metabolic control is a major determinant of the damage.

Heart rate variability in patients with ventricular arrhythmias: Effect of antiarrhythmic drugs

The purpose of this study was to investigate whether heart rate variability could be reliably assessed in patients with ventricular arrhythmias and to evaluate whether it is affected by antiarrhythmic drugs. The study was based on an analysis of 239 ambulatory electrocardiographic (ECG) recordings obtained from 67 patients with frequent and complex ventricular arrhythmias enrolled in the Antiarrhythmic Drug Evaluation Group (ADEG) study. In each recording, after exclusion of premature ventricular complexes, the number of times during a 24 h period in which two consecutive sinus RR intervals differed by more than 50 ms was calculated. The total 24 h count from each recording was then used as an index of heart rate variability. This method is a reliable marker of cardiac parasympathetic activity. Recordings were analyzed at baseline (n = 56), during longterm treatment with amiodarone (n = 17), flecainide (n = 22) or propafenone (n = 17) and after washout in selected patients (n = 5). Despite the presence of a different number of arrhythmias, total 24 h counts in the same patient appeared reproducible over time (r = 0.83 between two different recordings, n = 49, p Baseline counts (median 1,698, range 26 to 13,648) were not correlated (r = 0.15) with the number of arrhythmias. The three antiarrhythmic drugs had a disparate effect on total 24 h counts: no change was observed in patients treated with amiodarone (median percent change [Δ%]-8, p = NS), whereas a significant (p These results indicate that heart rate variability can reliably be assessed by this total 24 h counts method in patients with frequent ventricular arrhythmias. The presence or suppression of arrhythmias itself did not modify heart rate variability. Class IC antiarrhythmic drugs may significantly affect heart rate variability, and this influence may contribute to the overall effect of these agents on mortality.