Cardiovascular autonomic neuropathy (CAN) is a complication of type 2 diabetes strongly associated with all-cause mortality and cardiovascular morbidity. Since clinical sequelae manifest only at advanced stages, subclinical CAN – prevalent in ~20% of otherwise healthy patients with type 2 diabetes – may have an insidious and long-term contribution to cardiovascular risk. However, since it tends to co-exist with additional microvascular complications of type 2 diabetes, poor metabolic control and traditional cardiovascular risk factors, the independent mechanistic origins of poor prognosis are difficult to discern. Emerging evidence suggests that CAN coincides with left ventricular (LV) dysfunction even in the absence of coronary artery disease (ie: non-ischaemic diabetic cardiomyopathy). However, the significance of this association is unclear due to intersecting aetiologies. Therapeutic strategies for diabetic CAN and LV dysfunction remain undefined, notwithstanding a common benefit from hyperglycaemia amelioration.
The principal hypothesis assessed by this thesis is that subclinical CAN independently contributes to the LV dysfunction of non-ischaemic diabetic cardiomyopathy and that the autonomic cardiopathy indicated by this relation is amenable to an exercise intervention. Specifically, favourable adaptations of exercise capacity and the metabolic milieu following chronic exercise training are expected to mediate improvements of co-varying cardiac autonomic and LV dysfunction in apparently healthy patients with type 2 diabetes. Within the series of investigations conducted on this basis, secondary aims include determination of the utility of various methods of CAN assessment in its diagnosis and monitoring, clarifying the contribution of LV and vascular dysfunction to exercise intolerance in type 2 diabetes and defining the impact of CAN on novel markers of electrophysiological disturbance.
Chapter 1 describes the epidemiology and clinical implications of CAN and non-ischaemic diabetic cardiomyopathy, the data relevant to a purported association of these entities, and the basis for exercise training as a potential therapeutic modality. To further characterise evidence pertaining to alternative treatments for subclinical CAN, a systematic review of the literature for relevant randomised controlled trials is detailed in Chapter 2.
In Chapter 4 and Chapter 5, methodological qualities of specific tests for CAN are explored since traditional assessment on the basis of cardiac reflex responses may be insensitive to early disease. In the first original investigation in this thesis, the reliability of heart rate variability – the diminution of which is widely recognised as one of the first signs of CAN – was sought in patients with type 2 diabetes. Favourable relative reliability (intra- relative to inter-subject variation) supported the inclusion of heart rate variability in expanded diagnostic test batteries for CAN. Despite poor absolute reliability (intra-subject variation), the parameters most-suited to utility as clinical trial endpoints were identified.
An additional limitation of traditional CAN assessment relates to its restricted availability – mostly to neurophysiology referral laboratories. Heart rate recovery after exercise is well known to have high specificity for vagal function and is easily derived from the more commonly performed exercise stress test. Thus, Chapter 5 investigates the diagnostic accuracy of post-exercise heart rate recovery for CAN. Favourable area under the receiver-operator characteristics curve (0.82), sensitivity (93%) and negative predictive value (97%), but modest specificity (69%) and positive predictive value (43%) supported the utility of heart rate recovery as a screening tool to identify at-risk patients requiring referral for formal autonomic evaluation.
Chapter 6 builds on the body of work reviewed in Chapter 1 implicating CAN in the pathogenesis of non-ischaemic diabetic cardiomyopathy. To determine whether cardiac dysinnervation contributes to dysfunction, the association of cardiac sympathetic integrity (by radionuclide imaging) with LV function (by echocardiography) was sought on a global and regional basis. The diastolic dysfunction of type 2 diabetes demonstrated independent associations with regional markers of sympathetic integrity and clinical markers of global autonomic function, thereby supporting the hypothesised presence of a distinct autonomic cardiopathy.
Chapter 7 investigates a novel marker of arrhythmogenic risk in the setting of cardiac sympathetic dysinnervation in CAN. Elevated temporal repolarisation lability (quantified by beat-to-beat QT interval variability) is known to confer a poor prognosis in patients with heart disease, possibly due to sympathetic hyperactivity. This study identified worse repolarisation instability in type 2 diabetic patients with cardiac sympathetic dysinnervation, consistent with increased risks of arrhythmogenesis and sudden cardiac death. Moreover, associations of global cardiac sympathetic integrity with repolarisation variability during the sympathetic activation of standing pointed to the potential utility of this parameter as a novel non-invasive marker of sympathetic activity.
Subclinical CAN and LV dysfunction have been explicitly linked to exercise intolerance. In the context of the compelling relationship between exercise capacity and outcome, Chapter 8 describes an imaging study of the potential contributing mechanisms related to cardiac and peripheral vascular dysfunction. Independent associations of exercise capacity with LV systolic functional reserve and skeletal muscle blood flow reserve were synonymous with a multifactorial pathophysiology.
Chapter 9 reports outcomes from a controlled trial of exercise training in patients with non-ischaemic diabetic cardiomyopathy. A significant and clinically relevant increase in peak oxygen uptake (11%) in the intervention group over 6 months failed to translate to adaptations of the autonomic nervous system. The latter result was based on heart rate variability (co-primary endpoint) and heart rate recovery (utilising information derived from Chapters 4 and 5), in addition to baroreflex sensitivity, cardiac reflex tests, and chronotropism. Functional and structural features of non-ischaemic diabetic cardiomyopathy demonstrated no benefit from exercise training, except for one echocardiographic marker of myocardial fibrosis.
In summary, this thesis defines the clinical and research utility of novel methods of autonomic assessment, characterises potential contributions of LV dysfunction and repolarisation instability to the adverse prognosis of CAN, and demonstrates that exercise training may not be the solution to a dearth of therapeutic strategies for this complication.