Complexity of Impaired Parasympathetic Heart Rate Regulation in Diabetes

The autonomic nervous system is crucial for blood pressure and heart rate regulation. Sympathetic efferent fibers elicit vasoconstriction, raise heart rate and cardiac contractility, and promote sodium reabsorption through direct renal tubular actions and renin-angiotensin system activation. Parasympathetic efferent fibers rapidly reduce heart rate. Both autonomic branches are tightly controlled by baroreflex, stabilizing blood pressure in a feedback fashion (1). Severe autonomic failure due to sympathetic and parasympathetic dysfunction typically occurs in patients with long-standing and poorly controlled diabetes. The condition is associated with profound orthostatic hypotension, postprandial hypotension, a fixed heart rate, and exercise intolerance. Positron emission tomography or single photon emission tomography imaging with tracers taken up by adrenergic sympathetic nerve endings suggest that autonomic efferent nerves are irreversibly damaged in these patients (2,3). There are no causative treatments for late-stage disease and symptomatic treatment is difficult. Clinicians caring for autonomic failure patients are faced with the therapeutic dilemma that blood pressure is often markedly elevated in the supine position (4). Yet, antihypertensive treatment exacerbates orthostatic hypotension. Conversely, treatment of orthostatic hypotension with pressor agents might hasten cardiovascular and renal disease progression. The condition carries a poor prognosis.

More subtle changes in cardiovascular autonomic regulation are common early in the course of type 1 or type 2 diabetes. Typically, impaired parasympathetic heart rate control precedes sympathetic dysfunction. Simple bedside tests, such as respiratory sinus arrhythmia assessment during deep breathing, are often diagnostic (5). Heart rate variability and noninvasive baroreflex sensitivity measurements are also useful diagnostic tools, particularly in epidemiologic or clinical studies. Early-stage diabetic cardiovascular autonomic dysfunction with impaired parasympathetic heart rate control is a cardiovascular risk marker (6,7). Whether or not this measurement adds much prognostic information in addition to more readily available risk markers such as microalbuminuria is an unresolved issue. Yet, there may be a window of opportunity when cardiovascular autonomic neuropathy is recognized at an early stage. Treatments slowing the progression of autonomic dysfunction may be particularly beneficial in this setting. For example, in the Diabetes Control and Complications Trial (DCCT), intensive glycemic control substantially reduced the risk for diabetic cardiovascular autonomic neuropathy in type 1 diabetic patients (8). Several other treatments have been suggested but none has been validated in properly controlled clinical trials. Mechanistic insight from suitable animal models could unravel more promising treatment targets. Such studies are difficult because insight at the cellular or molecular level must be translated into whole animals and vice versa.

In this issue, Zhang et al. (9) conducted such a study in diabetic Akita mice. In these animals, a point mutation in the insulin 2 gene leads to production of a misfolded protein, pancreatic β-cell destruction, and a metabolic phenotype resembling type 1 diabetes. In an earlier study, the authors had observed diminished bradycardia to muscarinic cholinergic stimulation with carbamylcholine in diabetic Akita mice (10). In this model, impaired parasympathetic heart rate control may result in part from reduced cardiac responsiveness to the parasympathetic neurotransmitter acetylcholine. In the current study, the authors studied heart rate regulation in diabetic Akita mice and in wild-type animals equipped with radiotelemetry electrocardiogram transmitters in more detail. Akita mice showed abnormalities in heart rate variability and exhibited a smaller heart rate increase with atropine. The observation is consistent with impaired parasympathetic heart rate control. Insulin treatment ameliorated cardiac parasympathetic dysfunction. In cardiac atria, diabetic Akita mice exhibited decreased expression of G-protein coupled inward rectifying K⁺ channel (GIRK)-4 subunit, which is part of the potassium channel through which muscarinic acetylcholine receptors regulate heart rate. A possible limitation of these ex vivo experiments is that heart rate is generated in specialized pacemaker cells in the sinus node, which likely differ from cardiac atrial cells. Through a series of experiments using elegant pharmacologic, genetic, and electrophysiologic approaches, the authors demonstrated that the impairment in heart rate regulation in diabetic Akita mice could result from glycogen synthase kinase-3β hyperactivity secondary to insulin deficiency.

Given the prognostic implications and the symptomatic burden associated with diabetic cardiovascular autonomic dysfunction, it is surprising that studies in suitable animal models are few (11). The difficulty in assessing cardiovascular autonomic regulation in small animals and the lack of methodological standardization may be responsible for lack of progress in this area. For example, there is controversy in how parasympathetic and sympathetic activity affect heart rate variability in mice across different frequency ranges. Human low-frequency range heart rate variability is generated by sympathetic and parasympathetic activity. In mice, low-frequency heart rate variability is virtually abolished with atropine, consistent with mainly parasympathetic modulation (12). Spontaneous heart rate variability and power spectra in a healthy human being and in a mouse are illustrated in Fig. 1.

The mechanism disturbing parasympathetic heart rate control in diabetic Akita mice likely differs from late-stage human diabetic autonomic dysfunction. Indeed, not all diabetic mouse models reproduce human cardiovascular autonomic dysfunction. Nonobese diabetic mice exhibit improvements in heart rate variability and baroreflex sensitivity probably through selective sympathetic degeneration (13). Nevertheless, the study by Zhang et al. (9) raises several important issues. The study reminds us that the diagnosis “cardiac autonomic neuropathy” implicating irreversible neuronal damage can be misleading. Much like in diabetic Akita mice, functional and potentially reversible reductions in parasympathetic heart rate control can occur in human beings. More detailed physiologic (14) or pharmacologic (15) tests may be required to differentiate functional and structural parasympathetic dysfunction in diabetic patients. Furthermore, the cause of the change in parasympathetic heart rate control is difficult to localize. Responses to autonomic testing, heart rate variability, and baroreflex sensitivity can be affected by afferent baroreflex input, central nervous autonomic integration, efferent parasympathetic transmission, and end-organ responsiveness. In rabbits with alloxan-induced diabetes, impaired baroreflex heart rate regulation was attributed to impaired activation of central nervous parasympathetic pathways (16). Overall, observations in animal models and in patients strongly support the idea that different mechanisms can elicit cardiovascular autonomic dysfunction. Better dissection of these mechanisms using state-of-the-art integrative physiology may be required to develop better treatments and to target the right treatment to the right patient.