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Diabetes Volume 63, June 2014
1847
Jens Jordan and Jens Tank
Complexity of Impaired
Parasympathetic Heart Rate
Regulation in Diabetes
Diabetes 2014;63:1847–1849 | DOI: 10.2337/db14-0304
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 b-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
Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany
© 2014 by the American Diabetes Association. See http://creativecommons.org
/licenses/by-nc-nd/3.0/ for details.
Corresponding author: Jens Jordan, [email protected].
See accompanying article, p. 2097.
COMMENTARY
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
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Commentary
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-3b 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,
Diabetes Volume 63, June 2014
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 latestage 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”
Figure 1—The figure illustrates the profound differences in heart rate regulation between human subjects and mice. Shown are RR-interval
(RR-I) changes over 5 min in resting healthy human subject (top left panel). The mean RR-I is 852 ms corresponding to a heart rate of 71
bpm. Pulse intervals (PI) derived from telemetry blood pressure recordings in a healthy mouse (top right panel) over 1 min under resting
conditions are shown. The mean PI during the recording is 123 ms corresponding to a heart rate of 487 bpm. We applied power spectral
analysis using fast Fourier transformation after interpolation and resampling (4 Hz in human, 12 Hz in mouse) to analyze heart rate variability
in the frequency domain. The resulting power spectra are shown in the lower panels (left, human subject; right, mouse). Please note the
profound differences in the x- and y-axes scaling indicating an ;1,000 times higher maximum spectral power at much lower frequencies in
humans. The definition of low- and high-frequency ranges is somewhat arbitrary and may not reflect the same physiologic mechanism
in human subjects and mice. HF, high-frequency range, 0.15–0.4 Hz in humans, 1–6 Hz in mice; LF, low-frequency range, 0.04–0.15 Hz in
humans, 0.25–1 Hz in mice; PSD, power spectral density.
diabetes.diabetesjournals.org
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.
Duality of Interest. No potential conflicts of interest relevant to this article
were reported.
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