Can Heart Failure Impair Thinking?

Background

HF is among the most serious symptom of heart disease, killing about two-thirds of all patients within five years of diagnosis. Patients are treated with mediations such as ACE inhibitors and digitalis so that the heart does not have to work so strenuously to pump blood. HF has other effects as well.

High sympathetic and decreased parasympathetic activities are characteristic of HF and are manifested as blunted baroreceptor activity, diminished parasympathetic effects on the sinoatrial node, increased norepinephrine, decreased heart rate variability, and diminished responsiveness and number of 1-receptors. These characteristics may result from peripheral or central aberrations. The parasympathetic alterations may derive from reduced cardiac muscarinic receptors; however, they also may result from central nervous system (CNS) dysfunction.

The cognitive deficits also suggest CNS dysfunction, possibly developing from ischemic damage as a consequence of HF. The principal neurological deficit of HF patients appears to be delayed recall. This memory dysfunction suggests specific neural damage related to the hippocampus or frontal lobe or associated circuitry, rather than generalized deficits over the entire brain.

Approximately one-half of chronic HF patients exhibit obstructive sleep apnea (OSA) or Cheyne-Stokes breathing during sleep. OSA cases show significant gray matter loss in cerebellar, insular, and cortical areas, which may contribute to aberrant autonomic, cognitive, or breathing characteristics. Cheyne-Stokes breathing is sensitive to CO2 administration, suggesting deficient chemoreceptor integrative mechanisms in HF and specifically implicating cerebellar structures, which partially mediate such chemoreception. The continued presence of sleep-disordered breathing, despite optimal HF therapy and typical absence of gross anatomic features classically associated with OSA, such as obesity, micrognathia, or reduced upper airway dimensions, indicates a CNS component in the disturbed breathing in HF.

The collective evidence of disordered breathing during sleep, altered autonomic activity, and presence of cognitive deficits, with all characteristics occurring without obvious motor or primary sensory symptoms, suggests neural damage in sites serving specific roles in memory, CO2 regulation, and sympathetic and parasympathetic control.

A New Study

Accordingly, a new study has been conducted to evaluate whether neural areas underlying control of these characteristics are affected in advanced HF patients.

The study entitled "Regional Brain Gray Matter Loss in Heart Failure," was undertaken by Mary A. Woo, Paul M. Macey, Gregg C. Fonarow, Michele A. Hamilton, and Ronald M. Harper, all of the David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA. Their findings appear in the August 2003 edition of the Journal of Applied Physiology, one of 14 scientific journals published each month by the American Physiological Society (ASP) (http://www.the-aps.org).

Methodology

The following methodology was used:

Subjects: Nine advanced HF patients (mean age = 51 ± 10 yr; 6 men) and 27 healthy controls (mean age = 46 ± 12 yr; 22 men) participated in this study. The HF patients met national HF diagnostic criteria, and all patients exhibited systolic dysfunction and were in New York Heart Association Functional Class III–IV. Three HF cases had coronary artery disease, and six were classified as idiopathic for the underlying etiology of their disease. All HF patients were treated with optimal medical therapy and maintained stable weights. Four HF patients were taking aspirin, and four were taking warfarin.

All HF cases underwent a complete overnight polysomnographic recording before the study. Sleep-disturbed breathing was considered present if the respiratory distress index (RDI) was >5 or if more than 30 apneic events occurred per night. Twenty-four of the 27 control subjects were monitored in the scanner facility until quiet sleep was established.

Structural MRI Acquisition and Analysis: Anatomic T1-weighted image volumes were collected on an MRI scanner. The steady-state sequence was used, and no MRI contrast media were administered. The structural brain MRI data were analyzed. Voxel-based morphometry (VBM), a method for detecting regional gray matter volume changes in magnetic resonance images, was used. A "brain" mask, based on the segmented gray and white matter and removal of outlying unrelated clusters, was applied to segmented volumes, removing regions outside the brain from gray matter volumes. The total volume of gray matter was calculated from these volume-adjusted, segmented, and masked images. For regional comparisons, the volume-adjusted, segmented, and masked images were smoothed by using a filter, and smoothed images were analyzed for regional volumetric differences by using VBM.

Results

The results of this investigation showed the following:

Total gray matter volume differences: Whereas there was a tendency for increased overall gray matter in control subjects over HF cases, after correction for age and gender, that tendency was not statistically significant. With the exception of one HF subject (one of nine), no brain infarction sites in the sample were noted. The infarcted site of the one subject did not overlay any of the regional areas with reduced gray matter volume.

Insular cortex and basal ganglia: Significant gray matter loss occurred in both the left and right insular cortex, with the loss being substantially larger on the right side. The right side loss extended medially to the ventral putamen and globus pallidus of the basal ganglia. A localized area of loss in the anterior-dorsal portion of the left insula emerged. The smaller area on the left side was also continuous, with a region of loss in the left dorsal putamen and globus pallidus, largely sparing the caudate.

Deep and inferior temporal cortex-parahippocampal gyrus: An inferior temporal lobe cortical area bordering the hippocampus showed gray matter loss.

Cingulate gyrus, dorsal midbrain, and thalamus: The right cingulate cortex showed significant loss over portions of the entire extent of the structure. The deficits clustered in four regions of loss within the gyrus. The left cingulate gyrus showed virtually no loss. The right dorsal midbrain, extending to the posterior thalamus and also to the right medial thalamus, showed loss.

Cerebellum: Both cerebellar cortex and deep cerebellar nuclei were affected. Gray matter loss was found in a site overlapping the fastigial and globose nuclei and extended laterally to the dentate nucleus. Significant loss was apparent bilaterally in the caudal quadrangular lobule of the cerebellar cortex.

Ventral frontal, deep anterior parietal, superior lateral frontal, posterior parietal/occipital, and superior temporal cortex: The gray matter loss found in the right cingulate gyrus was adjacent to deep anterior parietal cortex loss. The anterior parietal cortex areas of loss did not reach the surface and were bilateral and extensive. The right caudal orbital frontal cortex showed an area of loss extending in a band from near the midline laterally to the lateral sulcus. The band of loss was sited at the rostral-caudal level immediately forward to the optic chiasm and extended deep to the surface. The right occipital cortex, overlapping the posterior parietal cortex, showed significant loss, principally on the right side. A small area of loss emerged on the left occipital cortex. An area of loss in the superior lateral frontal cortex was apparent. A region encompassing an area of the right-side superior surface of the temporal lobe and bordering the parietal cortex superiorly showed gray matter loss. This area lay in cortical sites external to the insula.

Sleep- disordered breathing: Sleep-disordered breathing of either an obstructive or Cheyne-Stokes nature (or both) was found in seven of nine HF cases. None of the 24 control cases showed indications of either type of sleep-disordered respiration during monitoring. None of the remaining three controls reported any signs of impaired breathing during sleep. The extent of breathing impairment in the HF group was substantial (RDI median = 14, range = 3–74). Of the seven cases with RDIs >5, four showed both Cheyne-Stokes and obstructed breathing, and three showed only obstructed events. One patient showed O2 desaturation to 70% during apneic events; the remaining cases did not desaturate <90%.

Limitations Of the Study

These data were derived from a small number of relatively young end-stage HF patients who were seen at a specialized HF clinic in a tertiary referral center. Subsets of patients who exhibit other physiological characteristics may reveal differently affected brain areas from those described here. It should be emphasized that the physiological deficits found in HF may result from neural dysfunction not associated with structural loss, i.e., the gray matter loss may be partially or largely independent of alterations in sympathetic tone, breathing, and cognitive deficits. The particular structures involved make such a relationship unlikely, although the possibility exists.

Conclusions

The localization of gray matter loss in HF, appearing in regions that have demonstrated their roles in cardiovascular, CO2, cognitive, and motor regulation suggests that characteristics of autonomic disturbances, memory deficits, and sleep-disordered breathing may partially derive from gray matter loss in the syndrome. The development of new therapies that protect, support, or repair these specific neurological sites may have promise in the treatment of this disease process. Examination of the developmental course and mechanism of such structural changes, and the relationship of these changes to HF outcome, will provide significant insights into the syndrome.

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Source: August 2003 edition of the Journal of Applied Physiology.

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.