Brain Damage With Heart Failure: Cardiac Biomarker Alterations and Gray Matter Decline

Abstract

Rationale: Heart failure (HF) following heart damage leads to a decreased blood flow due to a reduced pump efficiency of the heart muscle. A consequence can be insufficient oxygen supply to the organism including the brain. While HF clearly shows neurological symptoms, such as fatigue, nausea, and dizziness, the implications for brain structure are not well understood. Few studies show regional gray matter decrease related to HF; however, the underlying mechanisms leading to the observed brain changes remain unclear.

Objective: To study the relationship between impaired heart function, hampered blood circulation, and structural brain change in a case-control study.

Methods and results: Within a group of 80 patients of the Leipzig Heart Center, we investigated a potential correlation between HF biomarkers and the brain's gray matter density (GMD) obtained by magnetic resonance imaging. We observed a significant positive correlation between cardiac ejection fraction and GMD across the whole frontal and parietal medial cortex reflecting the consequence of HF onto the brain's gray matter. Moreover, we also obtained a relationship between GMD and the NT-proBNP (N-terminal prohormone of brain natriuretic peptide)-a biomarker that is used for screening, diagnosis, and prognosis of HF. Here, we found a significant negative correlation between NT-proBNP and GMD in the medial and posterior cingulate cortex but also in precuneus and hippocampus, which are key regions implicated in structural brain changes in dementia.

Conclusions: We obtained significant correlations between brain structure and markers of heart failure including ejection fraction and NT-proBNP. A diminished GMD was found with decreased ejection fraction and increased NT-proBNP in wide brain regions including the whole frontomedian cortex as well as hippocampus and precuneus. Our observations might reflect structural brain damage in areas that are related to cognition; however, whether these structural changes facilitate the development of cognitive alterations has to be proven by further longitudinal studies.

Keywords: brain imaging; coronary artery disease; gray matter; heart failure; magnetic resonance imaging.

Figure 1.

Orthogonal brain sections showing significant differences in gray matter density (GMD) with heart failure. A, Comparing coronary artery disease (CAD) patients with heart failure (CAD+, N=35) and participants with no detectable abnormality (NAD, N=22) reduced GMD values were found across the whole brain including a region within the posterior and middle cingulate cortex (respectively, PCC and MCC). B, The comparison between CAD+ patients and CAD patients with sufficient heart function (CAD−, N=20) showed reduced GMD in the same regions, namely the PCC and MCC. C, A negative correlation between GMD and the serum NT-proBNP (N-terminal prohormone of brain natriuretic peptide) concentration (initial measurement, NT-proBNP1) was found across the whole group of participants (N=80). Reduced GMD was related to higher NT-proBNP concentrations in the PCC and MCC up to regions within the precuneus. Results were obtained with threshold-free cluster enhancement (TFCE) with P<0.05 using family-wise error (FWE) correction for multiple comparisons.

Figure 2.

Orthogonal brain sections showing significant differences in gray matter density (GMD) between heart failure patients and healthy controls from the Leipzig Research Centre for Civilization Diseases (LIFE) cohort. A, Comparing coronary artery disease (CAD) patients with heart failure (CAD+, N=35) and healthy volunteers (LIFE, N=60) reduced GMD values were found across the whole brain including a region within the posterior and middle cingulate cortex (respectively, PCC and MCC). In addition, we also obtained reduced GMD values in subcortical brain regions as thalamus and hippocampus. The comparison between the healthy LIFE volunteers and the other 2 patients subcohorts (B, LIFE volunteers vs CAD patients with sufficient heart function, CAD−, N=20; and C, LIFE volunteers vs patients with no detectable abnormality, no abnormality detected [NAD], N=22) did not reveal major GMD differences. Results were obtained with threshold-free cluster enhancement (TFCE) with P<0.05 using family-wise error (FWE) correction for multiple comparisons.

Figure 3.

Orthogonal brain sections showing a comparison between gray matter density (GMD) group differences and correlations between GMD values and concentrations of serum NT-proBNP (N-terminal prohormone of brain natriuretic peptide). A, Reduced GMD was observed across the whole brain in patients with coronary artery disease (CAD) with heart failure (CAD+, N=35) compared with participants who showed no abnormality (no abnormality detected [NAD], N=22). B, A correlation analysis revealed a negative association between GMD and serum NT-proBNP concentrations (follow-up measurement, NT-proBNP2) across the whole group (N=80) in the left hippocampus. C, The parametric approach showed the same result as obtained with permutation tests as sown in (B). D, Dot-plot showing the negative correlation between GMD and serum NT-proBNP2 in the left hippocampus revealed with the parametric analysis. The red points show the fitted GMD within the statistical model while gray dots show the uncorrected GMD values. FWE indicates family-wise error.

Figure 4.

Orthogonal brain sections showing a comparison between gray matter density (GMD) group differences and correlations between GMD and ejection fraction (EF). A, Reduced GMD values were observed across the whole brain in patients with coronary artery disease (CAD) with heart failure (CAD+, N=35) compared with participants who showed no abnormality (NAD, N=22). In particular, reduced GMD was found in major parts of the median cortex as well as in frontal and prefrontal brain regions. B, Positive correlation between GMD and EF was found across the whole group (N=80, bottom row) in similar brain regions obtained with the group comparison as shown in (A). Results were obtained with threshold-free cluster enhancement (TFCE) with P<0.05 using family-wise error (FWE) correction for multiple comparisons.

Figure 5.

Orthogonal brain sections showing the correlation between brain’s gray matter density (GMD) and the ejection fraction (EF) of the heart across the whole group of 80 participants. A and B, Positive correlation was found in the left and right orbitofrontal cortex using both the initial (EF1, see [A]) and the follow-up EF measurements (EF2, see [B]). C and D, Positive correlation was also obtained in the whole frontal and parietal medial cortex when using the initial EF measurement (EF1, see [C]). Using the follow-up EF measurement (EF2), this correlation was only left in the precuneus (see [D]). Significant clusters were obtained using a nonparametric permutation approach using threshold-free cluster enhancement (TFCE) with a family-wise error (FWE) corrected P<0.05.

Figure 6.

Orthogonal brain sections showing a positive correlation between the heart ejection fraction (EF) and the brain’s gray matter density (GMD) across the whole group of 80 participants using a parametric approach with the general linear model (GLM). Significant clusters were obtained in same regions as revealed with nonparametric permutation tests (see Figure 5). The dot-plots show the correlation between EF and GMD in the right orbitofrontal cortex using both the initial (ejection fraction, initial measurement [EF1], see [A]) and the follow-up EF measurements (ejection fraction, initial measurement [EF2], see [B]). The red points show the fitted GMD within the statistical model while gray dots show the uncorrected GMD values.