Heart failure, cognition, and brain damage

This editorial refers to ‘Temporal changes in total and hippocampal brain volume and cognitive function in patients with chronic heart failure: the COGNITION.MATTERS-HF cohort study’†, by A. Frey et al., on page 1569. Potential mechanisms of functional effects of cardiac pathologies on the brain. Potential mechanisms of functional effects of cardiac pathologies on the brain. Cognitive impairment is a very frequent comorbidity in patients with chronic heart failure (HF).1,2 Over 40% of HF patients exhibit signs and symptoms of memory impairment, concentration difficulties, and attention deficits.3,4 Importantly, cognitive dysfunction in HF is associated with poor prognosis.4 The pivotal role of the bi-directional interactions between the heart and the brain for the pathophysiology of HF is increasingly recognized.1 However, the diagnosis of cognitive impairment in HF is frequently overlooked, and improved strategies for prevention and treatment are urgently needed. Neuropsychological screening tests are available to detect cognitive impairment but they are infrequently used. It is therefore of practical interest that magnetic resonance imaging (MRI) has emerged as a tool to identify and quantify neural correlates of cognitive function. In standard clinical MRI, white matter lesions (WMLs) are visible as hyperintensities on T2-weighted images (or FLAIR sequences) which—while in principle unspecific regarding the underlying pathophysiology—most often reflect ischaemic consequences of small vessel disease and are related to disturbed cognitive function in a location-specific manner.5 Data from the LIFE-Adult Study, a population-based study of 10 000 residents of Leipzig, Germany, show that WMLs are independently associated with HF, in addition to age, hypertension, and previous stroke.6 Another approach to identify neural correlates of cognitive performance is high-resolution anatomical MRI based on T1-weighted imaging, which allows for quantitative assessment of total brain volume but also of specified brain areas, e.g. the hippocampus. Using such an approach, data from the Leipzig heart study cohort identified characteristic volume reductions of several brain regions in patients with HF.7 Interestingly, the HF serum marker N-terminal prohormone of brain natriuretic peptide (NT-proBNP) correlated with variance of brain volume reductions of the cingulate cortex and precuneus, and also the hippocampus, all brain regions that are crucially related to various aspects of cognition.7 In the future, other MRI methods such as functional connectivity MRI based on resting state measurements, brain perfusion imaging based on arterial spin labelling, or diffusion tensor imaging (DTI) may provide even more detailed information about neural changes and their underlying physiology in HF and other cardiac diseases (see Table 1 for an overview of MRI methods of potential interest). Magnetic resonance methods of potential interest for pathophysiological information CBF, cerebral blood flow; HF, heart failure; fMRI, functional magnetic resonance imaging; MRI, magnetic resonance imaging. Magnetic resonance methods of potential interest for pathophysiological information CBF, cerebral blood flow; HF, heart failure; fMRI, functional magnetic resonance imaging; MRI, magnetic resonance imaging. Such neuroimaging approaches may provide the important prerequisite to prospectively assess the potential effects of non-pharmacological8 and pharmacological treatments on cognitive function in HF. To this end, it is important to understand the time course of the morphological changes in relation to the changes of cognitive function. This research requires a prospective cardiac, neurological, and psychological assessment, and brain MRI that is very rare in the literature. Therefore, the Cognition.Matters-HF study by Frey et al. is of high value, providing these details in 148 patients with HF.2 The study found more deficits in short- and medium-term verbal memory (47%), intensity of attention (41%), and working memory (25%) compared with a healthy control group. On MRI, HF patients showed a 11.09 times greater risk for medial temporal lobe atrophy, a 2.7 times greater risk for silent lacunes, and a 3.54 times greater risk for silent brain infarctions. In the current issue of the European Heart Journal,9 the authors now provide 3-year follow-up data on 105 of these patients. The main findings are that the impaired cognitive function and reduced hippocampal volume at baseline did not worsen further over time, and hippocampal volume did not decrease more than with normal ageing. Cognitive status at baseline was not predictive for progression of hippocampal atrophy. The volumes of WMLs increased by 6.2% per year, comparable with the changes in a ‘healthy’ population. The unique strength of the study is the careful and comprehensive characterization of the cohort. The patients had relatively mild HF and were optimally treated. Thus, the data set the stage to assess patients with more severe HF and longer duration of follow-up. Importantly, the risk of bias can be reduced by a more complete follow-up and a prospective control group. Regarding the interaction of HF progression and brain damage, the study demonstrates that the new neuroimaging methods are sensitive enough to show dynamical neural changes reflecting cognitive function within only a few years. Reasons why heart disease often goes along with brain disease seem so obvious that important aspects of this relationship are often overlooked (for a schematic overview, see Graphical abstract). Cardiovascular and cerebrovascular disease share similar risk factors, and cardioembolism is one of the most frequent sources of acute and chronic cerebral ischaemia. However, recent imaging data suggest that additional heart–brain pathophysiological pathways may be important in order to understand neuropsychiatric symptoms in patients with heart disease. These emerging pathways include alterations of chronic perfusion pressure and disturbed functional heart–brain coupling. The question of whether reduced cardiac output per se causes neurological/cognitive dysfunction eventually leading to dementia remains a matter of debate. Would cognitive function be impaired by chronically reduced cardiac output in the absence of other causes of brain damage? Such an explanation appears to contradict a pathophysiological paradigm in the neurological community reflected in the term ‘multi-infarct dementia’ which was introduced by Hachinski by stating ‘no evidence exists for continuous ischaemia in the brain. Decreased cerebral blood flow and metabolism are the result not the cause of dementia’.10 Even today—in the modern view of ‘vascular cognitive impairment’11—it is not clear whether the observed cerebral hypoperfusion (in dementia) is a ‘causative factor or a reflection of reduced metabolic demands’.11 In this line of thinking, cognitive disturbance is produced by ischaemic damage, e.g. a single stroke affecting large brain areas or multiple smaller even microscopic strokes, which might individually be ‘silent’ but with an overall impact on cognition. However, two lines of evidence support a pathophysiological role for chronic hypoperfusion in patients with HF. Patients with HF and reduced ejection fraction are characterized by volume reductions in the frontomedian brain regions including the orbitofrontal cortex as well as the cingulate cortex and precuneus.7 Additional evidence stems from an intervention study: an improvement in several cognitive domains (total Montreal Cognitive Assessment score, visuospatial, executive, and delayed recall) was observed in patients with HF after left ventricular assist device implantation.12 The heart’s impact on brain function has an additional level of complexity. It has been demonstrated that within every heartbeat there are profound modulations of perception and cognition. For example, perceptions in the visual and somatosensory domain have been shown to be attenuated during systole.13 The experience of emotions and the perception of pain and even racial stereotypes are modulated within one cardiac cycle.14 Probably related to the same physiological mechanisms, increases in blood pressure also go along with reduced emotion and pain perception. Interestingly, heartbeat-evoked potentials (HEPs) (i.e. a cortical representation of each heartbeat) have been identified as markers of heart–brain interaction. The amplitude of HEPs has also been shown to modulate, for example, perception of external stimuli.13,15 There is evidence that these HEPs are altered in patients with HF. Importantly, heart–brain interactions obviously are not unidirectional in physiology as well as in pathophysiology. Cerebral lesions due to stroke and epilepsy can cause imbalances in the autonomic nervous system leading to cardiac damage, and severe stress can induce Takotsubo cardiomyopathy. Also, the impact of chronic imbalances of central autonomic regulation after, for example, stroke in the insula is likely to be profound but very poorly understood. Assuming the correlations between biomarkers/proxies of cardiac function and markers of cognition and brain anatomy/function hold in all ‘directions of change’, not only could stabilization of cardiac function prevent cerebral dysfunction, but improvement of cardiac function might also—to some extent—lead to improvement of brain function (and perhaps in some situations also vice versa). Studies such as the Cognition.Matters-HF study9 published in this issue are therefore greatly needed not only to unravel the bidirectional pathology of the heart and cognition but also to provide the necessary visualization needed to monitor and potentially influence this process. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.