heart failure ( hf ) is a major health problem that affects over 5 million americans . hf is also associated with significant mortality , which can range from 5% to 50% on an annual basis . however , patient - centered goals such as quality of life , as well as ability to live and function independently , are of equal importance to patients , caregivers , and health care providers . cognitive impairment is considered to be common and directly related to poor outcomes in hf patients . cognitive impairment affects 2585% of patients with hf and develops earlier in these patients with hf as opposed to people without hf at a similar age [ 14 ] . patients with hf have up to a 2-fold increased risk of impaired cognitive function compared with age - matched controls in the domains of memory , psychomotor speed , attention , and executive function [ 46 ] . hyponatremia is also a frequent finding in patients with hf , with prevalence rates ranging from 8% to 28% , depending on hf severity , and is a marker for poor outcomes [ 710 ] . most commonly , hyponatremia observed in hf patients is chronic in nature and mild - to - moderate in severity . often , hyponatremia is considered by the clinician to be associated with minimal or no symptoms . however , limited data suggest that hyponatremia , due to any cause , may be associated with cognitive impairment and gait abnormalities . the specific role of hyponatremia in cognitive and functional outcomes in hf patients is largely unknown . the purpose of this study was to determine the association of hyponatremia with cognitive function and mobility in hf patients . we used standard cognitive and mobility tests that are relatively time sensitive and can be administered in a clinical setting by any trained personnel , including students and medical assistants . the findings from this investigation may help to determine when a hf patient is manifesting symptoms of hyponatremia that may be amenable to intervention . a prospective study was conducted in hf clinics based at 2 medical centers ( a university academic center and a veterans affairs medical center ) over an approximate 9-month time period ( october 2013 to june 2014 ) . the study protocol was approved by each center s institutional review board and all participants provided written informed consent . patients > 18 years of age with a documented diagnosis of either hfref ( heart failure with reduced ejection fraction ) or hfpef ( heart failure with preserved ejection fraction ) receiving beta blocker and loop diuretic therapy were eligible for the study . patients with hfref and hfpef were identified through physician diagnosis by heart failure specialists ( chart review ) and confirmed by ejection fraction ( hfref 40% , hfpef > 40% ) . patients were excluded if they had documented conditions known to cause cognitive impairment : stroke , dementia , alzheimer disease , or any other neurological disorder . patients with a history of significant psychological problems or with long - term use of narcotics , benzodiazepines , antipsychotics , or anti - depressants were also excluded from the study . patients requiring a wheelchair or any assistance with walking were waived from testing of mobility . trained personnel administered the montreal cognitive assessment ( moca ) version 7.1 to eligible patients ( permission to use the moca tool for the study was obtained ) . the moca assesses short - term recall , visuospatial abilities , executive function , attention , concentration , working memory , language , and orientation . one advantage of utilizing the moca tool is that it can be administered to patients in approximately 10 minutes , which makes the use of this tool potentially feasible in a clinical setting . moca scores range from 0 to 30 points , with lower scores reflecting worse cognitive function . the moca has been validated in non - hf patients ; a score < 26 suggests cognitive impairment [ 1416 ] . we further classified our sample into 3 cognitive categories using established moca cut - points of severity : mild cognitive impairment ( 2225 points ) , moderate impairment ( 1721 points ) , and severe impairment ( 016 points ) . mobility was assessed with the timed up and go test ( tug - t ) , a simple and observed measure of gait speed that can predict fall risk in older adults . multiple studies have confirmed the content validity , concurrent validity , and predictive validity of tug - t [ 1921 ] . subjects were required to stand up from a chair on the word  go  and walk on the floor to a line ( 3 meters away from the chair ) , turn around , and walk back to the chair and sit down . tug - t times were considered worse than average if they exceed 9.0 seconds for 6069-year - olds , 10.2 seconds for 7079-year - olds , and 12.7 seconds for individuals 8099-year - olds . in addition to the sodium measurement obtained at the time of the study visit , an additional sodium value was obtained nearest to the study visit date by chart review . additional lab values recorded were brain natriuretic peptide ( bnp ) levels , serum creatinine , blood urea nitrogen , albumin , hemoglobin , and ejection fraction ( ef ) . data are presented as mean standard deviation ( sd ) with differences reported as significant if p < 0.05 . comparisons between hyponatremic patients and non - hyponatremic subjects were made using simple t test for continuous variables and using the chi - square or fisher s exact tests for nominal and categorical variables , respectively . univariate analysis was used to test the correlation between serum sodium level , moca , and tug - t . patients > 18 years of age with a documented diagnosis of either hfref ( heart failure with reduced ejection fraction ) or hfpef ( heart failure with preserved ejection fraction ) receiving beta blocker and loop diuretic therapy were eligible for the study . patients with hfref and hfpef were identified through physician diagnosis by heart failure specialists ( chart review ) and confirmed by ejection fraction ( hfref 40% , hfpef > 40% ) . patients were excluded if they had documented conditions known to cause cognitive impairment : stroke , dementia , alzheimer disease , or any other neurological disorder . patients with a history of significant psychological problems or with long - term use of narcotics , benzodiazepines , antipsychotics , or anti - depressants were also excluded from the study . patients requiring a wheelchair or any assistance with walking were waived from testing of mobility . trained personnel administered the montreal cognitive assessment ( moca ) version 7.1 to eligible patients ( permission to use the moca tool for the study was obtained ) . the moca assesses short - term recall , visuospatial abilities , executive function , attention , concentration , working memory , language , and orientation . one advantage of utilizing the moca tool is that it can be administered to patients in approximately 10 minutes , which makes the use of this tool potentially feasible in a clinical setting . moca scores range from 0 to 30 points , with lower scores reflecting worse cognitive function . the moca has been validated in non - hf patients ; a score < 26 suggests cognitive impairment [ 1416 ] . we further classified our sample into 3 cognitive categories using established moca cut - points of severity : mild cognitive impairment ( 2225 points ) , moderate impairment ( 1721 points ) , and severe impairment ( 016 points ) . mobility was assessed with the timed up and go test ( tug - t ) , a simple and observed measure of gait speed that can predict fall risk in older adults . multiple studies have confirmed the content validity , concurrent validity , and predictive validity of tug - t [ 1921 ] . subjects were required to stand up from a chair on the word  go  and walk on the floor to a line ( 3 meters away from the chair ) , turn around , and walk back to the chair and sit down . tug - t times were considered worse than average if they exceed 9.0 seconds for 6069-year - olds , 10.2 seconds for 7079-year - olds , and 12.7 seconds for individuals 8099-year - olds . in addition to the sodium measurement obtained at the time of the study visit , an additional sodium value was obtained nearest to the study visit date by chart review . additional lab values recorded were brain natriuretic peptide ( bnp ) levels , serum creatinine , blood urea nitrogen , albumin , hemoglobin , and ejection fraction ( ef ) . data are presented as mean standard deviation ( sd ) with differences reported as significant if p < 0.05 . comparisons between hyponatremic patients and non - hyponatremic subjects were made using simple t test for continuous variables and using the chi - square or fisher s exact tests for nominal and categorical variables , respectively . univariate analysis was used to test the correlation between serum sodium level , moca , and tug - t . a total of 121 patients were evaluated ; most were males ( 91% ) and the mean age was 6610 years . no significant differences were seen between hyponatremic and non - hyponatremic patients with respect to age , sex , education level , systolic blood pressure , ejection fraction , serum creatinine , hemoglobin , or other co - morbidities . there was no difference in the use of hf - specific medications between the 2 groups except for the greater use of aldosterone antagonists and thiazide diuretics in the hyponatremic group ( table 1 ) . overall , 30% ( n=36 ) of the patients enrolled had study - defined hyponatremia with a mean serum sodium of 134 1.9 meq / l ( range 128136 meq / l ) . a total of 31 patients ( 86% ) had chronic hyponatremia , suggested by 2 consecutive sodium measurements 136 pre - study sodium levels ( 134.32.5 meq / l ) were measured at 84.563.6 days prior to the start of the study . only 5 hf patients had hyponatremia only on the study day ( mean , 135.00.7 meq / l ; p=0.2 ) . the overall moca score for hyponatremic and non - hyponatremic hf patients was consistent with mild cognitive impairment . the mean moca scores were not significantly different between the 2 groups ( 21.72.9 and 21.74.1 , p=0.92 ) . the prevalence of cognitive impairment was 92% among the hf hyponatremic patients and 76% among non - hyponatremic hf patient [ relative risk 1.2 ( confidence interval : 1.021.4 , p=0.02 ) ] . among those classified as cognitively impaired , there were no differences in baseline characteristics between patients who had hf with hyponatremia and those without hyponatremia except for the use of aldosterone antagonists ( 67% vs. 39% , respectively ) and thiazide diuretics ( 8% vs. 1% , respectively ) . in addition , there was no difference in the moca scores between the 2 groups when evaluating only those patients that were deemed to have cognitive impairment ( 21.22.43 vs. 20.13.1 , p=0.063 ) . there were also no differences seen in the severity of the cognitive impairment between the hyponatremic and non - hyponatremic groups ( table 2 ) . no significant correlation was found between sodium levels and moca score ( r2=0.0004 , p=0.8 ) . when examining the specific cognitive domains of the moca , we found significantly lower scores in all domains with the exception of lower orientation scores in hf patients with cognitive impairment , irrespective of sodium level . there were no differences in the subscores between patients with hyponatremia versus patients without hyponatremia who were cognitively impaired . ( table 3 ) the tug - t times did not differ between the hyponatremic and non - hyponatremic hf patients ( 13.54.5 seconds vs. 12.64.1 seconds , p=0.3 , respectively ) . the mean times for both groups in fact , 72% of hyponatremic patients and 62% of non - hyponatremic patients ( p=0.4 ) had tug - t times worse than average . no significant correlation was found between sodium levels and tug - t performance ( r2=0.21 , p=0.2 ) in regard to overall moca score and age , approximately 34% of patients were < 65 years of age ( 586 years ) . patients 65 years ( 727 years ) had significantly lower moca scores ( 19.82.9 vs. 21.82.4 p=0.0005 ) . there were no differences in tug - t times between the 2 groups when analyzed by age group . evaluating the data according to the type of hf , there was a significant difference in overall moca scores ( 21.23.7 vs. 23.33.6 , p=0.006 ) between patients with hfref ( ef=258% ) and hfpef ( ef=556% ) patients . there was no significant difference in the percent of patients with cognitive impairment between the hfref and hfpef groups ( 84.4% vs. 71% , p=0.086 ) . when evaluating patients with cognitive impairment , hfref patients had significantly lower moca scores compared to hfpef patients ( 20.13 vs. 21.52.6 , p=0.036 ) . when evaluating the individual moca cognitive domain scores , there were no differences between the 2 groups , and no significant difference was seen in tug - t times between hfref and hfpef patients ( 12.74 seconds vs. 13.34.8 seconds , p=0.592 ) . baseline variables , other than ejection fraction and diagnosis , were similar between the 2 groups . our study showed that in a sampling of ambulatory patients with hf , approximately 30% of patients had hyponatremia . we found a 92% prevalence of cognitive impairment in the hyponatremic group and 76% in hf patients without hyponatremia . both groups demonstrated similar declines in cognitive function as measured by overall moca score , but the difference was not statistically significant . sixty - five percent of hf patients in our sample had mobility impairment based on the tug - t times . we also found that patients with hfref had lower moca scores as compared to hfpef patients . in regard to the primary objective of the study , the results showed that hf patients with hyponatremia had a higher prevalence of cognitive impairment . however , our findings also showed that , in general , a significant number of hf patients even without hyponatremia have measurable cognitive impairment and are likely to be at greater than average risk of falling , irrespective of serum sodium level . the number of patients observed with hyponatremia is consistent with other reports in the literature . for example , results of the escape ( evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness ) trial reported community - associated hyponatremia in 23.8% of hospitalized patients with hf . hyponatremia was an independent predictor of mortality and rehospitalization even when adjusted for clinical and hemodynamic improvements . hyponatremia seen in hf is often due to excess fluid accumulation ( hypervolemic or dilutional hyponatremia ) . driving factors include increased sympathetic activity , stimulation of renin - angiotensin - aldosterone system , and the nonosmotic release of arginine vasopressin leading to sodium and water retention . hypervolemic hyponatremia seen in hf patients tends to be chronic and is not often associated with critical sodium levels ( e.g. , < 120 meq / l ) . patients with chronic hyponatremia and associated decrease in plasma osmolality will adapt over time , especially in regard to the central nervous system ( cns ) . to maintain cerebral osmolality , organic osmolytes play a critical role in cellular adaptation to chronic hyponatremia and decreased osmolality . acute hyponatremia involves rapid shifts of electrolytes between brain cells and plasma and cerebrospinal fluid . sodium , potassium , and chloride leave the cell and water enters , leading to cerebral edema . over time , the cns adapts to lower osmolality by increasing brain osmolality by shifting organic osmolytes ( e.g. , glutamate , glutamine , taurine , and phosphocreatine / creatine ) from brain cells into the extracellular fluid . it can be postulated that these shifts and resultant decrease in cellular organic osmolyte concentrations may decrease cognitive function and mobility in chronic hyponatremia . most patients defined as having hyponatremia in our study appeared to have consistent hyponatremia as measured by 2 consecutive sodium levels ( 86% of patients with hyponatremia ) . it can be postulated that the cns has likely adapted to a hyponatremic state in most of our hyponatremic patients . this suggestion is supported by our findings that 92% of our hyponatremic patients had cognitive impairment . in addition to cognitive impairment , the proportion of patients with above average tugt times was also higher in the hyponatremic group ( 72% vs. 62% , p>0.05 ) which is not an unexpected finding . our findings are consistent with other studies . a case - control study by renneboog et al . showed that 21% of patients with hyponatremia ( 1265 meq / l ) were admitted for falls as compared to 5.3% of control patients ( p < 0.001 ) . in the same study , 16 patients were evaluated for gait and underwent 8 attention tests . these patients had chronic hyponatremia ( 1283 meq / l ) and acted as their own control following correction of their hyponatremia ( 138  2 when patients were hyponatremic , gait and attentions tests were significantly worse as compared to following correction of the hyponatremia . in another retrospective study , 44 patients with chronic hyponatremia ( 124.84.9 meq / l ) underwent a battery of neuropsychological tests ; significant differences were seen in a number of tests , including finger - tapping test , simple reaction time , and in continuous performance tests . what appears to be clear from this study is that most patients evaluated have some form of cognitive impairment . it should be noted that the high percentage of patients observed to have cognitive impairment is related in part to the use of the moca instrument , which is more sensitive in detecting mild cognitive impairment as compared to the mini - mental state examination ( mmse ) . the mmse was developed as a screening tool for dementia and may not adequately assess mild cognitive impairment . recent studies in hf patients have indeed shown that the moca identified a higher percentage of patients with cognitive impairment as compared to the patients assessed with the mmse . these studies also showed , similar to our findings , that many hf patients have some form of cognitive impairment ( 2270% ) . the reasons for the high percentage of cognitive impairment in heart failure patients is not known and is likely related to a multitude of factors , including changes in cardiac output , cerebral perfusion pressure , and perhaps hyponatremia [ 2,3032 ] . in our study , there are very limited data on evaluation of cognitive function in patients with preserved ejection fraction [ 3335 ] . the study that most directly addresses cognitive impairment in hfpef patients also used the moca instrument . in that study , a secondary analysis of a cross - sectional study in 90 patients demonstrated that patients with systolic dysfunction had significantly lower moca scores compared to patients with diastolic heart failure . in addition , 61% ( 42 of 69 ) of systolic heart failure patients had a score below 26 on the moca compared with 52% ( 11 of 21 ) of participants with diastolic failure . the reason for the differences in scores between hfref or hfpef patients is unknown but may be related to a number of factors , including differences in cerebral perfusion , as well as neurohormonal and cytokine activation . however , patients with hfpef have cognitive impairment and , in general , the cognitive impairment is somewhat less severe than in hfref patients . our data also show that approximately 34% of patients with cognitive impairment were less than 65 years of age . in this group of patients , however , younger hf patients are at risk for cognitive impairment . cognitive impairment has been associated with poor outcomes in hf patients . in addition , cognitive impairment in hf patients may limit a patient s ability to actively manage their heart failure ( i.e. , self - care ) . cognitive impairment , especially in the domains we and others have identified , can make it more difficult for patients to follow medication plans ( medication adherence ) , self - monitor , and maintain dietary patterns . based on our results and those of others , it is important for clinicians to be cognizant of the high incidence of cognitive impairment in hf patients ( young , old , hfref , and hfpef ) and to screen for cognitive impairment when appropriate . one risk factor to take into consideration is hyponatremia . in patients with cognitive impairment , specific interventions such as family engagement , along with appropriate patient education and follow - up need , to be specifically designed to accommodate these patients . future research focusing on whether cognitive performance can be improved by correcting the underlying hyponatremia in hf patients could be an important next direction . at this time , correcting hyponatremia ( > 136 meq / l ) through better fluid management , medication optimization , and perhaps other non - drug therapies such as cardiac resynchronization therapy may need to be considered . there are a number of limitations in the present study , including the small sample size of hyponatremic patients . since the overall moca scores between the 2 groups were nearly identical , it is unlikely that recruitment of additional patients would have demonstrated any significant differences in actual moca score . however , when evaluating the moca score for patients with cognitive impairment , there was trend for patients without hyponatremia to have lower score . the study lacks power ( < 80% ) to show statistical significance between the groups . although , the clinical significance in the difference between the two scores ( 21.22.43 vs. 20.13.1 ) is probably minimal since both scores are within what is considered moderate cognitive impairment . another consideration is whether other confounding variables or disease severity may have contributed to our findings . we attempted to evaluate a number of potential variables that may influence cognitive function , including age , social factors ( education level ) , and physiological markers . as shown in table 1 , other than aldosterone antagonists and thiazide diuretic use , both groups were very similar in regards to potential confounding factors . another concern , as previously discussed , is ability of the standardized tests utilized in the study to detect differences in cognitive function and balance . it is possible that the use of different instruments may have found differences in severity of cognitive impairment between the 2 groups . for the most part it is likely that patients with more severe hyponatremia ( e.g. , 125 meq / l ) may have more cognitive dysfunction due to delirium and/or cognitive impairment . however , as seen in this study , patients in the ambulatory setting tend to have less severe hyponatremia , which suggests that the results of this study are generalizable to the outpatient population with heart failure . finally , we did not capture data on diuretic dose or timing of diuretic administration in relation to hyponatremia or measurement of serum sodium . our study shows that a high percentage of hf patients have cognitive and gait impairment . we also found that cognitive impairment occurs in younger hf patients and may be more severe in hfref patients as measured by 2 easily administered and validated instruments . our findings further support the approach of routinely evaluating cognition and mobility as part of a comprehensive care plan for hf patients .
backgroundthe association of hyponatremia with cognitive impairment and mobility in heart failure ( hf ) patients is unknown . the purpose of this study was to determine if hyponatremia is associated with cognitive and mobility impairment as measured by simple , validated , and time - sensitive tests.material/methodsthis was a prospective study in patients with reduced and preserved ejection fraction ( hfref , hfpef ) seen in outpatient hf clinics . 
 hyponatremia was defined as sodium level 136 
 meq / l . 
 cognitive function was measured using the montreal cognitive assessment ( moca ) tool , and mobility was measured with the timed up and go test ( tug - t).resultsa total of 121 patients were evaluated ; 30% were hyponatremic ( 1341.9 meq / l , range 128136 meq / l ) . 
 overall , 92% of hyponatremic patients had cognitive impairment ( moca < 26 ) compared to 76% of the non - hyponatremic patients [ relative risk 1.2 ( confidence interval : 1.021.4 , p=0.02 ) ] . in regard to mobility , 72% of hyponatremic patients and 62% of non - hyponatremic patients ( p=0.4 ) had tug - t times that were considered to be worse than average . 
 a total of 84% ( n=76 ) of hfref and 71% ( n=22 ) of hfpef patients had cognitive impairment ( p=0.86 ) . 
 hfref patients had significantly lower overall moca scores ( 21.23.7 vs. 23.33.6 , p=0.006 ) and similar tug - t times compared to hfpef patients.conclusionsmost heart failure patients ( hfref and hfpef ) seen in an ambulatory setting had impairment of cognitive function and mobility , with a higher prevalence among those with hyponatremia . 
 screening can be done using tests that can be administered in a clinical setting .