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Protective effect of angiotensin converting enzyme inhibitor on cognitive function in patients with heart failure

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https://www.eduzhai.net International Journal of Nursing Science 2012, 2(3): 14-22 DOI: 10.5923/j.nursing.20120203.01 Cognitive Protection by Angiotensin Converting Enzyme Inhibitors in Heart Failure Ponrathi Athilingam1,*, Cindy Munro2, Rita D’aoust3, Amy Karch4, Le way Che n5 1ACNP, FAANP, College of Nursing, University of South Florida, Tampa, 33612, Florida 2APRN, FAAN, College of Nursing, University of South Florida 3ANP-BC, CNE, FAANP, FNAP, College of Nursing, University of South Florida 4M S, RN, School of Nursing, University of Rochester, Rochester, 14642, NY 5MPH, FACC, Department of Cardiology, University of Rochester, Rochester, 14642, NY Abstract Card io-selective medications such as angiotensin converting enzyme (ACE) inhibitor centrally active or non-centrally-active and angiotensin receptor blocker (ARB) have been researched in animals and humans for potential cognitive benefits. This secondary analysis presents results of a published cross sectional study of 90 co mmunity-dwelling adults with heart failure (HF) who were screened for cognitive impairment using the Montreal Cognitive Assessment (MoCA). The mean MoCA score was 24.73 (SD 2.76). T-test on the MoCA score and ACE inhibitor (78% of part icipants) and centrally-active ACE inhib itor (60%) were statistically significant (p= 0.01) with no association to ARBs. Bivariate analysis indicated higher dosages of ACE inhib itors were associated with better cognitive function (R= 0.211, p =0.046) with no association to ARBs. In the mult iple regression model, covariates age, education, knowledge on HF medication, and mean arterial blood pressure accounted for 33.6% of variance and ACE inhib itor added 4.1 % of variance and remained statistically significant (p=0.021); age and mean arterial blood pressure were not significant in the final regression model. Findings fro m this study provided rationale to support the protective role of A CE inhib itors on cognitive decline among HF patients. Keywords Heart Failure, Angiotensin Converting Enzy me Inhibitors, Centrally Active ACE Inhibitor, Cognitive Impairment, Montreal Cognitive Assessment 1. Introduction Heart failure (HF) is a progressive disorder that occurs as a cumulat ive consequence of all affronts to the heart over one's life. HF is becoming increasingly common, with a high burden of morbidity and mortality; and has an enormous financial impact which is primarily associated with frequent readmissions[1].Approximately 50% of HF read missions have been attributed to lack of knowledge and adherence to self-care reco mmendations[2]. HF self-care management requires that patients recognize a change (such as increasing edema), evaluate the change, decide to take action (e.g., take an extra diuret ic dose) and imp lement a treat ment strategies prescribed[3]. For many persons with HF, however, cognitive impairment may interfere with their ability to comply with HF therapy and perform adequate self-care, which contributes to increased incidence of morbid ity, mortality, and higher read mission rates[4,5,6]. Research shows that cognitive impairment, particu larly declines in executive function and memory, is a growing problem in HF * Corresponding author: pathilin@health.usf.edu (Ponrathi Athilingam) Published online at http://journal.sapub.org/ nursing Copyright © 2012 Scientific & Academic Publishing. All Rights Reserved management[7-10]. Its prevalence in persons with HF ranges fro m 25% to 75%[11,12] and have a 4-fo ld greater risk than the general population of having mild cognitive impairment[13]. In a 9-year follo w-up of a community-based cohort of 205 HF patients, HF was associated with a mu lti-adjusted hazard ratio (HR) of 1.84 (95% confidence interval (CI) 1.35-2.51) for dementia and an HR of 1.80 (95% CI 1.25-2.61) for Alzheimer’s disease[14]. Given the serious impact of cognitive deficits on HF management, researchers have begun looking for therapies that may help protect cognition while improving HF outcomes. Hence, a secondary analysis was performed on a cross-sectional data set to examine benefits of cognitive protection using angiotensin converting enzyme (A CE) inhibitors and angiotensin receptor blocker (ARB) in HF. Current HF management includes drugs with various vascular effects that are identified as successful interventions in imp roving survival[15]. Cardio-selective med ications such as ACE inhib itors, ARBs and beta b lockers are considered life-sustaining drugs because they can prevent remodelling of the heart and thus reduce mortality and morb idity[17-19].Animal studies suggest cognitive protection of ACE inh ibitors[18,20]. In humans, however, the effects of ACE inh ibitors on cognition are controversial[21]. Zuccala and colleagues found that use of 15 International Journal of Nursing Science 2012, 2(3): 14-22 ACE inhibitors among patients with heart failure (N=1220) was associated with imp roving cognition (odds ratio=1.57; 95% CI 1.18-2.08)[22]. The probability of improving cognitive performance was higher for dosages above the med ian values, as co mpared with lower doses (odds ratios=1.90 and 1.42; p= .001), and increased with duration of the treatment (odds ratios for the lower, middle, and upper quartiles (1.25, 1.34, and 1.59; p= .007)[22]. This was supported in a study of 74 o lder adults that ACE inhibitors provided stability of cognitive function[23]. Ho wever, a recent animal study failed to demonstrate an effect on cognitive protection with the use of ACE inhibitor and A RBs [ 24 ]. 2. Physiology of ACE Inhibitors, ARBs and Cognitive Protection A complex system of neuroendocrine interactions protects the heart, endotheliu m, brain, and kidneys from physiologic variation[16,17]. The Ren in-Angiotensin System (RAS) regulates the vascular response to injury and inflammat ion[25.26]. Repeated response to injury and inflammat ion leads to endothelial dysfunction and microvascular damage[27]. In addit ion, the brain possesses an intrinsic RAS that is involved in memory and cognition[28,29].Although specific mechanis ms are unclear, stimulat ion of the RAS has been linked with the activation of inflammatory cytokines that may play a role in degenerative dementias[30].The Health ABC study provided evidence that ACE inhibitors may have additional cognitive p rotection for executive function, but only in a select group of elderly Caucasians with angiotensinogen gene polymorphisms known to be associated with increased RAS system activity[31]. Renin is responsible for the conversion of angiotensinogen to angiotensin I and provides additional substrate for A CE-mediated conversion to active peptide angiotensin II[32].Th is conversion takes place primarily on the vascular endothelial surface of the lungs with some local formation in the peripheral vasculature, and increases the availability of bradykinin [33,34]. ACE inhibitors block the conversion of angiotensin I to angiotensin II. Angiotensin II has been implicated in d isruption of memo ry and recall, since it was attenuated by central infusion of captopril in rats[33].It has also been reported that angiotensin II injected into the dorsal neostriatum five minutes following passive avoidance conditioning interfered with the recall of the conditioned response 24 hours later in rat models[34] and mouse models[35,36]. In addition to their presence in peripheral circulation, both angiotensin II and ACE (in the form of A CE2) are present in the brain, with the highest densities in the striatum of the brains of rats[37] and mice[38,39,40]. The mechanism of ACE2 in the brain on cognitive protection has been primarily examined in animal models and warrants further exp loration in HF. Figure 1 below illustrates the pathways of the RAS system. Figure 1. Schematic illustration of the Renin-Angiotensin System (RAS) Ponrathi Athilingam et al.: Cognitive Protection by Angiotensin Converting Enzyme Inhibitors in Heart Failure 16 A number of recent studies on vascular dementia indicated a rigorous control of vascular risk factors with ACE inhibitors and A RBs is indicated for primary and secondary prevention of vascular dementia, and perhaps for ameliorating mild cognitive impairment[41-43].The Card iovascular Health Study included 414 subjects who had taken ACE inhibitors and 640 who had taken other antihypertensive med ications, and found no association between exposure to all A CE inhib itors and risk for dementia (HR 1.01, 95% CI 0.88–1.15)[44]. Ho wever, the association of ACE inhibitors with cognition was found to depend on whether a specific drug crosses the blood-brain barrier.44 Centrally-active A CE inhib itors that cross the blood-brain barrier (e.g., captopril, fosinopril, monopril, lisinopril, perindopril, and trandolapril) were associated with 65% less decline in cognitive-function scores per year of exposure (p= .01) co mpared to non-centrally-act ive ACE inhibitors (e.g., accupril, benazepril, enalapril, moexip ril, quinapril, and ramipril)[44]. Similarly, a subgroup of 90 Japanese patients who were on A CE inhib itors that cross the blood-brain barrier (captopril & perindopril) co mpared to those on ACE inhibitors that do not (enalapril & imidapril) were found to have significantly lo wer risk of Alzheimer’s disease.45 In a recent mouse model, the brain-penetrating ACE inhib itor perindopril protected against cognitive impairment and showed suppression of hippocampal astrocyte activation and attenuation of superoxide[46]. Reviews of studies in both animals and humans found that ACE inhibitors and ARBs help to preserve cognitive function through a mechanism that is independent of the antihypertensive effects[41,43].In a recent an imal study, Tota and colleagues examined memory deficit by intracerebro- ventricu lar ad ministration of streptozotocin in rats and then gave ACE inhibitor perindopril (wh ich crosses the blood-brain barrier) for 21 days[35].Perindopril mitigated streprozotocin-induced neurodegeneration (as observed in histopathological studies) improved memo ry and cerebral blood flow and decreased oxidative stress with no effect on acetylcholinesterase expre ssion.35 Thus, blocking ACE act ivity with a centrally-active ACE inhibitor could decrease angiotensin II levels, thereby increasing acetylcholine concentration, potentially improving cognition[35] and reversing neurodegeneration, as demonstrated in animal models[35,46]. The controversial evidence on the use of ACE inhibitors and ARBs, especially the use of centrally -active ACE inhibitors warrants further exp loration in HF. This secondary analysis of a published cross-sectional study of cognition in HF[47] hypothesized that patients with HF who were taking ACE inhib itors and ARBs would have better cognitive function with higher score on Montreal Cognitive Assessment (MoCA) and HF patients taking centrally-active ACE inhib itors would also have better cognitive function (higher MoCA score) co mpared to HF patients not taking non-centrally active ACE inhib itors. Although patients may have normal range of scores on the MoCA, it is possible that clin ically they may have impairment in one or more do mains of cognitive impairment. Hence, this secondary analysis used scores fro m eight domains of the MoCA to understand HF patients’ cognitive profile and the influence of ACE inhibitors and ARBs on these eight cognitive domains. 3. Methods 3.1. Design and Sample A secondary analysis was conducted on data fro m a published cross-sectional study of 90 co mmunity-dwelling adults aged 50 and above with a clinical d iagnosis of HF as defined by the ICD-9-CM[47].Persons were included if they were in NYHA classification groups I-III and A merican Heart Association HF stage B,C, or D. Persons were e xcluded if they were : on continuous oxygen; listed for heart transplant with United Network for Organ Sharing status 1A or 1B; supported by a ventricular-assist device or ho me inotropic therapy; enrolled in a palliative or hospice care program; clinical diagnosis of dementia or Alzheimer’s Disease; and clinical h istory of stroke due to high-risk mu lti-infarct dementia. The primary study used the MoCA as a screening tool in patients with HF because it was found to be more sensitive than other tools[47].This study was approved by the human subject review board and participants were recruited fro m cardio logy clin ics affiliated with the Un iversity of Rochester by the PI. Eligib le participants were consented and identified with a code number. 4. Measures 4.1. Cogniti ve Function Cognitive function (the primary outcome of interest) was measured using the MoCA[48]. The Mo CA, a simp le cognitive screening tool has eight cognitive domains that are most co mmonly affected in heart failure patients: 1) visuo-spatial/executive function, 2) naming animals, 3) memo ry, 4) attention, 5) language, 6) abstraction, 7) delayed recall, and 8) orientation. The MoCA has a total score range of 0-30 and a fina l total score of 26 and above is considered normal, a score of 22 to 25 is classified as mild cognitive impairment, 17 to 21 is moderate cognitive impairment, and score below 17 is considered dementia. The scores from memo ry do main (0-1) were not included in the total score but were used to measure short term memo ry (score of zero indicates that person was unable to remember the 5 items in two trials). The MoCA was developed to screen older people who present with mild cognitive impairment but who usually perform within the normal range on the MMSE[49]. It has been validated and approved as a screening tool for mild cognitive impairment by the Canadian Guidelines for the Diagnosis and Management of Dementia with a Cronbach’s alpha .83[49]. It has also been recently validated as a screening tool for cognitive function in patients with stroke[50] and cardiovascular disease[51]. A recently 17 International Journal of Nursing Science 2012, 2(3): 14-22 published study found that 70% of HF part icipants had mild cognitive impairment identified by the MoCA[52]. The MoCA incorporates the clock drawing test (which has been reported as being 50% more sensitive among HF participants)[53]. The Mo CA involves a paper and pencil test in a question and answer format conducted by the interviewer. To min imize the ceiling effect of education, one point is added to the MoCA total score for participants with an education of high school or below[48]. HF were obtained fro m cardio logists’ records within the prior 6 months, and New Yo rk Heart Association (NYHA) functional classificat ion was determined based on patients’ symptoms on the day of the study by a cardio logy nurse practitioner. Depression which is highly associated with cognitive impairment was measured using GeriatricDepress ion Scale-15 (GDS-15),[54] co morbid ity data by Modified Cu mulat ive Illness Rating Scale,[55] and functional status was measured by Six-M inute Walk Test[56]. 4.2. Heart Failure Medicati ons Data on HF med ications including ACE inhib itors, ARBs, beta-blockers, aldosterone inhibitors, and HM G-CoA reductase inhibitors (statins) were obtained from patients and verified by chart rev iew. ACE inhib itors were further classified as centrally-active or non-centrally-act ive ACE inhibitors and examined for dose association with cognition. 4.3. Demographic and Clinical Vari ables Data were obtained using a demographic and clinical questionnaire created for the study to describe the sample. Clin ical variables, including ejection fract ion, HF stage, HF med ications, knowledge on HF medications, and etiology of 5. Data Collection and Analyses The demographic and clinical data questionnaire was administered first to develop rapport with patients, followed by other questionnaires and measures required for the primary study. Means and standard deviations were calculated for continuous variables. Frequencies were calculated for categorical variab les. Bivariate analyses were performed to ascertain associations between variables of interest and cognitive function measured by the MoCA. T-test was used to compare differences on total Mo CA score, and MoCA domain scores of those who were on ACE inhibitors and ARBs. Table 1. Demographic and clinical charact erist ics of the sample Descript io n N = 90 P ercent Mean and SD Range Age in Years Above 65 years 32 35 62.2 + 9.2 50-89 Education in years High School or less 44 65.6 13.83 + 2.76 10-22 Marital Status Married 62 68.9 Race Caucasian 70 77.8 Living Arrangement Spouse/ SOS 71 78.9 Family History of HF Yes 69 76.7 Etiology of HF Ischemic 45 50 EF % Beta-Blocker (mg) ACE Inhibitor (mg) Centrally-Active ACE ARB (mg) Diuretic (mg) Aldos. Antog. (mg) St at ins (mg) NYHA Class HF Stage Systolic BP Diastolic BP MAP 6MWT Met ers GDS-15 MICR EF < 40% Yes Yes Yes Yes Yes Yes Yes Class I Class II Class III Stage B Stage C Stage D < Mean Depressed >6 0-28 69 76.7 30 + 14 81 90 42.8±35.78 70 77.8 31.7±17.86 54 60 24.38±18.88 17 15.3 32.6±21.4 81 90 28.7±12.84 41 45.6 31.0±12.76 59 65.8 26.4±15.67 12 13.3 49 54.4 29 32.2 13 14.4 72 80 5 5.6 124.9 ± 21.8 68.7 ± 11.4 87.5 ± 14.1 19 21.1 482 +58 13 14.4 79 87.8 3.71 + 3.14 22.0 ± 4.6 Legends: EF: Ejection Fraction; ACE: Angiotensin Converting Enzyme; ARB: Angiotensin Receptor Blocker; Aldos. Antog.: Aldosterone Antagonist; HF: Heart Failure; NYHA Class: New York Heart Association Class; BP: Blood Pressure; MAP: Mean Arterial Blood Pressure 10- 60 2.5-200 5 - 80 5 - 80 2-300 10-80 12.5-50 10-80 90-197 40-94 59-127 107-648 0-13 16-40 Ponrathi Athilingam et al.: Cognitive Protection by Angiotensin Converting Enzyme Inhibitors in Heart Failure 18 6. Results The participants were mostly Caucasian (78%), mean age 62 years with SD+ 9 years (age ranged 50 to 89), male (66%), and married (69%). About 77% had lo w ejection fraction (≤40%). Ninety three percent of participants had prescriptions for either an A CE inhib itor or A RB; 77.8% (n = 70) were on ACE inhib itors, and 60% (n = 54) of those were on centrally-active ACE inhibitors. For consistency, ACE inhibitor and ARBs dosage was determined based on clinical equivalence dosing. See table 1 for details on demographic and clinica l variables. 6.1. Cogniti ve Score Associated wi th ACE Inhi bitors We hypothesized that patients with HF who had a prescription for ACE inhib itors would have better cognitive function with higher Mo CA total score and MoCA domain scores. This hypothesis was tested using an independent T-test to differentiate cognitive scores among the two groups. Levene’s test for equality of variance was assumed where indicated. As indicated in table 2, results were statistically significant for Mo CA total score (t = 2.25, df 88; p=.03). Although, the mean scores on all MoCA domains were significantly different a mong groups, visuo-spatial doma in (t =2.03, df 88; p= .026) and delayed recall (t = 2.56, df 88; p= .012) were statistically significant indicat ing that those who had a prescription fo r A CE inhibitor had scores that were significantly above the mean score on these domains. Table 2. T-test on MoCA Total and Domains Scores Differentiated by Prescription for ACE Inhibitors MoCA Tot al Score Visuo -sp at ial Naming Animals Memory Attent ion Language Abst ract io n Delayed Recall Orient at io n Yes - ACE Mean/SD 25.04 ± 2.81 3.91 ± 1.10 2.96 ± .20 1.26 ± .67 5.35 ± .67 2.10 ± .88 1.61 ± .62 3.34 ± 1.17 5.98 ± .15 NoACE Mean/SD 23.65 ± 2.32 3.4 ± .69 2.85 ± .37 1.20± .77 5.23±1.02 1.90± .85 1.60± .68 2.50±1.70 5.97±1.68 ME t sig 1.39 2.25 .030. .464 2.03 .026* .107 1.25 .092 .057 .465 .75 .121 .627 .53 .20 .69 .37 .014 .89 .93 .141 2.56 .012* .029 -1.43 .45 *Indicates Statistical significance at p <0.05 Bivariate analysis showed significant association with total MoCA score and ACE inh ibitor dosage (RS .211, p .046) indicating higher dosages of ACE inhibitors were associated with better cognitive protection with no association with ARBs. A mong the MoCA domain score delayed recall was associated with ACE inhib itor dosage (RS .263, p .012) and marginally with visuo-spatial do main (RS .187, p .07) with no association to ARBs. Bivariate analysis indicated significant association between age, education, knowledge of med ication, and mean arterial b lood pressure. As illustrated in table 3a and 3b, the covariates accounted for 33.6% of variance on the regression model and ACE inhib itor added 4.1 % of variance to the model and remained statistically significant (p .021). Table 3a. Summary of the Hierarchical Multiple Regression Model Model R R2 Adj. R2 S.E R2 F Sig. F Change Change Covariates .580 .336 .305 2.29 .336 10.774 .000** ACE inhibitor .614 .377 .340 2.24 .041 5.498 .021* *indicates significance at p <0.05 Table 3b. Coefficients Statistics of the Hierarchical Multiple Regression Model Age Edu. Know. Med. Mean AP ACE I Un st d. Coefficient B SE -.03 .029 .376 .094 .922 .292 St d. Coefficient Beta t -.10 8 -1.12 .376 3.99 .313 3.161 95% CI (EXP (B) Sig. Low Upper .226 -.075 .002 .000 -.048 .210 .002 .147 .917 .008 .018 .043 .463 .644 -.526 2.949 0.31 .013 .214 2.345 .021 .221 2.656 Keys= Edu: Education; Know Med: Knowledge of Medication, Mean AP: Mean Arterial Blood Pressure, ACEI: Angiotensin converting enzyme inhibitor Age and mean arterial b lood pressure was not a predictor in the final regression model. Other demographic and clin ical variab les including, NYHA class, ejection fraction, etiology of HF, depression, and functional ability were not associated with MoCA score. Chi-square analysis also indicated that participants who had no prescription for an ACE inhibitor or A RB scored <26 on the MoCA total score (X 2 (2) = 5.0, p .025). However, several participants (n=11) were on both an A CE inhib itor and ARB; cumu latively, this was not associated with total MoCA score (RS .159, p .134), but was significantly associated with visuo-spatial score (RS .238, p .02). Draw-a-clock test, a single item that tests visuo-spatial function was statistically significant with ACE prescription (RS .227, p= .032) with no association on the other two items (Copy Cube and Tria l Making) and ARBs. 6.2. Cogniti ve Scores and Centrally-Acti ve ACE Inhi bitors ACE inh ibitors were further classified as centrally-act ive or non-centrally act ive. A mong this sample 60% were on centrally-active A CE inhib itors. T-test indicated significant association between total MoCA score and centrally-active ACE inhibitor (t =2.56; p <.013) with similar results on MoCA domains visuo-spatial and delayed recall (p <.05). However, reg ression model on centrally-active ACE inhibitor added 1% variance on the model which was not statistically significant (p .285). 6.3. Blood Pressure Associated wi th ACE Inhi bitors 19 International Journal of Nursing Science 2012, 2(3): 14-22 Bivariate analysis indicated strong association between systolic b lood pressure and ACE inhibitor (rS .272, p .001) and mean arterial blood pressure (rS .249, p .018) with significant association on dosage. A total of 59% of the participants had a history of hypertension. Having a history of hypertension and a prescription for an A CE inhibitor or ARB had no significant association with cognitive function measured by the MoCA in this sample of part icipants. In addition, when entered as a covariate, regression model did not support the association between mean arterial blood pressure and MoCA score (t = .463, p .644). 6.4. Cogniti ve Score and association wi th other Heart Failure Medicati ons The MoCA total score was not associated with ARBs, aldosterone inhibit ion therapy, and statin therapy. However, the MoCA do main score on visuo-spatial (RS .23, p .032) and short term memory scores (RS .27, p .011) were strongly associated with aldosterone inhibition therapy. 7. Discussion Our data confirm previous findings that ACE inhibitors may have cognitive benefit among HF patients[22].A mong study participants, cognitive function on total MoCA score was strongly associated with taking any ACE inhibitors and centrally-active A CE inhib itors with significant dose association, a finding supported by several researchers [22,23,44,45]. In addition, significant association was identified on visuo-spatial and delayed recall domains that have been reported as common do mains of impairment in HF. It has been well docu mented that ACE inhibitor therapy leads to HF sympto m imp rovement, reduced hospitalization and enhanced survival in patients with HF [15,17,21].Cognitive function may have direct impact on HF patients’ ability to perform self-care management at home [2-4,7]Recently, among 250 veterans, cognitive impairment was associated with poor adherence to med ication reg imen (p .007)[57]. Result fro m this study supports the hypothesis that ACE inhib itors may protect cognition in persons with HF and may thus improve adherence, a hypothesis that needs further exp loration. On the contrary, no association was identified on ARBs alone among this sample of participants. This was contrary to the findings of Li and colleagues, who compared ACE inhibitor, A RB, and co mbination therapy among 819, 491 predominantly male (98%) US Veterans and reported a dose-response as well as additive effects on cognition from combination therapy with an A CE inhib itor and an ARB[58]. Li and colleagues also reported that combination therapy (ACE p lus ARB) was associated with a reduced risk for dementia over 4 years (p= .016) co mpared with ACE inhibitors alone.58 Among participants with pre-existing Alzheimer’s disease, comb ination therapy (A CE plus ARB) showed a lower risk of ad mission to a nursing home (p .0001)[58].Our sample (N=90) had a total of 17 (15.3%) participants who were on ARB alone and 11 participants (9.9%) on both ACE inhibitor and ARB. Th is fairly small sample o f part icipants may exp lain the non-association with cognitive function with co mbination therapy in our samp le. Although there was no association between total Mo CA score, ARBs and other cardiac medications, the MoCA domain visuo-spatial and short term memory scores were associated with aldosterone inhibition therapy. Particularly, draw-a-clock test, a single item that tests visuo-spatial function was statistically significant with prescription for ACE, and aldosterone inhibit ion therapy, a finding supported by Riegel and colleagues that draw-clock-test was 50% mo re sensitive in HF[53]. There is increasing evidence that hypertension may contribute to the development of cognitive impairment and that blood pressure lowering therapy might protect against cognitive deterioration and vascular dementia [15-17,59,60]. Although, bivariate analysis revealed association between MoCA score and systolic blood pressure, the findings was not supported by the regression model. In addit ion having a history of hypertension and a prescription for an A CE inhibitor o r ARB had no significant association with cognitive function measured by the MoCA in this sample of participants, warranting further explorat ion. A total of 93% of partic ipants in this study had a prescription for an ACE inhib itor and/or ARB, which is congruent with National data fro m the CMS quality index[61]. A major limitat ion of this study is the lac k of a control or comparison group. The MoCA was used as a screening tool for mild cognitive impairment, and we did not obtain a gold standard neuropsychological test battery to more thoroughly evaluate cognitive function. HF diagnosis was ascertained using ICD-9 codes that may have introduced inaccuracies [62]. 8. Summary and Implications for Nursing Practice ACE inhib itors are an important component of standard HF therapy and may confer an added benefit by improving cognitive function. It has been demonstrated that a co mplex chain of events leads to irreversible cardiac damage as shown in figure 1; leading eventually to overt HF. Angiotensin plays a prominent role in many of these events and thus the interruption of these progressive deleterious events is vital is protecting end organs[63]. There is conflicting evidence about the potential benefits of ACE inhibitors for the treatment of cognitive protection whether in HF, or other chronic health conditions such as diabetes, stroke, Parkinson’s disease and Alzheimer’s disease. The results from this study added evidence that ACE inhib ition has emerged as a potential modality of cognitive protection possible by min imizing irreversible damage to heart and brain. Evidence is also emerg ing on the selective use of ACE inhibitors in individuals who carry specific genotypes as it may offer additional cognitive benefit beyond lowering vascular risk[64]. Future research on ACE genotypes may Ponrathi Athilingam et al.: Cognitive Protection by Angiotensin Converting Enzyme Inhibitors in Heart Failure 20 substantiate the use of ACE inhib ition in clinica l application [12] Vogels RLC, Scheltens P, Schroeder-Tanka JM , Weinstein for avoiding or min imizing cognitive impairment. HC. Cognitive impairment in heart failure: a systematic review of the literature. Eur J Heart Fail 2007;9:440e9. 9. Conclusions The results suggest that ACE inhibit ion occupies a pivotal role in protecting end organs and are well-tolerated by most individuals. The prescription of ACE Inhibitors protects the vascular wall against various injuries and maintains blood flow to the brain and peripheral vasculature and thus may be a protective factor for cognit ive deteriorat ion in older adults with HF and other comorbid conditions such as hypertension and diabetic. [13] Sauve M J, Lewis WR, Blankenbiller M , Rickabaugh B, Pressler SJ. 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