Heart failure (HF) is one of the most frequent cause of hospitalization in elderly and often coexists with concurrent geriatric syndromes, like cognitive disturbances; various pathophysiological mechanisms are shared by HF and cognitive decline, notably a substrate of low-grade inflammation. We investigated whether SNPs in the purinergic receptor (P2X7R) and apolipoprotein (APO) E genes, both involved in a series of inflammatory responses, are associated to HF or cognitive impairment and are able to predict post-discharge mortality in the elderly. We prospectively analyzed 198 patients (age 85 ± 8 years, predominantly females) admitted to a Geriatric unit for acute HF, whose diagnosis was based on clinical signs, brain natriuretic peptide (BNP) values and ecocardiography in uncertain diagnosis (BNP values between 100 and 400 pg/mL); cognitive performance was assesed by Short Portable Mental Status Questionnaire (SPMSQ). In all the participants, SNPs rs208294 and rs3751143 for P2X7R gene and rs429558 and rs7412 for APOE gene were assessed. Information on all-cause mortality was adjudicated by medical records review 36 months after discharge. We found no relationship between P2X7R and APOE polymorphisms and 36-month post-discharge mortality; a better outcome for overall survival was observed in patients with BNP values below the median (281 pg/mL) (p=0.002) persisting after adjustment for renal function and age, and in those with cognitive impairment (p<0.001). Patients harboring APOE-ε4 genotype showed higher BNP concentrations than noncarriers (1289.9 ± 226.9 vs 580.5 ± 90.2 pg/mL respectively,p=0.004), whereas none of the studied SNPs were associated to impairment in cognitive performance. In conclusion, neither P2X7R or APOE genotype seem to predict long-term mortality in elderly patients. Interestingly, APOE-ε4 genotype was associated to higher BNP values, suggesting a putative interaction between genetic and biochemical markers in identifying people at risk for HF.
Pasqualetti Giuseppe,Seghieri Marta,Santini Eleonora, et al. P2X7 Receptor and APOE Polymorphisms and Survival from Heart Failure: A Prospective Study in Frail Patients in a Geriatric Unit[J]. Aging and disease,
2017, 8(4): 434-441.
Table 1B Biochemical variables of the study group (n=198).
A carriers C carriers
702.0 ± 115.0 674.3 ± 167.0
C carriers T carriers
626.2 ± 162.6 721.6 ± 103.4
ε4 carriers ε4 noncarriers
1289.9 ± 226.9 580.5 ± 90.2
Cognitive impairment (% of patients)
A carriers C carriers
C carriers T carriers
APOE rs429358 rs7412
ε4 carriers ε4 noncarriers
Table 2 Association between genotypes and BNP value (A) or percentage of cognitive impairment (B) in the study population.
Figure 1. Overall survival curves of all the patients according to genetic profiles of the studied polymorphisms
Survival curves were calculated with the Kaplan Meier method.
T-T C-T C-C
38 100 52
A-A C-A C-C
111 55 8
Suppl Table A Genotypes, allele frequencies and Hardy-Weinberg Equilibrium (HWE) of the studied polymorphisms
Charlson comorbidity index
Suppl Table B Proportional hazards regression analysis showing BNP impact on reduced overall survival
Dharmarajan K, Dunlay SM (2016). Multimorbidity in older adults with heart failure. Clin Geriatr Med, 32(2): 277-89.
van de Vorst IE, Koek HL, de Vries R, Bots ML, Reitsma JB, Vaartjes I (2016). Effect of vascular risk factors and diseases on mortality in individuals with dementia: a systematic review and meta-analysis. J Am Geriatr Soc, 64(1): 37-46.
Briasoulis A, Androulakis E, Christophides T, Tousoulis D (2016). The role of inflammation and cell death in the pathogenesis, progression and treatment of heart failure. Heart Fail Rev, 21(2): 169-76.
Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G (2016). Neuroinflammation pathways: a general review. Int J Neurosci, 13:1-29.
Di Virgilio F (2015). P2X receptors and inflammation. Curr Med Chem, 22(7): 866-77.
Rodrigues RJ, Tomé AR, Cunha RA (2015). ATP as a multi-target danger signal in the brain. Front Neurosci, 28(9): 148.
Portales-Cervantes L, Niño-Moreno P, Salgado-Bustamante M, García-Hernández MH, Baranda-Candido L, Reynaga-Hernández Eet al (2012). The His155Tyr (489C>T) single nucleotide polymorphism of P2RX7 gene confers an enhanced function of P2X7 receptor in immune cells from patients with rheumatoid arthritis. Cell Immunol, 276(1-2): 168-75.
Gu BJ, Zhang W, Worthington RA, Sluyter R, Dao-Ung P, Petrou Set al (2001). A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor. J Biol Chem, 276(14): 11135-42.
Erlinge D, Burnstock G (2008). P2 receptors in cardiovascular regulation and disease. Purinergic Signal, 4(1): 1-20.
Mezzaroma E, Toldo S, Farkas D, Seropian IM, Van Tassell BW, Salloum FNet al (2001). The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci USA, 108(49):19725-30.
SilverMA, MaiselA, YancyCW, McCulloughPA, BurnettJCJr, FrancisGS et al; BNP Consensus Panel (2004). A clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular diseases. Congest Heart Fail, 10(5 Suppl 3):1-30.
Sandanger Ø, Ranheim T, Vinge LE, Bliksøen M, Alfsnes K, Finsen AVet al (2013). The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res, 99(1):164-174.
Butts B, Gary RA, Dunbar SB, Butler J (2015). The importance of NLRP3 inflammasome in heart failure. J Card Fail, 21(7): 586-93.
Zhang X, Sha M, Yao Y, Da J, Jing D (2015). Increased B-type-natriuretic peptide promotes myocardial cell apoptosis via the B-type-natriuretic peptide/long non-coding RNA LSINCT5/caspase-1/interleukin 1β signaling pathway. Mol Med Rep, 12(5): 6761-67.
Dubyak GR (2012). P2X7 receptor regulation of non-classical secretion from immune effector cells. Cell Microbiol, 14(11): 1697-706.
Eslick GD, Thampan BV, Nalos M, McLean AS, Sluyter R (2009). Circulating interleukin-18 concentrations and a loss-of-function P2X7 polymorphism in heart failure. Int J Cardiol, 11;137(1): 81-3.
Lopez MF, Krastins B, Ning M (2009). The role of apolipoprotein E in neurodegeneration and cardiovascular disease. Expert Rev Proteomics,11(3): 371-81.
Mahley RW (2016). Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. J Mol Med (Berl), 94(7): 739-46.
Bu G (2009). Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci, 10: 333-344.
Jurkovicova D, Goncalvesova E, Sedlakova B, Hudecova S, Fabian J, Krizanova O (2006). Is the ApoE polymorphism associated with dilated cardiomyopathy? Gen Physiol Biophys, 25(1): 3-10.
Economou-Petersen E, Aessopos A, Kladi A, Flevari P, Karabatsos F, Fragodimitri Cet al (1998). Apolipoprotein E epsilon4 allele as a genetic risk factor for left ventricular failure in homozygous beta-thalassemia. Blood, 92(9): 3455-9.
The Criteria Committee of the New York Heart Association (1994). Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, Mass: Little, Brown & Co; 253-256.
Iwaz JA, Maisel AS (2016). Recent advances in point-of-care testing for natriuretic peptides: potential impact on heart failure diagnosis and management. Expert Rev Mol Diagn, 16(6): 641-50.
Maisel A, Mueller C, Adams KJr, Anker SD, Aspromonte N, Cleland JGet al (2008). State of the art: using natriuretic peptide levels in clinical practice. Eur J Heart Fail, 10(9): 824-39.
Pfeiffer E (1975). A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. J Am Geriatr Soc 23(10): 433-41.
Peng K, Liu L, Wei D, Lv Y, Wang G, Xiong W,et al (2015) P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation. Int J Mol Med, 35(5): 1179-88.
Di Virgilio F, Solini A (2002). P2 receptors: new potential players in atherosclerosis. Br J Pharmacol, 135(4): 831-42.
Holmes MV, Frikke-Schmidt R, Melis D, Luben R, Asselbergs FW, Boer JM,et al (2014). A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease. Atherosclerosis, 237(1): 5-12.
Thunberg U, Tobin G, Johnson A, Söderberg O, Padyukov L, Hultdin Met al (2002). Polymorphism in the P2X7 receptor gene and survival in chronic lymphocytic leukaemia. Lancet, 360(9349): 1935-9.
Tamam Y, Tasdemir N, Yalman M, Tamam B (2011). Association of apolipoprotein E genotypes with prognosis in multiple sclerosis. Eur Rev Med Pharmacol Sci, 15(10): 1122-30.
Paneesha S, Starczynski J, Pepper C, Delgado J, Hooper L, Fegan Cet al (2006). The P2X7 receptor gene polymorphism 1513 A-->C has no effect on clinical prognostic markers and survival in multiple myeloma. Leuk Lymphoma, 47(2): 281-4.
Solini A, Simeon V, Derosa L, Orlandi P, Rossi C, Fontana Aet al (2015). Genetic interaction of P2X7 receptor and VEGFR-2 polymorphisms identifies a favorable prognostic profile in prostate cancer patients. Oncotarget, 6(30): 28743-54.
Christensen K, Johnson TE, Vaupel JW (2006). The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet, 7(6): 436-48.
Ewbank DC (2007). Differences in the association between apolipoprotein E genotype and mortality across populations. J Gerontol A Biol Sci Med Sci, 62: 899-907.
Leto L, Testa M, Feola M (2015). Correlation between B-type natriuretic peptide and functional/cognitive parameters in discharged congestive heart failure patients. Int J Endocrinol, 2015: 239136.
Yaffe K, Peltz CB, Ewing SK, McCulloch CE, Cummings SR, Cauley JAet al (2016). Long-term cognitive trajectories and mortality in older women. J Gerontol A Biol Sci Med Sci, 71(8): 1074-80.
Rodriguez-Pascual C, Paredes-Galan E, Vilches-Moraga A, Ferrero-Martinez AI, Torrente-Carballido M, Rodriguez-Artalejo F (2014). Comprehensive geriatric assessment and 2-year mortality in elderly patients hospitalized for heart failure. Circ Cardiovasc Qual Outcomes, 7(2): 251-8.
Bleumink GS, van Duijn CM, Kingma JH, Witteman JC, Hofman A, Stricker BH (2004). Apolipoprotein E epsilon4 allele is associated with left ventricular systolic dysfunction. Am Heart J, 147(4): 685-9.
van der Cammen TJ, Verschoor CJ, van Loon CP, van Harskamp F, de Koning I, Schudel WJet al (1998). Risk of left ventricular dysfunction in patients with probable Alzheimer’s disease with APOE*4 allele. J Am Geriatr Soc, 46(8): 962-7.
Beltrami M, Palazzuoli A, Ruocco G, Aspromonte N (2016). The predictive value of plasma biomarkers in discharged heart failure patients: the role of plasma BNP. Minerva Cardioangiol, 64(2): 147-56.