- Email: [email protected]
Left ventricle diastolic function and cognitive performance in adults with Down syndrome
International Journal of Cardiology 203 (2016) 816–818
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Left ventricle diastolic function and cognitive performance in adults with Down syndrome Davide L. Vetrano a,⁎, Angelo Carfì a, Vincenzo Brandi a, Paolo D. L'Angiocola b, Sonia Di Tella a, Maria Camilla Cipriani a, Manuela Antocicco a, Giuseppe Zuccalà a, Vincenzo Palmieri c, Maria Caterina Silveri a, Roberto Bernabei a, Graziano Onder a a b c
Department of Geriatrics, Orthopedics and Neurosciences, Catholic University of the Sacred Heart, Rome, Italy Department of Cardiology, Department of Cardiology, “E. Profili” Hospital, Fabriano, Italy Sports Medicine Unit, Catholic University of the Sacred Heart, Rome, Italy
a r t i c l e
i n f o
Article history: Received 3 November 2015 Accepted 5 November 2015 Available online 6 November 2015 Keywords: Down syndrome Adults Diastolic dysfunction Alzheimer's disease Amyloidosis
To the Editor: Introduction Down Syndrome (DS), also known as trisomy 21, is the most common chromosomal disorder in human beings, affecting about 1/700 live births. This condition is one of the most frequent causes of cognitive impairment and is considered a relevant risk factor for early onset Alzheimer's disease (AD diagnosed in subjects under the age of 65). Amyloid overproduction is observed in DS and is thought to be induced by the presence of an extra amyloid precursor protein (APP) gene located on the trisomic redundant chromosome. In this context it has been shown that by the age of forty, all persons with DS virtually develop typical AD neuropathological features [1]. Deposition of amyloid beta (Aβ) and neurofibrillary tangles within central nervous system tissue, that is typically observed in AD, starts early in life of individuals affected by DS. AD and cardiac diastolic dysfunction might share some common pathological pathways [2]. Indeed, protein disarray, typical feature in AD, is ⁎ Corresponding author at: Centro Medicina dell'Invecchiamento, Dipartimento di Geriatria, Ortopedia e Neuroscienze, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Roma, Italy. E-mail address: [email protected] (D.L. Vetrano).
http://dx.doi.org/10.1016/j.ijcard.2015.11.041 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
thought to be involved in the pathogenesis of some of the most common cardiac diseases (heart failure, cardiomyopathies, etc.) impairing left ventricular diastolic function [3] as well. In addition, higher rate of diastolic dysfunction was observed in both subjects with DS and in those with AD, when compared with controls [4]. Therefore, aim of the present study was to investigate the association between diastolic dysfunction and cognitive performance in a sample of adults affected by DS. Methods We enrolled 48 adults with DS who were consecutively admitted to the geriatric day hospital of Catholic University of Rome, Italy [5]. Inclusion criteria were age ≥ 18 years old and diagnosis of DS. Participants (N = 12) affected by ischemic heart diseases, heart failure, stroke, cardiac rhythm disturbances, diabetes, or on any cardiovascular drug therapy or with history of previous cardiac surgery were excluded, leading to a final sample of 36 subjects. Informed consent was obtained from all participants or tutors. All participants underwent comprehensive echocardiographic evaluation according to European Society of Cardiology guidelines. Left ventricular diastolic function was assessed by trans-mitral pulsed Doppler (PD) flows measurement and tissue Doppler Imaging (TDI) study of the mitral annulus wall. Early ventricular filling (E wave and Em) and atrial contribution (A wave and Am) were measured. Isovolumetric relaxation time (IVRT) and E wave deceleration time (DT) were also assessed. E/A and the E/Em ratios were obtained. An E/Em ratio ≥8 identified the presence of left ventricle diastolic dysfunction. Cognitive performance of participants was assessed through two different tests: the Raven's Matrices (RM) and the verbal and performance scores of the Wechsler Adult Intelligence Scale (WAIS). Such tests are validated to properly assess the verbal and non-verbal intellectual performance of adult subjects and have been previously shown to be reliable instruments for the evaluation of persons with DS and other intellectual disabilities [6–8]. Data are given as mean ± Standard Deviation (SD) or absolute number and percentage (%) where appropriate. Adjusted (age, sex, BMI and heart rate) means of cognitive performance scores were obtained by the analysis of covariance (ANCOVA) according to the presence of diastolic dysfunction (E/Em ≥8). Given their non-normal
Correspondence
817
distribution, WAIS verbal and performance scores were log-transformed for the ANCOVA. For these variables geometric means calculated from the log-transformed values are presented. A p value b 0.05 was considered significant. Analyses were run using the software for biostatistics SPSS 20.0. Results Within the sample (mean age ± SD 36.1 ± 9.7 years; 75% women), 22 (61%) participants presented with left ventricle diastolic dysfunction (E/Em ≥8). Prevalence of overweight and obesity was high (respectively 33% and 39%; Table 1). Participants' mean scores of Raven's matrices and WAIS scales (verbal and performance) were, respectively, 13.4 ± 5.9, 8.9 ± 3.7 and 9.0 ± 4.2. After adjusting for potential confounders, as shown in Fig. 1, participants with left ventricle diastolic dysfunction showed lower cognitive scores in respect to those with preserved diastolic function: Raven's matrices 11.1 ± 1.1 vs 16.9 ± 1.4 (p = 0.002); WAIS verbal score 6.7 ± 2.3 vs 10.0 ± 1.1 (p = 0.003); WAIS performance score 6.7 ± 2.3 vs 10.1 ± 1.1 (p = 0.007). Discussion The results of the present study show that diastolic dysfunction is prevalent and independently associated to poor cognitive verbal and non-verbal performance in adults with Down syndrome. Six out of ten participants of the present study presented with diastolic dysfunction. Previous studies conducted on trisomy 21 fetuses showed altered trans-valvular Doppler flows across both atrioventricular valves, compatible with impaired diastolic function [9]. Similarly, Al-Biltagi and coll. reported significantly altered left and right ventricle diastolic parameters in children with DS when compared with controls, as evaluated through pulsed Doppler flows and tissue Doppler [10]. Finally, Vis and coll. reported higher rates of mild to moderate diastolic dysfunction in adults with DS when compared with healthy controls (57% vs 33%; p b 0.05) [4]. The association between diastolic dysfunction and cognitive impairment has already been described in general population without DS. In particular, several evidences suggested a higher prevalence of diastolic Table 1 Sample Characteristics. General characteristics
N = 36
Age (years) Sex (F) Body mass index (kg/m2) b25 25–30 N30 Heart rate (beats/min)
36.1 ± 9.7 27 (75)
Cognitive performance Raven's Matrices WAIS verbal score WAIS performance score Echocardiography parameters LA volume index (ml/m2) LV mass index (g/m2) LV volume index (ml/m2) Ejection fraction (%) E/A b1 1–2 N2 DT E wave IVRT E/Em ≥8
10 (28) 12 (33) 14 (39) 62 ± 12
13.4 ± 5.9 8.9 ± 3.7 9.0 ± 4.2
25 ± 6 57 ± 13 52 ± 14 59 ± 5 3 (8) 25 (69) 8 (22) 217 ± 50 79 ± 13 22 (61)
WAIS = Wechsler Adult-Intelligence-Scale; LA = Left Atrium; LV = Left Ventricle; DT = Deceleration Time; IVRT = Iso-Volumetric Relaxation Time.
Fig. 1. Cognitive performance (adjusted means and standard error) by presence of left ventricle diastolic dysfunction. For WAIS Verbal score and Performance score geometric means are presented. Scores adjusted for age, sex, BMI and heart rate.
dysfunction among individuals with AD as compared with controls, when evaluated by both trans-valvular Doppler flows and TDI [11]. At the same time, individuals with heart failure (both with reduced and preserved ejection fraction) have been shown to present higher prevalence of cognitive impairment compared with controls [12,13]. Different factors might explain the association between diastolic dysfunction and poor cognitive status. First, cardiac dysfunction, through brain hypo-perfusion, could contribute to cognitive impairment [14]. However, we evaluated individuals with DS free from known cardiovascular disease in order to exclude its potential contribution to the levels of diastolic dysfunction and cognitive impairment. Second, diastolic dysfunction might share some common pathways with AD, a condition often observed in adults with DS, by modulation of the presenilin gene and Aβ expression [15,16]. In this context, recent
818
Correspondence
evidences show that amyloid deposition, causing cognitive impairment in many neurodegenerative diseases including AD, are involved in the pathogenesis of some of the commonest cardiac diseases (cardiac hypertrophy and dilated and ischemic cardiomyopathies). The ubiquitineproteasome system dysfunction and the proteins misfolding, impair the well-functioning of myocardial syncytium, a phenomenon known as proteotoxicity. In cardiac amyloidosis, deposition of amyloid derived from wild type transthyretin in the myocardium interstitium and intramural coronary vessels is associated with left ventricular wall thickening, diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF). Similarly, in autopsy studies, older adults with HFpEF presented higher transthyretin deposits when compared to those without HF [17]. For several neurodegenerative conditions as Parkinson's disease and Huntington's disease it was reported a systemic deposition of misfolded protein in central nervous system [18,19]. The involvement of a similar mechanism might be hypothesized in DS, contributing to explain our results. Finally, a common and direct pathway linking cardiac and cognitive function in DS might be hypothesized. In this context, Shinohara and coll. produced chimeric mice in order to study the gene dosage effects of an extra copy of human chromosome 21. In this study, a correlation between the levels of retention (percentage) of the extra chromosome 21, in either the brain, heart and other organs and the grade of cognitive impairment and heart abnormalities was reported. Proportionally according to the level of chimerism, ventricles appeared filled with myocardial cells with abnormal trabecular patterns potentially responsible for impaired ventricular function [20]. A relevant limitation of the present study relates to its crosssectional design which does not allow to address specific cause-effect mechanisms. In addition, even if the cognitive assessment relied on previously adopted instruments, our findings need confirmation from future studies using different assessment scales. In conclusion, the increment in life expectancy observed in persons with DS makes it necessary to better understand mechanisms involved in the development of diseases occurring in adult age in this population. In this context, assessment of risk factors and pathological pathways contributing to worsening of cognitive status and development of AD represents a research priority. Our results show an independent association between diastolic dysfunction and poor cognitive performances in adults affected by DS without cardiovascular disease. If confirmed in longitudinal studies these data might contribute to shed light on complex mechanisms leading to increased risk of cognitive impairment and AD in this population. Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
References [1] D. Hartley, T. Blumenthal, M. Carrillo, G. DiPaolo, L. Esralew, K. Gardiner, et al., Down syndrome and Alzheimer's disease: common pathways, common goals, Alzheimers Dement. 11 (6) (2015 Dec 12) 700–709. [2] F. Lai, R.S. Williams, A prospective study of Alzheimer disease in Down syndrome, Arch. Neurol. 46 (8) (1989 Aug) 849–853. [3] M.S. Willis, C. Patterson, Proteotoxicity and cardiac dysfunction – Alzheimer's disease of the heart? N. Engl. J. Med. 368 (5) (2013 Jan 31) 455–464. [4] J.C. Vis, R.H. de Bruin-Bon, B.J. Bouma, A.P. Backx, S.A. Huisman, L. Imschoot, et al., ‘The sedentary heart’: physical inactivity is associated with cardiac atrophy in adults with an intellectual disability, Int. J. Cardiol. 158 (3) (2012 Jul 26) 387–393. [5] A. Carfì, M. Antocicco, V. Brandi, C. Cipriani, F. Fiore, D. Mascia, et al., Characteristics of adults with Down syndrome: prevalence of age-related conditions, Front. Med. (Lausanne) 1 (51) (2014 Dec 3)http://dx.doi.org/10.3389/fmed.2014.00051. [6] P. Breia, R. Mendes, A. Silvestre, M.J. Gonçalves, M.J. Figueira, R. Bispo, Adults with Down syndrome: characterization of a Portuguese sample, Acta Med. Port. 27 (3) (2014 May-Jun) 357–363. [7] G. Bernert, M. Sustrova, E. Sovcikova, R. Seidl, G. Lubec, Effects of a single transdermal nicotine dose on cognitive performance in adults with Down syndrome, J. Neural Transm. Suppl. 61 (2001) 237–245. [8] G. Andreou, C. Galanopoulou, K. Gourgoulianis, A. Karapetsas, P. Molyvdas, Cognitive status in Down syndrome individuals with sleep disordered breathing deficits (SDB), Brain Cogn. 50 (1) (2002 Oct) 145–149. [9] S.A. Clur, K. Oude Rengerink, J. Ottenkamp, C.M. Bilardo, Cardiac function in trisomy 21 fetuses, Ultrasound Obstet. Gynecol. 37 (2) (2011 Feb) 163–171. [10] M. Al-Biltagi, A.R. Serag, M.M. Hefidah, M.M. Mabrouk, Evaluation of cardiac functions with Doppler echocardiography in children with Down syndrome and anatomically normal heart, Cardiol. Young 23 (2) (2013 Apr) 174–180. [11] A.N. Çalık, K.S. Özcan, G. Yüksel, B. Güngör, E. Aruğarslan, F. Varlibas, et al., Altered diastolic function and aortic stiffness in Alzheimer's disease, Clin. Interv. Aging 9 (2014 Jul 16) 1115–1121. [12] M. Belohlavek, P. Jiamsripong, A.M. Calleja, E.M. McMahon, C.L. Maarouf, T.A. Kokjohn, et al., Patients with Alzheimer disease have altered transmitral flow: echocardiographic analysis of the vortex formation time, J. Ultrasound Med. 28 (11) (2009 Nov) 1493–1500. [13] P. Athilingam, R.F. D'Aoust, L. Miller, L. Chen, Cognitive profile in persons with systolic and diastolic heart failure, Congest Heart Fail 19 (1) (2013 Jan-Feb) 44–50. [14] M. Suwa, T. Ito, Correlation between cognitive impairment and left ventricular diastolic dysfunction in patients with cardiovascular diseases, Int. J. Cardiol. 136 (3) (2009 Aug 21) 351–354. [15] C. Qiu, L. Fratiglioni, A major role for cardiovascular burden in age-related cognitive decline, Nat. Rev. Cardiol. 12 (5) (2015 May) 267–277. [16] A. Li, C. Zhou, J. Moore, P. Zhang, T.H. Tsai, H.C. Lee, et al., Changes in the expression of the Alzheimer's disease—associated presenilin gene in drosophila heart leads to cardiac dysfunction, Curr. Alzheimer Res. 8 (3) (2011 May) 313–322. [17] S.F. Mohammed, S.A. Mirzoyev, W.D. Edwards, A. Dogan, D.R. Grogan, S.M. Dunlay, et al., Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction, JACC Heart Fail 2 (2) (2014 Apr) 113–122. [18] G.C. Melkani, A.S. Trujillo, R. Ramos, R. Bodmer, S.I. Bernstein, K. Ocorr, Huntington's disease induced cardiac amyloidosis is reversed by modulating protein folding and oxidative stress pathways in the Drosophila heart, PLoS Genet. 9 (12) (2013), e1004024http://dx.doi.org/10.1371/journal.pgen.1004024. [19] S. Jain, D.S. Goldstein, Cardiovascular dysautonomia in Parkinson disease: from pathophysiology to pathogenesis, Neurobiol. Dis. 46 (3) (2012 Jun) 572–580. [20] T. Shinohara, K. Tomizuka, S. Miyabara, S. Takehara, Y. Kazuki, J. Inoue, et al., Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down's syndrome, Hum. Mol. Genet. 10 (11) (2001 May 15) 1163–1175.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Left ventricle diastolic function and cognitive performance in adults with Down syndrome Davide L. Vetrano a,⁎, Angelo Carfì a, Vincenzo Brandi a, Paolo D. L'Angiocola b, Sonia Di Tella a, Maria Camilla Cipriani a, Manuela Antocicco a, Giuseppe Zuccalà a, Vincenzo Palmieri c, Maria Caterina Silveri a, Roberto Bernabei a, Graziano Onder a a b c
Department of Geriatrics, Orthopedics and Neurosciences, Catholic University of the Sacred Heart, Rome, Italy Department of Cardiology, Department of Cardiology, “E. Profili” Hospital, Fabriano, Italy Sports Medicine Unit, Catholic University of the Sacred Heart, Rome, Italy
a r t i c l e
i n f o
Article history: Received 3 November 2015 Accepted 5 November 2015 Available online 6 November 2015 Keywords: Down syndrome Adults Diastolic dysfunction Alzheimer's disease Amyloidosis
To the Editor: Introduction Down Syndrome (DS), also known as trisomy 21, is the most common chromosomal disorder in human beings, affecting about 1/700 live births. This condition is one of the most frequent causes of cognitive impairment and is considered a relevant risk factor for early onset Alzheimer's disease (AD diagnosed in subjects under the age of 65). Amyloid overproduction is observed in DS and is thought to be induced by the presence of an extra amyloid precursor protein (APP) gene located on the trisomic redundant chromosome. In this context it has been shown that by the age of forty, all persons with DS virtually develop typical AD neuropathological features [1]. Deposition of amyloid beta (Aβ) and neurofibrillary tangles within central nervous system tissue, that is typically observed in AD, starts early in life of individuals affected by DS. AD and cardiac diastolic dysfunction might share some common pathological pathways [2]. Indeed, protein disarray, typical feature in AD, is ⁎ Corresponding author at: Centro Medicina dell'Invecchiamento, Dipartimento di Geriatria, Ortopedia e Neuroscienze, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Roma, Italy. E-mail address: [email protected] (D.L. Vetrano).
http://dx.doi.org/10.1016/j.ijcard.2015.11.041 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
thought to be involved in the pathogenesis of some of the most common cardiac diseases (heart failure, cardiomyopathies, etc.) impairing left ventricular diastolic function [3] as well. In addition, higher rate of diastolic dysfunction was observed in both subjects with DS and in those with AD, when compared with controls [4]. Therefore, aim of the present study was to investigate the association between diastolic dysfunction and cognitive performance in a sample of adults affected by DS. Methods We enrolled 48 adults with DS who were consecutively admitted to the geriatric day hospital of Catholic University of Rome, Italy [5]. Inclusion criteria were age ≥ 18 years old and diagnosis of DS. Participants (N = 12) affected by ischemic heart diseases, heart failure, stroke, cardiac rhythm disturbances, diabetes, or on any cardiovascular drug therapy or with history of previous cardiac surgery were excluded, leading to a final sample of 36 subjects. Informed consent was obtained from all participants or tutors. All participants underwent comprehensive echocardiographic evaluation according to European Society of Cardiology guidelines. Left ventricular diastolic function was assessed by trans-mitral pulsed Doppler (PD) flows measurement and tissue Doppler Imaging (TDI) study of the mitral annulus wall. Early ventricular filling (E wave and Em) and atrial contribution (A wave and Am) were measured. Isovolumetric relaxation time (IVRT) and E wave deceleration time (DT) were also assessed. E/A and the E/Em ratios were obtained. An E/Em ratio ≥8 identified the presence of left ventricle diastolic dysfunction. Cognitive performance of participants was assessed through two different tests: the Raven's Matrices (RM) and the verbal and performance scores of the Wechsler Adult Intelligence Scale (WAIS). Such tests are validated to properly assess the verbal and non-verbal intellectual performance of adult subjects and have been previously shown to be reliable instruments for the evaluation of persons with DS and other intellectual disabilities [6–8]. Data are given as mean ± Standard Deviation (SD) or absolute number and percentage (%) where appropriate. Adjusted (age, sex, BMI and heart rate) means of cognitive performance scores were obtained by the analysis of covariance (ANCOVA) according to the presence of diastolic dysfunction (E/Em ≥8). Given their non-normal
Correspondence
817
distribution, WAIS verbal and performance scores were log-transformed for the ANCOVA. For these variables geometric means calculated from the log-transformed values are presented. A p value b 0.05 was considered significant. Analyses were run using the software for biostatistics SPSS 20.0. Results Within the sample (mean age ± SD 36.1 ± 9.7 years; 75% women), 22 (61%) participants presented with left ventricle diastolic dysfunction (E/Em ≥8). Prevalence of overweight and obesity was high (respectively 33% and 39%; Table 1). Participants' mean scores of Raven's matrices and WAIS scales (verbal and performance) were, respectively, 13.4 ± 5.9, 8.9 ± 3.7 and 9.0 ± 4.2. After adjusting for potential confounders, as shown in Fig. 1, participants with left ventricle diastolic dysfunction showed lower cognitive scores in respect to those with preserved diastolic function: Raven's matrices 11.1 ± 1.1 vs 16.9 ± 1.4 (p = 0.002); WAIS verbal score 6.7 ± 2.3 vs 10.0 ± 1.1 (p = 0.003); WAIS performance score 6.7 ± 2.3 vs 10.1 ± 1.1 (p = 0.007). Discussion The results of the present study show that diastolic dysfunction is prevalent and independently associated to poor cognitive verbal and non-verbal performance in adults with Down syndrome. Six out of ten participants of the present study presented with diastolic dysfunction. Previous studies conducted on trisomy 21 fetuses showed altered trans-valvular Doppler flows across both atrioventricular valves, compatible with impaired diastolic function [9]. Similarly, Al-Biltagi and coll. reported significantly altered left and right ventricle diastolic parameters in children with DS when compared with controls, as evaluated through pulsed Doppler flows and tissue Doppler [10]. Finally, Vis and coll. reported higher rates of mild to moderate diastolic dysfunction in adults with DS when compared with healthy controls (57% vs 33%; p b 0.05) [4]. The association between diastolic dysfunction and cognitive impairment has already been described in general population without DS. In particular, several evidences suggested a higher prevalence of diastolic Table 1 Sample Characteristics. General characteristics
N = 36
Age (years) Sex (F) Body mass index (kg/m2) b25 25–30 N30 Heart rate (beats/min)
36.1 ± 9.7 27 (75)
Cognitive performance Raven's Matrices WAIS verbal score WAIS performance score Echocardiography parameters LA volume index (ml/m2) LV mass index (g/m2) LV volume index (ml/m2) Ejection fraction (%) E/A b1 1–2 N2 DT E wave IVRT E/Em ≥8
10 (28) 12 (33) 14 (39) 62 ± 12
13.4 ± 5.9 8.9 ± 3.7 9.0 ± 4.2
25 ± 6 57 ± 13 52 ± 14 59 ± 5 3 (8) 25 (69) 8 (22) 217 ± 50 79 ± 13 22 (61)
WAIS = Wechsler Adult-Intelligence-Scale; LA = Left Atrium; LV = Left Ventricle; DT = Deceleration Time; IVRT = Iso-Volumetric Relaxation Time.
Fig. 1. Cognitive performance (adjusted means and standard error) by presence of left ventricle diastolic dysfunction. For WAIS Verbal score and Performance score geometric means are presented. Scores adjusted for age, sex, BMI and heart rate.
dysfunction among individuals with AD as compared with controls, when evaluated by both trans-valvular Doppler flows and TDI [11]. At the same time, individuals with heart failure (both with reduced and preserved ejection fraction) have been shown to present higher prevalence of cognitive impairment compared with controls [12,13]. Different factors might explain the association between diastolic dysfunction and poor cognitive status. First, cardiac dysfunction, through brain hypo-perfusion, could contribute to cognitive impairment [14]. However, we evaluated individuals with DS free from known cardiovascular disease in order to exclude its potential contribution to the levels of diastolic dysfunction and cognitive impairment. Second, diastolic dysfunction might share some common pathways with AD, a condition often observed in adults with DS, by modulation of the presenilin gene and Aβ expression [15,16]. In this context, recent
818
Correspondence
evidences show that amyloid deposition, causing cognitive impairment in many neurodegenerative diseases including AD, are involved in the pathogenesis of some of the commonest cardiac diseases (cardiac hypertrophy and dilated and ischemic cardiomyopathies). The ubiquitineproteasome system dysfunction and the proteins misfolding, impair the well-functioning of myocardial syncytium, a phenomenon known as proteotoxicity. In cardiac amyloidosis, deposition of amyloid derived from wild type transthyretin in the myocardium interstitium and intramural coronary vessels is associated with left ventricular wall thickening, diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF). Similarly, in autopsy studies, older adults with HFpEF presented higher transthyretin deposits when compared to those without HF [17]. For several neurodegenerative conditions as Parkinson's disease and Huntington's disease it was reported a systemic deposition of misfolded protein in central nervous system [18,19]. The involvement of a similar mechanism might be hypothesized in DS, contributing to explain our results. Finally, a common and direct pathway linking cardiac and cognitive function in DS might be hypothesized. In this context, Shinohara and coll. produced chimeric mice in order to study the gene dosage effects of an extra copy of human chromosome 21. In this study, a correlation between the levels of retention (percentage) of the extra chromosome 21, in either the brain, heart and other organs and the grade of cognitive impairment and heart abnormalities was reported. Proportionally according to the level of chimerism, ventricles appeared filled with myocardial cells with abnormal trabecular patterns potentially responsible for impaired ventricular function [20]. A relevant limitation of the present study relates to its crosssectional design which does not allow to address specific cause-effect mechanisms. In addition, even if the cognitive assessment relied on previously adopted instruments, our findings need confirmation from future studies using different assessment scales. In conclusion, the increment in life expectancy observed in persons with DS makes it necessary to better understand mechanisms involved in the development of diseases occurring in adult age in this population. In this context, assessment of risk factors and pathological pathways contributing to worsening of cognitive status and development of AD represents a research priority. Our results show an independent association between diastolic dysfunction and poor cognitive performances in adults affected by DS without cardiovascular disease. If confirmed in longitudinal studies these data might contribute to shed light on complex mechanisms leading to increased risk of cognitive impairment and AD in this population. Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
References [1] D. Hartley, T. Blumenthal, M. Carrillo, G. DiPaolo, L. Esralew, K. Gardiner, et al., Down syndrome and Alzheimer's disease: common pathways, common goals, Alzheimers Dement. 11 (6) (2015 Dec 12) 700–709. [2] F. Lai, R.S. Williams, A prospective study of Alzheimer disease in Down syndrome, Arch. Neurol. 46 (8) (1989 Aug) 849–853. [3] M.S. Willis, C. Patterson, Proteotoxicity and cardiac dysfunction – Alzheimer's disease of the heart? N. Engl. J. Med. 368 (5) (2013 Jan 31) 455–464. [4] J.C. Vis, R.H. de Bruin-Bon, B.J. Bouma, A.P. Backx, S.A. Huisman, L. Imschoot, et al., ‘The sedentary heart’: physical inactivity is associated with cardiac atrophy in adults with an intellectual disability, Int. J. Cardiol. 158 (3) (2012 Jul 26) 387–393. [5] A. Carfì, M. Antocicco, V. Brandi, C. Cipriani, F. Fiore, D. Mascia, et al., Characteristics of adults with Down syndrome: prevalence of age-related conditions, Front. Med. (Lausanne) 1 (51) (2014 Dec 3)http://dx.doi.org/10.3389/fmed.2014.00051. [6] P. Breia, R. Mendes, A. Silvestre, M.J. Gonçalves, M.J. Figueira, R. Bispo, Adults with Down syndrome: characterization of a Portuguese sample, Acta Med. Port. 27 (3) (2014 May-Jun) 357–363. [7] G. Bernert, M. Sustrova, E. Sovcikova, R. Seidl, G. Lubec, Effects of a single transdermal nicotine dose on cognitive performance in adults with Down syndrome, J. Neural Transm. Suppl. 61 (2001) 237–245. [8] G. Andreou, C. Galanopoulou, K. Gourgoulianis, A. Karapetsas, P. Molyvdas, Cognitive status in Down syndrome individuals with sleep disordered breathing deficits (SDB), Brain Cogn. 50 (1) (2002 Oct) 145–149. [9] S.A. Clur, K. Oude Rengerink, J. Ottenkamp, C.M. Bilardo, Cardiac function in trisomy 21 fetuses, Ultrasound Obstet. Gynecol. 37 (2) (2011 Feb) 163–171. [10] M. Al-Biltagi, A.R. Serag, M.M. Hefidah, M.M. Mabrouk, Evaluation of cardiac functions with Doppler echocardiography in children with Down syndrome and anatomically normal heart, Cardiol. Young 23 (2) (2013 Apr) 174–180. [11] A.N. Çalık, K.S. Özcan, G. Yüksel, B. Güngör, E. Aruğarslan, F. Varlibas, et al., Altered diastolic function and aortic stiffness in Alzheimer's disease, Clin. Interv. Aging 9 (2014 Jul 16) 1115–1121. [12] M. Belohlavek, P. Jiamsripong, A.M. Calleja, E.M. McMahon, C.L. Maarouf, T.A. Kokjohn, et al., Patients with Alzheimer disease have altered transmitral flow: echocardiographic analysis of the vortex formation time, J. Ultrasound Med. 28 (11) (2009 Nov) 1493–1500. [13] P. Athilingam, R.F. D'Aoust, L. Miller, L. Chen, Cognitive profile in persons with systolic and diastolic heart failure, Congest Heart Fail 19 (1) (2013 Jan-Feb) 44–50. [14] M. Suwa, T. Ito, Correlation between cognitive impairment and left ventricular diastolic dysfunction in patients with cardiovascular diseases, Int. J. Cardiol. 136 (3) (2009 Aug 21) 351–354. [15] C. Qiu, L. Fratiglioni, A major role for cardiovascular burden in age-related cognitive decline, Nat. Rev. Cardiol. 12 (5) (2015 May) 267–277. [16] A. Li, C. Zhou, J. Moore, P. Zhang, T.H. Tsai, H.C. Lee, et al., Changes in the expression of the Alzheimer's disease—associated presenilin gene in drosophila heart leads to cardiac dysfunction, Curr. Alzheimer Res. 8 (3) (2011 May) 313–322. [17] S.F. Mohammed, S.A. Mirzoyev, W.D. Edwards, A. Dogan, D.R. Grogan, S.M. Dunlay, et al., Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction, JACC Heart Fail 2 (2) (2014 Apr) 113–122. [18] G.C. Melkani, A.S. Trujillo, R. Ramos, R. Bodmer, S.I. Bernstein, K. Ocorr, Huntington's disease induced cardiac amyloidosis is reversed by modulating protein folding and oxidative stress pathways in the Drosophila heart, PLoS Genet. 9 (12) (2013), e1004024http://dx.doi.org/10.1371/journal.pgen.1004024. [19] S. Jain, D.S. Goldstein, Cardiovascular dysautonomia in Parkinson disease: from pathophysiology to pathogenesis, Neurobiol. Dis. 46 (3) (2012 Jun) 572–580. [20] T. Shinohara, K. Tomizuka, S. Miyabara, S. Takehara, Y. Kazuki, J. Inoue, et al., Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down's syndrome, Hum. Mol. Genet. 10 (11) (2001 May 15) 1163–1175.