- Email: [email protected]
73 Age-specific relationship between aortic pulse wave velocity and left ventricular geometry and function in hypertension
Abstracts XIXth National Congress, Italian SocieO, f o r the Stu&, o f Athetvscletvsis
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COGNITIVE DYSFUNCTION IN ASYMPTOMATIC PERIPHERAL ARTERIAL DISEASE: IS THERE A ROLE FOR INFLAMMATION AND HYPERCOAG ULABILITY?
R.A. MaJngiafico, F. Sarnataro, M. MaJngiafico, C.E. Fiore. (\linica Medica.
Unic,ersit~'l di (~tmnia. Italy E-mail: [email protected] Asymptomatic peripheral arterial disease (PAD), a highly prevalent condition in the general older population, is associated with an increased risk of cerebrovascular events because of coexisting clinical or subclinical cerebral atherosclerosis. We investigated whether cognitive function is impaired in stroke- and TIA-free PAD patients and whether inflammatory and hemostatic markers axe associated with neuropsychological performance. Cognitive performances of 164 well-functioning, community-dwelling, PAD patients were compared with those of 164 age-, gender- and education-matched healthy control subjects on six neuropsychological tests. Levels of C-reactive protein (CRP), D-dimer, and fibrinogen were also analyzed in all participants. PAD patients scored significantly worse (P < 0.0001) than control subjects on five cognitive tests assessing domains of verbal working memory, attention, perceptuo-motor speed, mental flexibility, visuoconstructive skills, and visual memory. Multiple linear regression analyses showed that CRP and D-dimer were significant, independent predictors of poorer performances on four and three cognitive tests, respectively, within PAD patients. PAD patients show cognitive impairment in a range of psycometric tests, and CRP and D-dimer appear to be independent negative predictors of some cognitive performances. These findings suggest the need for screening for PAD among at-risk subjects in order to identify patients to be treated for prevention of functional decline and dementia. They also support the hypothesis that inflammation and hypercoagulability are implicated in the pathophysiology of cognitive dysfunction associated with PAD.
[•
AGE-SPECIFIC RELATIONSHIP BETWEEN AORTIC PULSE WAVE VELOCITY AND LEFT VENTRICULAR GEOMETRY AND FUNCTION IN HYPERTENSION
M.R. Mannarino, M. Pirro, G. Pucci, G. Savaxese, G. Vaudo, L. Pasqualini, G. Schillaci. Medicina Inte~Tm. Angiologia e Malattie da Arteriosclerosi.
Unic,ersit~'l di Perugia. Italy E-mail: [email protected] Aortic pulse wave velocity (PWV), traditionally considered a marker of arterial stiffness, has been associated to reduced left ventricular (LV) ejection time in young people. We hypothesized that the relationship between aortic PWV and LV geometry and function might be age-dependent. To esplore this hypothesis, 231 uncomplicated patients with never-treated essential hypertension over a wide age range (18 88 years) underwent aortic pulse wave velocity (PWV) determination with the SphygmoCor system, and echocardiography, from which the mean velocity of circumferential fiber shortening (VCF) was calculated as a measure of the velocity of myocardial shortening, and relative wall thickness (RWT) was taken as a measure of LV concentric remodeling. Patients were divided in 3 age groups (<40 years, 40 59 years, ~>60 years). In the young, aortic PWV was directly associated to VCF (r +0.34, p 0.013), but not to RWT (r +0.01, p n.s.). The opposite was found in the older group, in which increasing aortic PWV was accompanied by a concentric LV geometric pattern (r +0.39 with RWT, p 0.028), and a reduced VCF (r 0.402, p 0.034). Intermediate values were found in the middle-aged group (r +0.23, p < 0.01 with RWT, r +0.05, p n.s. with VCF). In conclusion, the relation between aortic PVW and the lel~ ventricle is strongly age-dependent. These data suggest that in young people aortic PWV is partly determined by an increased velocity of myocardial shortening. With increasing age, a relationship between aortic PWV (as a measure of arterial stiffness) and LV concentric geometry emerges, which ultimately leads to a depressed LV systolic function.
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N
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NON SENSE MUTATION IN ABCG5 GENE CAUSING I~-SITOSTEROLEMIA
L. Mannucci 1 , R Bertucci 1 , O. Guardamagn a2 , R Indigeno 1 , L. Liberatoscioli1 , L. Pisciotta3, S. Bertolini3, G. Federici 1 , C. Cortese 1 . 1Department of Inte~Tzal
Medicine Unic,ersitv of Rome "Tor ~'brgata"; 2Department of Pediatrics Unic,ersiO~ of Turin; 3Department of Inte~vtal Medicine Unic,ersiO~ of Genoa. [taO~ E-mail: [email protected] 15-sitosterolemia is an autosomal recessive disorder characterised by elevated plasma levels of plant sterols and cholesterol due to increased intestinal sterol absorption and reduced biliary excretion. 15-sitosterolemic patients axe frequently hypercholesterolemic and can develop tendon xanthomas, atherosclerosis and premature coronary heart disease. Sitosterolemia is caused by gene mutations in either of two ATP-binding cassette half transporters, ABCG5
S17
and ABCGS. We describe a novel nonsense mutation which was found in exon 10 of ABCG5 by genomic DNA sequencing on blood samples from a 10-year-old girl from Iran showing clinical and biochemical features of Sitosterolemia, including xanthomas of the knees and the Achilles tendon, circulating IJ-sitosterol level of 380 ~tmol/L (90th% up to 10 ~tmol/L) as measured through Gas Chromatography/Mass Spectrometry and a serum total cholesterol of 379mg/dl. The mutation was due to a C to T transition at nucleotide 1336 on both alleles of the ABCG5 gene resulting in a premature stop codon at residue 446 (R446Stop). The patient has been treated with Ezetimibe 5 mg/d and then 10mg/d. The IJ-sitosterol and serum total cholesterol were reduced, at the two different dosages, by 15% and 42% and by 37% and 52% respectively. We have described a novel mutation causing I%sitosterolemia. Ezetimibe, the new potent inhibitor of cholesterol absorption, appears to be the ideal choice for the reduction of circulating I~-sitosterol and cholesterol which axe both often elevated in this condition.
OF PENTRAXIN 3 EXPRESSION r•'] MODULATION ENDOTHELIAL CELLS: ROLE OF HDL
IN
E Marchesi 1 , G.D. Norata 2, A. Mantovani 3, M. Fazia4, E Cipollone4, A. Mezzetti4, G. Chiesa 1 , A i . Catapano 2. 1Dipartimento di Scienze
Fa~vzacologiche. Unic,ersit~'l degli Stluti di Milano. Italy; 2Uentro SISA per lo Studio dell'Aterosclerosi. Ospedale Bassini. (Tnisello Balsamo. ItaO~; 3[stituto di Ricerche Fa~vtacologiche Mario Negri. Mihmo. [taO~; d Unic,ersit~'l G. D 'Annunzio. (;~ieti. [taO~ E-maih patmarch78 @tiscali.it Introduction: Pentraxin 3 (PTX3), the prototype member of the long pentraxin family, is a protein of the acute phase, that is induced by inflammatory stimuli in macrophages, endothelial cells and smooth muscle cells. Furthermore its expression was observed in atherosclerotic plaques. The role of PTX3 during atherogenesis, however, is still ill defined. Aim of our study was to investigate the modulation of PTX3 expression in atherogenesis. Results: Incubation with HDL (200 mg/mL) increased PTX3 expression in human umbilical vein endothelial cells (2.79-fold vs control cells). The PI3k/Akt and PKC intracellular signaling pathways were mainly responsible for the effect observed. In vivo the expression of PTX3 was increased in mice overexpressing human Apo AI compared to Apo AI / mice. The expression of PTX3 is also significantly higher in carotid plaques from asymptomatic patients (5.63 fold), compared to plaques from symptomatic patients. Finally a significantly inverse correlation between PTX3 plasma level and the intima-media thickness was observed in a cohort of 100 subjects randomly selected from the PLIC study. Conclusion: We demonstrate for the first time that PTX3, unlike other protein of the acute phase, may play an important atheroprotective role in the development and progression of atherosclerosis. We are currently developing double KO mice (ApoE / , PTX3 / ) to address this issue.
F-~] THE HUMAN AORTA ENDOTHELIOPATHY: ULTRASTRUCTURAL STUDY IN PATIENTS TREATED WITH BPAC G. Martines 1 , L. Stellin1 , C. Zuch 1 , G.R Esposito 1 , M. Scorsin 1 , R Boldrini 2, M.R. Bovolenta2, A. Aleotti2. 1Department of Medical Therapy. Unic,ersitv
"G. d'Annunzio ". (;~ieti-Pescara; 2Department of (~trdioc,ascular Surge~,. "Uitt~'l di Lecce" Hospital "~'TllaMaria" Group. Italy E-maih [email protected] The ultrastructural research has emphasized the physiopathology of experimental and human atherogenesis. The ultrastructural study has been carried out on human aorta intraoperatory biopsies of patients subjected to triple bypass.The endotheliopathy initially shows a thin endothelial lamina delimited by a layer of macrophages drawing also residual parietal cells and burst out in the lumen. We have often observed activate platelects trapped in the beneath endothelial area. In the following phase the endothelial space results enlarged and contains plasmatic material; macrophages and endothelial lamina stand reciprocally attempting to restore continuity. In the further phase we can observe the detaching-rupture of the endothelial cytoplasmus from their anchorage, it remarks numerous platelets. The platelets, cellular material and macrophagic residual migration towards the lesion in the initial stage of microthrombosis. This thrombogenetic phase shows the precariousness of the endothelial wall which promptly responds with a metabolic code of defence. The results of this study point out the infinite morpho-functional and morpho-structural variations of the endotheliopathy, explain the molecular biology data and confirm that the compensation mechanisms (fluidity, emoreology, etc.) permit long survival also in patients with dramatically injured aorta.
[•
COGNITIVE DYSFUNCTION IN ASYMPTOMATIC PERIPHERAL ARTERIAL DISEASE: IS THERE A ROLE FOR INFLAMMATION AND HYPERCOAG ULABILITY?
R.A. MaJngiafico, F. Sarnataro, M. MaJngiafico, C.E. Fiore. (\linica Medica.
Unic,ersit~'l di (~tmnia. Italy E-mail: [email protected] Asymptomatic peripheral arterial disease (PAD), a highly prevalent condition in the general older population, is associated with an increased risk of cerebrovascular events because of coexisting clinical or subclinical cerebral atherosclerosis. We investigated whether cognitive function is impaired in stroke- and TIA-free PAD patients and whether inflammatory and hemostatic markers axe associated with neuropsychological performance. Cognitive performances of 164 well-functioning, community-dwelling, PAD patients were compared with those of 164 age-, gender- and education-matched healthy control subjects on six neuropsychological tests. Levels of C-reactive protein (CRP), D-dimer, and fibrinogen were also analyzed in all participants. PAD patients scored significantly worse (P < 0.0001) than control subjects on five cognitive tests assessing domains of verbal working memory, attention, perceptuo-motor speed, mental flexibility, visuoconstructive skills, and visual memory. Multiple linear regression analyses showed that CRP and D-dimer were significant, independent predictors of poorer performances on four and three cognitive tests, respectively, within PAD patients. PAD patients show cognitive impairment in a range of psycometric tests, and CRP and D-dimer appear to be independent negative predictors of some cognitive performances. These findings suggest the need for screening for PAD among at-risk subjects in order to identify patients to be treated for prevention of functional decline and dementia. They also support the hypothesis that inflammation and hypercoagulability are implicated in the pathophysiology of cognitive dysfunction associated with PAD.
[•
AGE-SPECIFIC RELATIONSHIP BETWEEN AORTIC PULSE WAVE VELOCITY AND LEFT VENTRICULAR GEOMETRY AND FUNCTION IN HYPERTENSION
M.R. Mannarino, M. Pirro, G. Pucci, G. Savaxese, G. Vaudo, L. Pasqualini, G. Schillaci. Medicina Inte~Tm. Angiologia e Malattie da Arteriosclerosi.
Unic,ersit~'l di Perugia. Italy E-mail: [email protected] Aortic pulse wave velocity (PWV), traditionally considered a marker of arterial stiffness, has been associated to reduced left ventricular (LV) ejection time in young people. We hypothesized that the relationship between aortic PWV and LV geometry and function might be age-dependent. To esplore this hypothesis, 231 uncomplicated patients with never-treated essential hypertension over a wide age range (18 88 years) underwent aortic pulse wave velocity (PWV) determination with the SphygmoCor system, and echocardiography, from which the mean velocity of circumferential fiber shortening (VCF) was calculated as a measure of the velocity of myocardial shortening, and relative wall thickness (RWT) was taken as a measure of LV concentric remodeling. Patients were divided in 3 age groups (<40 years, 40 59 years, ~>60 years). In the young, aortic PWV was directly associated to VCF (r +0.34, p 0.013), but not to RWT (r +0.01, p n.s.). The opposite was found in the older group, in which increasing aortic PWV was accompanied by a concentric LV geometric pattern (r +0.39 with RWT, p 0.028), and a reduced VCF (r 0.402, p 0.034). Intermediate values were found in the middle-aged group (r +0.23, p < 0.01 with RWT, r +0.05, p n.s. with VCF). In conclusion, the relation between aortic PVW and the lel~ ventricle is strongly age-dependent. These data suggest that in young people aortic PWV is partly determined by an increased velocity of myocardial shortening. With increasing age, a relationship between aortic PWV (as a measure of arterial stiffness) and LV concentric geometry emerges, which ultimately leads to a depressed LV systolic function.
[
•
N
E
W
NON SENSE MUTATION IN ABCG5 GENE CAUSING I~-SITOSTEROLEMIA
L. Mannucci 1 , R Bertucci 1 , O. Guardamagn a2 , R Indigeno 1 , L. Liberatoscioli1 , L. Pisciotta3, S. Bertolini3, G. Federici 1 , C. Cortese 1 . 1Department of Inte~Tzal
Medicine Unic,ersitv of Rome "Tor ~'brgata"; 2Department of Pediatrics Unic,ersiO~ of Turin; 3Department of Inte~vtal Medicine Unic,ersiO~ of Genoa. [taO~ E-mail: [email protected] 15-sitosterolemia is an autosomal recessive disorder characterised by elevated plasma levels of plant sterols and cholesterol due to increased intestinal sterol absorption and reduced biliary excretion. 15-sitosterolemic patients axe frequently hypercholesterolemic and can develop tendon xanthomas, atherosclerosis and premature coronary heart disease. Sitosterolemia is caused by gene mutations in either of two ATP-binding cassette half transporters, ABCG5
S17
and ABCGS. We describe a novel nonsense mutation which was found in exon 10 of ABCG5 by genomic DNA sequencing on blood samples from a 10-year-old girl from Iran showing clinical and biochemical features of Sitosterolemia, including xanthomas of the knees and the Achilles tendon, circulating IJ-sitosterol level of 380 ~tmol/L (90th% up to 10 ~tmol/L) as measured through Gas Chromatography/Mass Spectrometry and a serum total cholesterol of 379mg/dl. The mutation was due to a C to T transition at nucleotide 1336 on both alleles of the ABCG5 gene resulting in a premature stop codon at residue 446 (R446Stop). The patient has been treated with Ezetimibe 5 mg/d and then 10mg/d. The IJ-sitosterol and serum total cholesterol were reduced, at the two different dosages, by 15% and 42% and by 37% and 52% respectively. We have described a novel mutation causing I%sitosterolemia. Ezetimibe, the new potent inhibitor of cholesterol absorption, appears to be the ideal choice for the reduction of circulating I~-sitosterol and cholesterol which axe both often elevated in this condition.
OF PENTRAXIN 3 EXPRESSION r•'] MODULATION ENDOTHELIAL CELLS: ROLE OF HDL
IN
E Marchesi 1 , G.D. Norata 2, A. Mantovani 3, M. Fazia4, E Cipollone4, A. Mezzetti4, G. Chiesa 1 , A i . Catapano 2. 1Dipartimento di Scienze
Fa~vzacologiche. Unic,ersit~'l degli Stluti di Milano. Italy; 2Uentro SISA per lo Studio dell'Aterosclerosi. Ospedale Bassini. (Tnisello Balsamo. ItaO~; 3[stituto di Ricerche Fa~vtacologiche Mario Negri. Mihmo. [taO~; d Unic,ersit~'l G. D 'Annunzio. (;~ieti. [taO~ E-maih patmarch78 @tiscali.it Introduction: Pentraxin 3 (PTX3), the prototype member of the long pentraxin family, is a protein of the acute phase, that is induced by inflammatory stimuli in macrophages, endothelial cells and smooth muscle cells. Furthermore its expression was observed in atherosclerotic plaques. The role of PTX3 during atherogenesis, however, is still ill defined. Aim of our study was to investigate the modulation of PTX3 expression in atherogenesis. Results: Incubation with HDL (200 mg/mL) increased PTX3 expression in human umbilical vein endothelial cells (2.79-fold vs control cells). The PI3k/Akt and PKC intracellular signaling pathways were mainly responsible for the effect observed. In vivo the expression of PTX3 was increased in mice overexpressing human Apo AI compared to Apo AI / mice. The expression of PTX3 is also significantly higher in carotid plaques from asymptomatic patients (5.63 fold), compared to plaques from symptomatic patients. Finally a significantly inverse correlation between PTX3 plasma level and the intima-media thickness was observed in a cohort of 100 subjects randomly selected from the PLIC study. Conclusion: We demonstrate for the first time that PTX3, unlike other protein of the acute phase, may play an important atheroprotective role in the development and progression of atherosclerosis. We are currently developing double KO mice (ApoE / , PTX3 / ) to address this issue.
F-~] THE HUMAN AORTA ENDOTHELIOPATHY: ULTRASTRUCTURAL STUDY IN PATIENTS TREATED WITH BPAC G. Martines 1 , L. Stellin1 , C. Zuch 1 , G.R Esposito 1 , M. Scorsin 1 , R Boldrini 2, M.R. Bovolenta2, A. Aleotti2. 1Department of Medical Therapy. Unic,ersitv
"G. d'Annunzio ". (;~ieti-Pescara; 2Department of (~trdioc,ascular Surge~,. "Uitt~'l di Lecce" Hospital "~'TllaMaria" Group. Italy E-maih [email protected] The ultrastructural research has emphasized the physiopathology of experimental and human atherogenesis. The ultrastructural study has been carried out on human aorta intraoperatory biopsies of patients subjected to triple bypass.The endotheliopathy initially shows a thin endothelial lamina delimited by a layer of macrophages drawing also residual parietal cells and burst out in the lumen. We have often observed activate platelects trapped in the beneath endothelial area. In the following phase the endothelial space results enlarged and contains plasmatic material; macrophages and endothelial lamina stand reciprocally attempting to restore continuity. In the further phase we can observe the detaching-rupture of the endothelial cytoplasmus from their anchorage, it remarks numerous platelets. The platelets, cellular material and macrophagic residual migration towards the lesion in the initial stage of microthrombosis. This thrombogenetic phase shows the precariousness of the endothelial wall which promptly responds with a metabolic code of defence. The results of this study point out the infinite morpho-functional and morpho-structural variations of the endotheliopathy, explain the molecular biology data and confirm that the compensation mechanisms (fluidity, emoreology, etc.) permit long survival also in patients with dramatically injured aorta.