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T2238C ANP gene variant and risk of recurrent myocardial infarction in a cohort of Italian patients with ischemic heart disease. A retrospective study.

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Presentation on theme: "T2238C ANP gene variant and risk of recurrent myocardial infarction in a cohort of Italian patients with ischemic heart disease. A retrospective study."— Presentation transcript:

1 T2238C ANP gene variant and risk of recurrent myocardial infarction in a cohort of Italian patients with ischemic heart disease. A retrospective study. S. Rubattu, M. De Giusti, A. Farcomeni, S. Sciarretta, S. Abbolito, F. Comito, S. Cangianiello, E. Greco Squillace, E. Dito, B. Pagliaro, M. Cotugno, S. Marchitti, F. Bianchi, S. Di Castro, R. Stanzione, A. Battistoni, S. Burocchi, M. Caprinozzi, M. Volpe Capri Cardiovascular Conference 2.0 28/29 Marzo 2014

2 Background (1) Atrial natriuretic peptide (ANP) is a cardiac hormone that exerts vasodilator, natriuretic and diuretic properties ANP is encoded by NPPA gene (Natriuretic Peptide Precursor A), located within MTHFR gene locus-NPPB on chromosome 1p36, and it is synthesized as pre-ProANP 1-152. The carboxy terminal end, α- ANP1-28, and the NT-pro ANP (1-126) are cleaved by corin. ANP binds both NPR-A and NPR-C receptors. NPR-A is linked to guanylate cyclase which increases, when activated, intracellular cGMP levels, with consequent activation of protein kinase G (PKG) and phosphodiesterase (PDE). The NPR-C receptor, when activated, inhibits adenylate cyclase and decreases intracellular cAMP levels.

3 Volpe M, Rubattu S, Burnett J Jr. Eur Heart J. 2013 Nov 13. [Epub ahead of print]

4 Aim of the study Previous studies have shown that T2238C allelic variant of the NPPA gene, with the C minor allele frequency ranging from 13-23% in the general population, increases, regardless of the presence of other risk factors, the incidence of a first event of stroke and of acute myocardial infarction. More recent studies have also shown that C2238 minor allele carrier status exerts a negative prognostic role on cardiovascular outcome in patients affected by stable angina, regardless of treatment and of traditional risk factors. In vitro studies have shown the ability of C2238 minor allele to induce endothelial damage. Ex vivo studies have documented the negative impact of C2238 minor allele on endothelial function. In vitro studies have shown the ability of C2238 minor allele to induce endothelial damage. Ex vivo studies have documented the negative impact of C2238 minor allele on endothelial function. The aim of our study was to verify whether presence of C2238/ANP variant allele may increase the risk of acute coronary syndromes recurrence, regardless of treatment, of conventional risk factors and of coronary artery disease severity in patients who already had an acute coronary event.

5 Methods Monocentric retrospective study 379 patients, referred to our center for acute coronary syndrome (first event or recurrence) in the period between March 2001 and December 2012, were retrospectively recruited for this study. Each patient underwent coronary angiography during hospitalization. Genetic screening for the T2238C allele status was performed, after informed consent, in each patient. Out of 379 subjects, 345 were subsequently followed at our center (at least 1 visit for year), whereas clinical documentation of the follow-up for the remaining 34 patients was provided by the patient. The mean follow-up was 5.10 years ± 3:51. The data collected covered demographic characteristics, presence/ absence of traditional risk factors and of metabolic syndrome, history of critical coronary disease, past and current drug therapy, echocardiographic parameters (EF), type of revascularization.

6 Main clinical characteristics of the study cohort at the time of the first ACS T2238C allele carriers n (%) Gender n (%) Smoke n (%) Hyperten sion n (%) Diabetes mellitus n (%) Dyslipide mia n (%) Mean age at enrollmen t (yrs) STEMI, NSTEMI, UA n (%) Metabolic Syndrome n (%) Carriers: 103 (27,2%) Wild- Type: 276 (72,8%) Men: 305 (80,5%) Women: 74 (19,5%) Never: 112 (29,6%) Yes: 71 (18,7%) Former: 196 (51,7%) Yes: 279 (73,6%) No: 100 (26,4%) Yes: 114 (30,1%) No: 265 (69,9%) Yes: 237 (62,5%) No: 142 (37,5%) 62,54 ± 9,2 STEMI: 176 (46,4%) NSTEMI: 73 (19,2%) UA: 127 (33,5%) Yes: 23 (6,1%) No: 341 (90%) Missing: 15 (3,9%)

7 Results Univariate analysis PredictorHR (95% C.I.)P-value T2238C1,321 (1,000 – 1,730)0,035 Gender1,066 (0,771 – 1,474)0,699 Diabetes mellitus1,122 (0,879 – 1,432)0,355 Dyslipidemia1,240 (0,956 – 1,607)0,105 Hypertension0,818 (0,620 – 1,079)0,155 Metabolic Syndrome0,927 (0,550 – 1,562)0,775 Beta-Blocker Therapy0,711 (0,551 – 0,918)0,009 Anti-Aldosteronic Therapy0,766 (0,361 – 1,624)0,487 Thiazides Therapy0,600 (0,336 – 1,072)0,085 Acetylsalicylic Acid Therapy0,711 (0,553 – 0,915)0,008 Nitrates Therapy1,233 (0,949 – 1,602)0,116 Calcium Antagonists Therapy1,006 (0,732 – 1,384)0,969 ACE-inhibitors Therapy0,881 (0,672 – 1,156)0,362 ARBs Therapy0,813 (0,577 – 1,145)0,235 Statin Therapy0,726 (0,562 – 0,938)0,014

8 Results Multivariate analysis Results Multivariate analysis PredictorHR (95% C.I.)P-value T2238C1,321 (1,010 – 1,730)0,042 Dyslipidemia1,471 (1,104 – 1,959)< 0,001 Beta-Blocker Therapy0,691 (0,519 – 0,920)0,011 Acetylsalicylic Acid Therapy 0,798 (0,614 – 1,037)0,091 Statin Therapy0,619 (0,453 – 0,847)0,002

9 Results Cox regression and Kaplan Meyer analyses Results Cox regression and Kaplan Meyer analyses p = 0,035

10 Conclusions Our study demonstrates that carrier status of C2238/ANP allelic variant of the NPPA gene exerts a negative prognostic role for recurrence of acute coronary syndromes in patients who already had a first acute coronary event, regardless of anthropometric characteristics, type of revascularization and of drug therapy. Our data support the need to include, in the future, the characterization of this variant in clinical practice, with particular regard to patients with coronary artery disease and/or cardiovascular risk factors, in order to improve the prognostic classification of these subjects and to improve their clinical and therapeutic management. Our study demonstrates that carrier status of C2238/ANP allelic variant of the NPPA gene exerts a negative prognostic role for recurrence of acute coronary syndromes in patients who already had a first acute coronary event, regardless of anthropometric characteristics, type of revascularization and of drug therapy. Our data support the need to include, in the future, the characterization of this variant in clinical practice, with particular regard to patients with coronary artery disease and/or cardiovascular risk factors, in order to improve the prognostic classification of these subjects and to improve their clinical and therapeutic management.


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