Οκνθπζηεϊλαηκία: έρεη θιηληθή αμία;

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1 Οκνθπζηεϊλαηκία: έρεη θιηληθή αμία; Νηθόιανο Γ. Παηζνπξάθνο Καξδηνιόγνο Εληαηηθνιόγνο Επηκειεηήο Καξδηνινγηθνύ Σκήκαηνο Τπεύζπλνο Μνλάδαο Εκθξαγκάηωλ Σδάλεην Γεληθό Ννζνθνκείν Πεηξαηά

2 EΠΙΚΟΤΡΙΚΟΙ ΠΑΡΑΓΟΝΣΕ ΚΑΡΔΙΑΓΓΕΙΑΚΟΤ ΚΙΝΔΤΝΟΤ Πόζν ηνπο ρξεηαδόκαζηε; Τν 50% ησλ εκθξαγκάησλ κπνθαξδίνπ αλαπηύζζνληαη ζε άηνκα πνπ δελ έρνπλ δπζιηπηδαηκία Τν 20% ησλ θαξδηαγγεηαθώλ ζπκβακάησλ επηζπκβαίλεη ζε άηνκα πνπ δελ έρνπλ ηνπο θιαζηθνύο παξάγνληεο θηλδύλνπ (δπζιηπηδαηκία, ππέξηαζε, θάπληζκα, ζαθραξώδε δηαβήηε) Hackam DG et all JAMA Aug 20;290(7): Review. Khot UN, et all JAMA Aug 20;290(7):

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4 Αζζελήο 54 εηώλ, κε ειεύζεξν θαξδηνινγηθό θαη νηθνγελεηαθό ηζηνξηθό, πξνζέξρεηαη ζην ΤΕΠ ιόγσ δηάρπηνπ πξνθάξδηνπ άιγνπο κε πθέζεηο θαη εμάξζεηο από 15 min 11 ιεπηά κεηά.

5 ηεθαληνγξαθία-αγγεηνπιαζηηθή

6 Η θιεγκνλή παίδεη έλα ζεκαληηθό ξόιν ζηελ εμέιημε ηεο αζεξνζθιήξπλζεο θαη ηωλ επηπινθώλ ηεο. Braunwald s HD 2012

7 . Γηα λα είλαη ρξήζηκνη νη επηθνπξηθνί παξάγνληεο θηλδύλνπ; Να κπνξνύλ λα πξνβιέπνπλ κειινληηθά θαξδηαθά ζπκβάκαηα Να πξνζθέξνπλ πξόζζεηε πξνγλσζηηθή αμία ζηνπο γλσζηνύο παξάγνληεο θηλδύλνπ θαη ζηα κνληέιια πνπ ζηεξίδνληαη ζε απηνύο Να είλαη αμηόπηζηε, αλαπαξαγώγηκε θαη θηελή ε κέζνδνο πξνζδηνξηζκνύ ηνπο Consensus panel,davidson et all,mh Am J Cardiol Jun 16;101(12A):51F-57F. Review

8 Η ρξεζηκόηεηά ηνπο θπξίωο απεπζύλεηαη ζηελ αλεύξεζε ηωλ αζζελώλ απηώλ πνπ βξίζθνληαη ζε κεγαιύηεξν θίλδπλν αζεξνζθιήξπλζεο. Consensus panel,davidson et all,mh Am J Cardiol Jun 16;101(12A):51F-57F. Review

9 Υπεξνκνθπζηετλαηκία Έρεη ζπζρεηηζηεί βηβιηνγξαθηθά: κε πςειό θίλδπλν θαξδηαγγεηαθήο λόζνπ, αγγεηαθνύ εγθεθαιηθνύ επεηζνδίνπ θιεβηθήο ζξόκβσζεο άλνηαο ζπκπεξηιακβαλνκέλεο θαη ηεο λόζνπ Alzheimer. Καηά πόζν όκσο απηή ε ζπζρέηηζε έρεη θιηληθή ζεκαζία είλαη έλα ζέκα πνπ απαζρνιεί ηελ επηζηεκνληθή θνηλόηεηα ηα ηειεπηαία 40 ρξόληα

10 H Oμοκυςτεΐνθ είναι ζνα αμινοξφ που παράγεται ωσ ενδιάμεςο προϊόν κατά τον μεταβολιςμό ενόσ άλλου αμινοξζοσ τθσ μεκειονίνθσ.

11 Η κέηξεζε ηεο νκνθπζηεΐλεο γίλεηαη κε εμέηαζε αίκαηνο θαη ηα θπζηνινγηθά ηεο επίπεδα είλαη 5-15κmol/L κmol/L ήπηα ππεξνκνθπζηετλαηκία Τηκέο κεηαμύ, κmol/l σο κέηξηα ελώ ηηκέο άλσ ησλ 100κmol/L σο ζνβαξή

12 Παράγοντεσ που ρυκμίηουν τθν ολικι ομοκυςτεϊνθ ςτον οργανιςμό

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14 Homocysteine and Nutrition: The Vitamin Connection It is estimated that in about two-thirds of cases of hyperhomocysteinemia, vitamin deficiency is the primary cause. Selhub J, Jacques PF, et.al. Vitamin Status and intake as primary determinants of HCYemia in an elderly population. JAMA 1993; 270:

15 Epidemiology Prevalence of hyperhomocysteinemia is not insignificant: 1. general population: 5-10% 2. elderly population: 30-40% 3. pts with vascular disease: 20-40%. Annu Rev Med 1998;49: HCY and cardiovascular disease. Refsum H, Ueland PM, et.al. JAMA 1993;270: Vitamin status and intake as primary determinants of HCYemia in an elderly population. Selhub J, Jacques PF, et.al. Jacques PF, Bostom AG, Wilson PW, et.al. Determinants of plasma total HCY concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73:

16 Oκνθπζηεΐλε θαη ζηεθαληαία λόζνο

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18 Kαηά ηνλ κεηαβνιηζκό ηεο ηα πξντόληα ηεο νμείδσζήο ηεο ζπλδένληαη κε ηηο LDL ιηπνπξσηετλεο ε πξόζιεςε ησλ νπνίσλ από ηα καθξνθάγα ζρεκαηίδνπλ αθξώδε θύηηαξα πνπ πξνζβάιινπλ ην ελδνζήιην

19 Η νκνθπζηεΐλε σο ακθηιεγόκελνο δείθηεο θαξδηαγγεηαθνύ θηλδύλνπ εκθαλίδεηαη από ην 1969 όηαλ ζε αζζελείο πνπ απεβίσζαλ από θαξδηαγγεηαθή λόζν αληρλεύηεθαλ πςειέο πνζόηεηεο ηεο.

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21 Υπάξρνπλ κειέηεο ζε αζζελείο κε ζηεθαληαία λόζν ή ηζηνξηθό εγθεθαιηθνύ πνπ έδεημαλ όηη απηνί πνπ είραλ θαηά 25% ρακειόηεξε νκνθπζηεΐλε δηέηξεραλ ρακειό θίλδπλν λα εθδειώζνπλ λέν θαξδηαθό επεηζόδην. Booth, G. CMAJ July; 163(1):

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23 SEARCH: 2 separate randomised treatment comparisons in 12,064 post-mi patients Homocysteine-lowering comparison Folic acid 2mg + Vitamin B 12 1mg daily vs Placebo Mean (SD) duration: 6.7 (1.5) years

24 SEARCH: Reduction in HOMOCYSTEINE with allocation to FOLATE/B 12 versus placebo Mean (SD) baseline: 13.5 (5) µmol/l Reduction µmol/l percent Month % Year % Year % AVERAGE %

25 Event SEARCH: FOLATE/B 12 on MAJOR VASCULAR EVENTS Folate allocation Risk ratio & 95% CI Active Placebo Active better Placebo better (n=6033) (n=6031) Non-fatal MI 431 (7.1%) 429 (7.1%) Coronary revascularisation 590 (9.8%) 591 (9.8%) CHD death 463 (7.7%) 422 (7.0%) Major coronary events 1229 (20.4%) 1185 (19.6%) 4.7% SE 4.2 increase Fatal stroke 59 (1.0%) 65 (1.1%) Non-fatal stroke 218 (3.6%) 222 (3.7%) Total stroke 269 (4.5%) 265 (4.4%) 1.8% SE 8.7 increase Non-coronary revascularisation 178 (3.0%) 153 (2.5%) 16.9% SE 11.9 increase MAJOR VASCULAR EVENTS 1537 (25.5%) 1493 (24.8%) 4.0% SE 3.7 increase

26 SEARCH: FOLATE/B 12 on MAJOR VASCULAR EVENTS by year of follow-up Year of follow-up Folate allocation Risk ratio & 95% CI Active Placebo Active better Placebo better /6033 (4.4%) 228 /6031 (3.8%) /5751 (3.8%) 236 /5783 (4.1%) /5483 (4.2%) 197 /5511 (3.6%) /5202 (3.7%) 194 /5257 (3.7%) /4958 (4.5%) 192 /5010 (3.8%) /4680 (4.1%) 209 /4749 (4.4%) /4400 (4.9%) 237 /4467 (5.3%) /5751 (22.1%) 1265 /5783(21.9%) 1.8% SE 4.0 increase ALL FOLLOW-UP 1537 /6033 (25.5%) 1493 /6031(24.8%) 4.0% SE 3.7 increase

27 SEARCH: FOLATE/B 12 on MAJOR VASCULAR EVENTS by baseline HOMOCYSTEINE Homocysteine (µmol/l) Folate allocation Risk ratio & 95% CI Active Placebo Active better Placebo better < /1735 (20.9%) 377 /1736 (21.7%) 11 < /2255 (25.0%) 521 /2315 (22.5%) /2043 (29.9%) 595 /1980 (30.1%) ALL PATIENTS 1537 /6033 (25.5%) 1493 /6031 (24.8%) 4.0% SE 3.7 increase

28 SEARCH: Effects of Folate/B 12 on Mortality Cause of death Folate allocation Risk ratio & 95% CI Active Placebo Active better Placebo better (n=6033) (n=6031) CHD 463 (7.7%) 422 (7.0%) Stroke 59 (1.0%) 65 (1.1%) Other vascular 51 (0.8%) 58 (1.0%) All vascular 573 (9.5%) 545 (9.0%) 5.5% SE 6.1 increase Neoplastic 260 (4.3%) 251 (4.2%) Respiratory 67 (1.1%) 65 (1.1%) Other medical 67 (1.1%) 78 (1.3%) Non-medical 16 (0.3%) 11 (0.2%) All non-vascular 410 (6.8%) 405 (6.7%) 1.6% SE 7.0 increase All causes 983 (16.3%) 950 (15.8%) 3.8% SE 4.6 increase

29 Summary of SEARCH findings in context of meta-analyses of previous trials Lowering homocysteine with folic acid supplementation is safe, but does not reduce the risk of vascular events

30 Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on individuals. Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. METHODS: In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46 969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring nonmelanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancer incidence rate ratio (RR). FINDINGS: During a weighted average scheduled treatment duration of 5 2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57 3 nmol/l for the folic acid groups vs 13 5 nmol/l for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1 06, 95% CI , p=0 10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0 23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0 13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. INTERPRETATION: Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials Vollset, Clarke for the B-Vitamin Treatmennt Trialists Collaboration The Lancet 2013 Jan 24. pii: S (12) /S (12)

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32 BVTT meta-analysis: Effects of FOLATE on MAJOR VASCULAR EVENTS by trial Trial Events (%) Treatment Control (n=11,658) (n=11,707) Risk ratio (CI) (n=17,691) (n=17,691) CHAOS (11.8) 95 (10.1) 1.21 ( ) WENBIT 327 (21.2) 313 (20.2) 1.06 ( ) VISP 300 (16.4) 300 (16.2) 1.01 ( ) NORVIT 978 (52.2) 1011 (53.9) 0.96 ( ) WAFACS 376 (13.8) 366 (13.5) 1.02 ( ) HOPE (28.7) 796 (28.8) 1.01 ( ) SEARCH 1537 (25.5) 1493 (24.8) 1.04 ( ) Total 4419 (25.0) 4374 (24.7) 1.02 ( ) 99% CI 95% CI 0.5 Treatment 1.0 Control 2.0 better better

33 Effects of BVTT of B-vitamins on coronary events, in published trials Figure 1: Effects BVTT of B-vitamins on coronary events, in published trials Events (%) Treatment Control (n=17,783) (n=17,820) RR (CI) HOST 129(12.5) 150(14.6) 0.92 ( ) WENBIT 135 (8.8) 113 (7.3) 1.22 ( ) VISP 114 (6.2) 123 (6.6) 0.91 ( ) NORVIT 329(17.6) 314(16.7) 1.05 ( ) WAFACS 283(10.4) 280(10.3) 1.01 ( ) HOPE-2 341(12.4) 349(12.6) 0.97 ( ) SEARCH 1229(20.4) 1185(19.6) 1.05 ( ) ALL 2560(14.4) 2514(14.1) 1.01 ( ) 2 Heterogeneity: ; p=0.4 99% CI 95% CI 0.5 Treatment 1.0 Control 2.0 better better

34 Effects of BVTT of B-vitamins on stroke events, in published trials Figure 2: Effects BVTT of B-vitamins on stroke events, in published trials Events (%) Treatment Control (n=17,783) (n=17,820) RR (CI) HOST 37 (3.6) 41 (4.0) 0.95 ( ) WENBIT 28 (1.8) 39 (2.5) 0.72 ( ) VISP 152 (8.3) 148 (8.0) 1.07 ( ) NORVIT 49 (2.6) 49 (2.6) 1.00 ( ) WAFACS 79 (2.9) 69 (2.5) 1.15 ( ) HOPE (4.0) 147 (5.3) 0.67 ( ) SEARCH 269 (4.5) 265 (4.4) 1.01 ( ) ALL 725 (4.1) 758 (4.3) 0.96 ( ) 2 Heterogeneity: ; p=0.3 99% CI 95% CI 0.5 Treatment 1.0 Control 2.0 better better

35 BVTT meta-analysis: Effects of FOLATE on CANCER by year of follow-up Events (%) Treatment Control (n=16,751) (n=16,796) HR (CI) Year of follow-up Year (1.7) 309 (1.8) 0.93 ( ) Year (2.0) 279 (1.7) 1.16 ( ) Year (1.7) 219 (1.5) 1.12 ( ) Year (1.7) 193 (1.5) 1.11 ( ) Year (1.9) 193 (1.8) 1.02 ( ) Years (3.0) 257 (3.0) 1.02 ( ) Total 1521 (9.1) 1450 (8.6) 1.05 ( ) Test for trend : ; p=0.9 99% CI 95% CI 0.5 Treatment 1.0 Control 2.0 better better

36 Effects of BVTT of B-vitamins on cancer events, in published trials Figure 3: Effects BVTT of B-vitamins on cancer events, in published trials Events (%) Treatment Control (n=14,924) (n=14,943) RR (CI) WENBIT 85 (5.5) 69 (4.5) 1.25 ( ) NORVIT 79 (4.2) 65 (3.5) 1.20 ( ) WAFACS 187 (6.9) 192 (7.1) 0.97 ( ) HOPE-2 358(13.0) 340(12.3) 1.09 ( ) SEARCH 678(11.2) 639(10.6) 1.07 ( ) ALL 1387 (9.3) 1305 (8.7) 1.08 ( ) 2 Heterogeneity: ; p=0.7 99% CI 95% CI 0.5 Treatment 1.0 Control 2.0 better better

37 BVTT meta-analysis: Effects of FOLATE on CANCER SUBTYPES Events (%) Treatment Control (n=16,751) (n=16,796) HR (CI) Cancer Subtypes Colorectal 175 (1.0) 160 (1.0) 1.10 ( ) Other gastrointestinal 129 (0.8) 123 (0.7) 1.05 ( ) Prostate 265 (1.6) 233 (1.4) 1.14 ( ) Other genitourinary 178 (1.1) 173 (1.0) 1.02 ( ) Lung 206 (1.2) 186 (1.1) 1.11 ( ) Breast 111 (0.7) 132 (0.8) 0.83 ( ) Melanoma 44 (0.3) 46 (0.3) 0.96 ( ) Haematological 93 (0.6) 95 (0.6) 0.98 ( ) Other 320 (1.9) 302 (1.8) 1.07 ( ) ALL 1521 (9.1) 1450 (8.6) 1.05 ( ) 99% CI 95% CI 0.5 Treatment 1.0 Control 2.0 better better

38 Effects of BVTT of B-vitamins on mortality, in published trials Figure 4: Effects BVTT of B-vitamins on mortality, in published trials Events (%) Treatment Control (n=18,723) (n=18,762) RR (CI) CHAOS-2 74 (7.9) 74 (7.9) 1.00 ( ) HOST 448(43.4) 436(42.6) 1.02 ( ) WENBIT 73 (4.7) 58 (3.7) 1.28 ( ) VISP 99 (5.4) 117 (6.3) 0.78 ( ) NORVIT 184 (9.8) 181 (9.6) 1.02 ( ) WAFACS 250 (9.2) 256 (9.4) 0.97 ( ) HOPE-2 470(17.0) 475(17.2) 0.99 ( ) SEARCH 983(16.3) 950(15.8) 1.04 ( ) ALL 2581(13.8) 2547(13.6) 1.02 ( ) 2 Heterogeneity: 7 99% CI 95% CI 3.7; p= Treatment 1.0 Control 2.0 better better

39 Summary of BVVT Meta-Analysis and overall CONCLUSIONS Lowering homocysteine with folic acid supplementation is safe, but does not reduce the risk of vascular events

40 The Lancet, Volume 378, Issue 9791, August 2011, Pages

41 ΤΜΠΕΡΑΜΑ: Σύκθσλα κε ηηο νδεγίεο ηεο Επξσπατθήο Καξδηνινγηθήο Eηαηξίαο(ESC) γηα ηελ πξόιεςε ησλ θαξδηαγγεηαθώλ λνζεκάησλ πνπ εθδόζεθαλ ην θζηλόπσξν ηνπ 2012 ε κέηξεζε ησλ ηηκώλ ηεο ίζσο πξέπεη λα γίλεηαη πξνγλσζηηθά ζε λεαξά άηνκα κε πξόωξε, ε αλεμήγεηε από ηνπο ζπκβαηηθνύο παξάγνληεο θηλδύλνπ εκθάληζε θαξδηαγγεηαθήο λόζνπ ή ζε άηνκα κεηξίνπ θηλδύλνπ πνπ έρνπλ νηθνγελεηαθό ηζηνξηθό(classiib) ελώ είλαη ζαθείο όηη δελ ζα πξέπεη λα κεηξάηαη(class III) ωο πξνγλωζηηθόο παξάγνληαο θηλδύλνπ. Η Ακεξηθαληθή Καξδηνινγηθή εηαηξία (AHA) δελ θαηαηάζζεη ηελ νκνθπζηεΐλε σο παξάγνληα θηλδύλνπ θαη δελ ζπληζηά θακία ζεξαπεία πιελ ηεο ζσζηήο δηαηξνθήο ε νπνία πξνζθέξεη ζηνλ νξγαληζκό ηηο απαξαίηεηεο πνζόηεηεο θπιιηθνύ νμένο βηηακίλεο Β6 θαη Β12 θαη ηεο αληηκεηώπηζεο ησλ θιαζζηθώλ παξαγόλησλ θηλδύλνπ

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