ABSTRACT
Acute coronary syndrome (ACS) is a clinical manifestation of coronary atherosclerosis. In recent years, inflammation is known to have an important role in the pathogenesis of atherosclerosis and plaque instability. Several inflammatory markers have also been studied in relation to cardiovascular events (CVE) such as death due to vascular causes , AMI , stroke , and recurrent cardiac ischemia. This study aims to demonstrate that high levels of IgG anti-Hp-HSP60II3, IFN-γ, and neopterin are biomarker of CVE risk in ACS patient and IgG anti-HpHSP60II3, IFN-γ, and neopterin are better biomarker than hs -CRP. Cohort study conducted in 66 patients with acute coronary syndrome undergoing treatment at the Intensive Cardiac Care Unit (ICCU) Sanglah Hospital in Denpasar and willing to be subjects in research . Subjects were observed until the CVE occur or until a period of six months ( 180 days ) . Of the 66 patients with ACS , there were 13 patients (19.7 %) APTS , 11 patients (16.7 %) NSTEMI, and 42 patients (63.6 %) STEMI. In the six-month observation period, 15 (22.7%) patients had CVE, which consisted of 11 (16.7%) vascular deaths, three (4.5%) IMA and one (1.5%) recurrent cardiac ischemia. Of the 15 subjects with CVE, 13 subjects with STEMI and 2 remaining with UA. Normality test results showed that most of the observed data are not normally distributed. Median value of antiHpHSP60II3, IFN-γ, neopterin, and hs-CRP levels are 1.26 (OD), 0.73 pg / mL, 15.18 nmol / L, and 17.92 mg / L respectively. CVE incidence rate in the group of subjects with high levels of neopterin is 5 times higher than the group of subjects with low levels of neopterin, statistically significant with p = 0.005. The mean time of occurrence CVE on subjects with high neopterin levels are 129.09 days, and CVE in the group of subjects with high neopterin levels occur earlier than the group of subjects with low levels, statistically significant with p = 0.008. When confounding variables such as dyslipidemia, diabetes mellitus (DM), hypertension, obesity, smoking, and age are controlled, only neopterin levels affect the incidence of CVE, with the incidence rate ratio 6.46 (95% CI; 1.45 - 28.74), P = 0.014. Analysis using the Partial List Square program (PLS) showed that levels of IFN-γ and anti-HpHSP60II3 have no effect on the incidence CVE either directly or indirectly. Only neopterin give significant effect on the incidence CVE with a coefficient of 0.491 or 49.1% (P <0,05). There is no difference in the cumulative incidence CVE and in the incidence rate ratio CVE between groups of subjects with high and low levels of IFN-γ. That results are similarly for the anti-HpHSP60II3 and hs-CRP. Our examination of anti-Hp-HSP60II3 is the first examination performed in Indonesia and the levels found between 0.69 OD until 1.80 OD. With limitations in the examination of plasma IFN-γ, IFN-γ examination in further research should be done on histopathological or experimental studies on animal atherosclerotic plaque. H`s-CRP results were not significant in our study, and some other studies have same results with us, so that the predictive value of hs-CRP in order to predict the CVE on ACS patient should be investigated further. Further studies with a longer observation time is needed to obtain a more appropriate results. Keywords : neopterin, acute coronary syndrome, cardiovascular events.
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DAFTAR ISI Halaman SAMPUL DALAM..............................................................................................................i PRASYARAT GELAR.......................................................................................................ii LEMBAR PERSETUJUAN...............................................................................................iii PENETAPAN PANITIA PENGUJI...................................................................................iv UCAPAN TERIMAKASIH................................................................................................v ABSTRAK.......................................................................................................................viii ABSTRACT.......................................................................................................................ix DAFTAR ISI……………………………………………………………………................x DAFTAR GAMBAR………………………………………………………….................xii DAFTAR TABEL……………………………………………………………................xiii DAFTAR SINGKATAN ATAU TANDA……………………………………...............xiv DAFTAR LAMPIRAN....................................................................................................xvi BAB I PENDAHULUAN……………………………………………………................…1 1.1 Latar Belakang…………………………………………………………….......1 1.2 Rumusan Masalah………………………………………………………....…..9 1.3 Tujuan Penelitian………………………………………………………….......9 1.4 Manfaat Penelitian………………………………………………………..….10 BAB II KAJIAN PUSTAKA……………………………………………………..……...12 2.1 Epidemiologi dan Gambaran Klinis Sindroma Kroner Akut………......….…12 2.2 Faktor Risiko Klasik Sindroma Koroner Akut………………………………16 2.3 Patogenesis Aterosklerosis dan Ruptur Plak aterosklerotik.............................22 2.4 Helicobacter pylori dan Aterosklerosis................ …………………………..35 BAB III KERANGKA KONSEP DAN HIPOTESIS PENELITIAN…………..........….61 3.1 Kerangka Berpikir…………………………………………………................61 3.2 Kerangka Konsep.............................................................................................64 3.2 Hipotesis Penelitian………………………………………...………..............65 BAB IV METODE PENELITIAN……………………………………...……….............66 4.1 Rancangan Penelitian ………………………......……………........................66 4.2 Tempat dan Waktu Penelitian ………………….....………...…….................67 4.3 Populasi dan Sampel………………………………………………… ...........68 4.4 Besar Sampel………………………………………………...………............69 4.5 Variabel Penelitian…………………………………………………..........….69 4.6 Prosedur Penelitian………………………………………...…………...........75 4.7 Analisis Data…………………………………………………………............78 BAB V HASIL PENELITIAN……………………………………...………...................81 5.1 Karakteristik Data...........................................................................................82 5.2 Gambaran Klinis Penderita SKA dan KKv..................................................84 5.3 Uji Normalitas dan Homogenitas Data ...........................................................85
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5.4 Penentuan Titik Potong (Cut off Point) Kadar Anti-HpHSP60II3, IFN-, Neopterin dan hs-CRP............ ...........................................................86 5.5 Perbedaaan Angka Insiden KKv antara Kelompok Kadar Neopterin tinggi dan Rendah......................................................................................................87 5.6 Perbedaaan Angka Insiden KKv antara Kelompok Kadar IFN- Tinggi dan Rendah ............................................................................................................87 5.7 Perbedaan Kejadian KKv antara Kelompok Kadar Anti-HpHSP60II3 Tinggi dan Rendah...........................................................................................88 5.8 Perbedaan Kejadian KKv antara Kelompok Kadar hs-CRP Tinggi dan Rendah......................................................................................................89 5.9 Analisis Perbedaan Rerata Waktu Terjadinya KKv antara Kadar Neopterin Tinggi dan Rendah...........................................................................................89 5.10 Analisis Perbedaan Waktu Terjadinya KKv antara Kelompok Kadar IFN- Tinggi Dan Rendah.....................................................................................................91 5.11Perbedaan Waktu Terjadinya KKv antara Kelompok Anti-HpHSP60II3 Tinggi dan Rendah..........................................................................................93 5.12Perbedaan Waktu Terjadinya KKv antara Kelompok hs-CRP Tinggi Dan Rendah.....................................................................................................94 5.13Cox Regression model....................................................................................96 5.14Analisis Jalur Hubungan Neopterin, IFN, dan Anti-HpHSP60II3 terhadap Kejadian KKv.................................................................................................97 BAB VI PEMBAHASAN...............................................................................................100 6.1 Karakteristik Data..........................................................................................100 6.2 Neopterin sebagai Faktor Risiko KKv pada SKA.........................................101 6.3 IFN -γ sebagai Faktor Risiko KKv pada SKA...............................................104 6.4 HpHSP60II3 sebagai Faktor Risiko KKv pada SKA....................................107 6.5 Hs-CRP sebagai Faktor Risiko KKv pada SKA............................................109 6.6 Analisis Jalur Hubungan Neopterin terhadap KKv........................................111 6.7 Nilai Baru / Novelty........................................................................................112 6.8 Keterbatasan Penelitian..................................................................................113 BAB VII SIMPULAN DAN SARAN.............................................................................115 7.1 Simpulan........................................................................................................115 7.2 Saran..............................................................................................................116 DAFTAR PUSTAKA……………………………………………………………..........118 LAMPIRAN-LAMPIRAN..............................................................................................128
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DAFTAR GAMBAR Halaman 2.1 Gambaran Klinis pada SKA.........................................................................................13 2.2 Tahap Pembentukan Aterosklerosis ……....................................................................24 2.3 Pembentukan Sumbat Fibrous.………..............……………………………........…..25 2.4 Peranan IFN γ dalam Aterosklerosis............................................................................28 2.5 Beberapa Kelas Limfosit dengan Sitokin yang Diproduksi dan Peranannya dalam Aterosklerosis.......………...............………….....................…….30 2.6 Produksi Neopterin oleh Makrofag..............................................................................32 2.7 Pembentukan CRP.......................................................................................................34 2.8 Hasil Mikrograf Elektron Scanning H. pylori di Permukaan Sel Lambung................36 2.9 Gambaran Histologis Mukosa Lambung......................................................…...……37 2.10 Reaksi Imun terhadap HSP sebagai Autoantigen dalam Hubungannya dengan Aterosklerosis……..……......................................................................……..44 2.11 Aktivasi Makrofag oleh Sitokin dari Th1......................……………………………54 2.12 Peranan Th1 Spesifik HSP60 dalam Aterogenesis....................................................57 2.13 Homologi Urutan Asam Amino HSP60....................................................................59 3.1 Kerangka Berpikir…..............………………………………………………………..61 3.2 Kerangka Konsep…..............………………………………………………………...64 4.1 Rancangan Penelitian Kohort......................................................................................67 4.2 Alur Penelitian.............................................................................................................77 5.1 Kurva Insiden Kumulatif KKv menurut Waktu antara Kelompok Subjek dengan Kadar Neopterin Tinggi dan Rendah...........................................................................90 5.2 Kurva Insiden Kumulatif KKv menurut Waktu antara Kelompok Subjek dengan Kadar IFN Tinggi dan Rendah...................................................................................92 5.3 Kurva Insiden Kumulatif KKv menurut Waktu antara Kelompok Subjek dengan Kadar Anti-HpHSP60II3 Tinggi dan Rendah...............................................................94 5.4 Kurva Insiden Kumulatif KKv menurut Waktu antara Kelompok Subjek dengan Kadar hs-CRP Tinggi dan Rendah...............................................................................95 5.5 Bagan Model Analisis Jalur Efek Anti-HpHSP60II3, IFN, dan Neopterin dengan Kejadian KKv..............................................................................................................99
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DAFTAR TABEL Halaman 2.1 Berbagai Jenis Sitosol Berdasarkan Berat Molekulnya dan Tempat Pembentukannya……...........…………………………………………...……………47 5.1 Kejadian Kardiovaskuler berdasarkan Karakteristik Subjek.......................................82 5.2 Karakteristik Demografik, Faktor Risiko Klasik, dan Penanda Inflamasi...............83 5.3 Gambaran Klinis SKA dan KKv..............................................................................85 5.4 Rentang nilai, titik Potong (cut off point) Anti-HpHSP60II3, IFN, Neopterin dan hs-CRP.........................................................................................................................86 5.5.Perbedaan Angka Insiden KKv antara Kelompok Kadar Neopterin Tinggi dan Rendah...................................................................................................................87 5.6 Perbedaan Angka Insiden KKv antara Kelompok Kadar IFN tinggi dan rendah...........................................................................................................................88 5.7 Perbedaan Angka Insiden KKv antara Kelompok Kadar Anti-HpHSP60II3 Tinggi dan Rendah...................................................................................................................88 5.8.Perbedaan Angka Insiden KKv antara Kelompok Kadar CRP Tinggi dan Rendah.........................................................................................................................89 5.9.Hasil Analisis Kaplan Meier Perbedaan Rerata Waktu Terjadinya KKv antara Kelompok Subjek dengan Kadar Neopterin Tinggi dan Rendah......................90 5.10 Hasil Analisis Kaplan-Meier Perbedaan Rerata Waktu Terjadinya KKv Subjek dengan Kadar IFN Tinggi dan Rendah......................................................................91 5.11 Hasil Analisis Kaplan Meier Perbedaan Waktu Terjadinya KKv pada Subjek dengan Kadar Anti-HpHSP60II3 Tinggi dan Rendah.......................................93 5.12 Hasil Analisis Kaplan Meier Perbedaan Waktu Terjadinya KKv pada Subjek dengan Kadar hs-CRP Tinggi dan Rendah......................................................95 5.13 Hasil Analisis Regresi Cox Pengaruh Neopterin, IFN, Anti-HpHSP60II3 dan hs-CRP terhadap Insiden KKv.............................................................................96 5.14 Hasil Analisis Regresi Cox Pengaruh Neopterin, IFN, Anti-HpHSP60II3, hs-CRP, Dislipidemia, DM, Hipertensi, Obesitas, Merokok dan Umur terhadap Insiden KKv.................................................................................................................97 5.15 Hasil Analisis Jalur Hubungan Neopterin, IFN-, dan Anti-HpHSP60II3 terhadap KKv……………………………...…………………………………………98
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DAFTAR SINGKATAN ATAU TANDA SINGKATAN ACC AHA APC APTS AST ATP III BCDF CagA ` CDC CD14 CFU CKMB CRP DNA DM ECLIA EDTA EKG ELISA ENA-78 g GRO- H. pylori HDL HP-NAP hs-CRP HSP60 HSPs Hu-HSP60 IgG anti-Hp-HSP60 ICAM-1 IFN-γ IL IMA IMT IRD JNC VII kDa KKv KV
: American College of Cardiology : American heart association : antigen presenting cell : Angina Pektoris Tidak Stabil : aspartate aminotransferase : Adult Treatment Panel III : B-cell differentiation factor : cytotoxin-associated gene A : Centers for Disease Control : Cluster of Differentiation 14 : Coloni forming unit : Creatin Kinase Muscle Band : C reactive protein : Deoxy ribonucleic acid : Diabetes Mellitus : electro chemiluminescent immuno assay : Ethylenediaminetetraacetic : elektrokardiogram : Enzyme Link Immunosorben assay : epithelial-cell-derived neutrophil-activating peptide 78 : gram : growth-related oncogen : Helicobacter pylori : High Density Lipoprotein : Helicobacter pylori neutrophil activating protein : high sensitive C reaktive protein : heat shock protein 60 : soluble HSP : human HSP60 : Immunoglobulin G anti-H.pylori-HSP60 : Intracelluler adhesion molecule 1 : Interferon γ : Interleukin : Infark miokard akut : Indeks masa tubuh : instalasi rawat darurat : Joint National Committee on Prevention, Detection, Evaluation and treatment high blood pressure : kilo Dalton : Kejadian Kardiovaskuler : Koefisien Variasi
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L LDH LDL LPS mg MHC mL MMP-9 nmol NSTEMI OD oxLDL PCR PJK PKV PERKENI ROC RR RSUP SD s.d. SKA SKRT STEMI Th TCR TLR TNF-α UPIJ VacA VICAM-1
: liter : lactate dehydrogenase : Low Density Lipoprotein : lipopolisakarida : miligram : Major Histocompatibility Complex : mililiter : matrix metalloproteinase-9 : nanomol : Non ST Elevation Myocardial Infarction : Optical Density : Oxidized LDL : Polymerase Chain Reaction : Penyakit Jantung Koroner : Penyakit Kardiovaskuler : Perkumpulan Endokrinologi Indonesia : receiver operator curve : Risiko Relatif : Rumah Sakit Umum Pusat : Standar Deviasi : sampai dengan : Sindroma Koroner Akut : Survey Kesehatan Rumah Tangga : ST Elevation Myocardial Infarction : T helper : T Cell Receptor : toll like reseptor : Tumor necrosis factor α : Unit Pelayanan Intensif Jantung : vacuolating cytotoxin A : vascular adhesion molecule
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DAFTAR LAMPIRAN
1. 2. 3. 4. 5. 6. 7.
Cara Pemeriksaan Laboratorium…………………………………………..………..128 Surat Keterangan Kelaikan Etik.................................................................................132 Surat Ijin Penelitian....................................................................................................133 Informasi kepada Pasien dan Formulir Persetujuan…………………………...……134 Kuesioner Penelitian..................................................................................................137 Data Hasil Penelitian..................................................................................................144 Hasil Analisis Satistik…………………………………...………………………….148
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