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Hubungan faktor rnetabolik dengan respons inflamasi pada sindrorn koroner akut pasien diabetes rnelitus tipe 2. Kajian efek kurkurnin terhadap faktor rnetabolik dan respons inflamasi pada sindrorn koroner akut. = The relationship of metabolic factor and inflammatory responses in acute coronary syndrome of diabetes mellitus type 2 patients. Study of curcumin effects on metabolic factor and inflammatory responses in acute coronary disease.

Latar Belakang : Masalah Diabetes rnelitus (DM) rnerupakan salah satu rnasalah kesehatan rnasyarakat di dunia, terrnasuk di Indonesia. Penyakit kardiovaskular rnerupakan penyebab utama (75-80%) kernatian pada DM, tigaperernpatnya disebabkan penyakit jantung koroner (PJK). Sekitar 34,2 % pasien sindrorn koroner akut (SKA) yang dirawat di ICCD RSCM rnenderita DM. Mortalitas SKA pada pasien DM rnasih tinggi dan prognosis SKA pada pasien DM rnasih buruk. Terdapat banyak faktor yang berperan pada kejadian aterosklerosis dan SKA pada pasien DM antara lain adanya gangguan rnetabolik karena hiperglikernia dan terbentuknya advances glycation end product (AGE), stres oksidatif, dislipidemia aterogenik pada DM berupa kadar trigliserida yang tinggi, kolesterol HDL yang rendah dan adanya small dense LDL, serta resistensi insulin. Faktor risiko tradisional lain yang sering diternukan bersama yaitu hipertensi dan obesitas, kondisi protrornbotik dan hiperkoagulasi. Penatalaksanaan berdasarkan pengendalian faktor risiko tersebut rnasih belurn rnernuaskan. Respons inflamasi rnernpunyai peran penting dalam patogenesis aterosklerosis rnulai lesi awal sampai sindrorn koroner akut. Peningkatan respons inflamasi (hsCRP) dapat rnernprediksi bencana kardiovaskular dan rnernprediksi prognosis pasca SKA. Penelitian pada populasi DM rnenunjukkan adanya peningkatan inflamasi. Penelitian respons inflamasi pada pasien SKA DM belurn pemah dilaporkan. Pada keadaan normal terdapat keseirnbangan sitokin pro dengan antiinflamasi. Rasio sitokin pro dan antiinflamasi pada SKA, khususnya pasien OM belurn pemah diteliti. Hubungan antara faktor rnetabolik (glukosa darah, gliko Hb dan lipid) dengan respons inflamasi pada pasien SKA DM juga belurn pemah diteliti. Upaya untuk rnenurunkan respons inflamasi pada saat ini antara lain dengan aspirin, obat hipolipidemik statin dan insulin sensitizer. Walaupun aspirin dan statin digunakan secara rutin pada pasien SKA dan terbukti rnenurunkan inflamasi, namun rnorbiditas dan rnortalitas pasien SKA rnasih cukup tinggi, sehingga ingin dilihat apakah penambahan obat lain pada terapi standar dapat lebih rnenurunkan inflamasi. Kurkurnin pada hewan coba dan rnanusia rnenunjukkan efek hipolipidemik (penurunan absorpsi dan peningkatan katabolisrne) dan hipoglikernik (efek terhadap ppAR-y). Kurkurnin juga rnenunjukkan efek antiinflamasi. Pada penelitian ini ingin dilihat efek kurkurnin sekaligus terhadap faktor rnetabolik dan respons inflamasi pada pasien SKA. IDENTIFIKASI MASALAH Uraian di atas rnenunjukkan kesenjangan yang berkaitan dengan repons inflamasi pada pasien SKA OM. Sampai saat ini belurn jelas hubungan faktor rnetabolik dengan respons inflamasi pada SKA DM. Demikian juga efek kurkurnin terhadap faktor rnetabolik dan respons inflamasi pada SKA belurn diketahui. TUJUAN Menilai respons inflamasi pada SKA DM serta hubungannya dengan faktor rnetabolik (glukosa darah, gliko Hb, kolesterol total, kolesterol LDL, kolesterol HDL dan trigliserida); rnenilai rasio sitokin pro dan antiinflamasi pada pasien SKA DM, dan rnernbuktikan efek kurkurnin terhadap faktor rnetabolik dan respons inflamasi pada pasien SKA. TEMPAT PENELITIAN Penelitian dilakukan di ICCD RSCM, ICCD RS Persahabatan, ICCD RS MMC dan ICCD RS Medistra, Poliklinik Kardiologi Departernen Penyakit Dalam FKUIlRSCM dan Poliklinik Pelayanan Jantung Terpadu RSCM. SUBYEK PENELITIAN Pasien SKA (DM dan non DM) dan PJK (DM dan non DM). RANCANGAN PENELITIAN Ada dua desain penelitian : I. Desain observasional untuk melihat respons inflamasi (hscRP, IL-6, IL-lO, VCAM dan ICAM) pada SKA DM PJK DM, SKA non DM dan PJK non DM; serta menilai hubungan faktor metabolik (glukosa darah puasa, glukosa darah 2 jam PP, gliko Hb, kolesterol total, kolesterol LDL, kolesterol HDL dan trigliserida) dengan respons inflamasi (hsCRP, IL-6, IL-lO, VCAM dan ICAM) pada SKA DM. 2. Penelitian intervensional yang merupakan uji acak tersamar ganda untuk menilai efek kurkumin terhadap faktor metabolik (glukosa darah puasa, glukosa darah 2 jam pp dan gliko HB) dan efek kurkumin terhadap respons inflamasi (hsCRP, IL-6, VCAM dan ICAM). HASIL Pada penelitian observasional di analisis 146 subyek penelitian terdiri dari 84 pasien SKA, 30 pasien SKA DM dan 54 pasien SKA non DM, dan 62 pasien pJK yang terdiri dari 25 pasien PJK DM dan 37 pasien PJK non DM. Hasil penelitian pada keempat kelompok pasien tersebut menunjukkan: 1. Respons inflamasi pada pasien SKA DM lebih tinggi daripada PJK DM (hsCRP, p=O.OO;IL-6,p=O,OO;IL-lO, p=0,00) dan SKA non DM (ICAM, p=0,03). 2. Rasio sitokin proinflamasi dan antiinflamasi (IL-6IIL-IO) pada SKA DM tidak berbeda dengan PJK DM (p=0,21) dan SKA non DM (p=0,51). 3. Terdapat hubungan faktor metabolik dengan respons inflamasi pada SKA DM : trigliserida dengan IL-6 (r=-0,39, p=0,03) dan IL-lO (r=-0,37, p=0,04). Pada penelitian intervensional dilakukan randomisasi pada 75 pasien SKA menjadi empat kelompok, yang terdiri dari kelompok kurkumin dosis rendah 15 pasien, kelompok kurkumin dosis sedang 15 pasien, kelompok kurkumin dosis tinggi 15 pasien dan kelompok plasebo 30 pasien. Hasil penelitian pada keempat kelompok tersebut menunjukkan : 1. Kurkumin dosis rendah menunjukkan penurunan hs CRP setelah 1 minggu dalam bulan pertama setelah intervensi, terdapat perbedaan bermakna dengan plasebo (p=O,04). Kelompok kurkumin dosis rendah, dosis sedang dan dosis tinggi menunjukkan penurunan terhadap kadar IL-6 tetapi tidak berbeda bermakna dibandingkan dengan plasebo. Kurkumin dosis rendah, dosis sedang dan dosis tinggi tidak menunjukkan penurunan terhadap VCAM dan ICAM setelah intervensi 2 bulan. 2. Kelompok kurkumin dosis rendah cenderung menurunkan kadar gliko Hb setelah intervensi 2 bulan (p=O,06), namun tidak berbeda bermakna dibandingkan dengan plasebo, demikian juga kurkumin dosis sedang dan dosis tinggi menunjukkan penurunan terhadap gliko Hb, juga tidak terdapat perbedaan bermakna dibandingkan dengan kelompok plasebo. 3. Ada kecenderungan kurkumin dosis rendah menurunkan kolesterol total dan kolesterol LDL, tetapi tidak terdapat perbedaan bermakna dibandingkan dengan plasebo. Ada kecenderungan kurkumin dosis rendah meningkatkan kolesterol HDL,tetapi tidak terdapat perbedaan bermakna dibandingkan dengan kelompok plasebo. 4. Ada kecenderungan pola dosis eskalasi terhadap respons inflamasi dan faktor metabolik, di mana kurkumin dosis rendah menunjukkan efek terbaik, kemudian diikuti dosis sedang dan terakhir dosis tinggi. KESIMPULAN Pada penelitian ini, respons inflamasi pasien SKA DM lebih tinggi daripada PJK DM, SKA non DM dan PJK non DM . Tidak terdapat perbedaan rasio sitokin pro dan antiinflamasi (IL- 6IIL-1O) pada SKA DM dibandingkan dengan PJK DM dan SKA non DM. Selain itu, pada penelitian ini juga ditemukan sebagian hubungan faktor metabolik dengan respons inflamasi. Kurkumin dosis rendah menurunkan kadar hsCRP 1 minggu setelah intervensi dalam bulan pertama pada SKA. Ada kecenderungan kurkumin dosis rendah menurunkan kadar gliko Hb padaSKA.
Kata Kunci : Respons inflamasi, faktor metabolik, sindrom koroner akut, kurkumin.



PROBLEM BACKGROUND Diabetes mellitus (DM) was one of the public health problems worldwide, including in Indonesia. Cardiovascular disease was the main cause of death (75-80%) in DM, three-fourths of this death was caused by coronary heart disease (CHD). Approximately 34.2% of patients with acute coronary syndrome (ACS) receiving care at ICCU of Dr. Cipto Mangunkusumo General Hospital (RSCM) suffered from DM. Mortality rates of ACS in DM patients were still high and ACS prognosis in DM patients were still unfavorable. There are many factors playing a part in atherosclerosis and :ACS incidence in DM patients, such as metabolic disorders due to hyperglycemia and the formation of advanced glycation end product (AGE), oxidative stress, atherogenic dyslipidemia in DM in the form of high triglyceride level and low HDL cholesterol as well as an increase in small dense LDL, and insulin resistance. In addition, other risk factors of CHD frequently encountered with DM were hypertension, obesity, thrombocyte hyperaggregation and hypercoagulation. The management of this disease which was based on the control of risk factors was not yet satisfactory. Inflammatory response played an important role in pathogenesis of atherosclerosis, beginning with early lesion up to acute coronary syndrome. Increase in inflammatory responses (hsCRP) could predict cardiovascular disaster and predict post-ACS prognosis. Studies in DM population showed an increase in inflammation. In-depth studies on inflammatory responses in ACS DM patients have not yet been reported. In normal condition, there was a balance of proinflammatory and antiinflammatory cytokines. The ratio of proinflammatory and antiinflammatory cytokines in ACS, particularly DM patients has not been studied. The relationship between metabolic factor (blood glucose, glyco Hb and lipid) and inflammatory response in ACS DM patients has not yet also been studied. Currently, the effort to decrease inflammatory response is made, among others, by aspirin, statin hypolipidemic medication and insulin sensitizer. Although aspirin and statin were used routinely in ACS patients and have proved to reduce inflammation, morbidity and mortality rates of ACS patients were still high. Thus, we would like to observe whether an addition of other medications in standard therapy could reduce inflammation better. Curcumin in experimental animals and humans showed hypolipidemic effect (decrease in absorption and increase in catabolism) and hypoglycemia (effect on PPAR-y). Curcumin also demonstrated antiinflammatory effect. In this study we would like to observe the effects of curcumin on both metabolic factors and inflammatory responses in ACS patients. PROBLEM IDENTIFICATION The above elaboration showed a discrepancy associated with inflammatory response in DM ACS patients. Up to now, the relationship of metabolic factor and inflammatory response in DM ACS has not been clear yet. Likewise, the effects of curcumin on metabolic factor and inflammatory response in ACS have not yet been identified. OBJECTIVES To evaluate inflammatory responses in DM ACS and its relationship with metabolic factors (glucose, blood, glyco Hb, total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride); to evaluate the ratio of pro inflammatory and antiinflammatory cytokines (IL-61IL-IO) in ACS DM patients, and to identify the effects of curcumin on metabolic factors and inflammatory responses in ACS patients. SETTING The study was conducted at ICCU of RSCM, ICCU of Persahabatan, ICCU of RS MMC and ICCU of Medistra Hospital, Cardiology Polyclinic, Department of Internal Medicine, Faculty of Medicine University of Indonesia! RSCM and Integrated Cardiac Service Polyclinic of RSCM. STUDY SUBJECTS ACS patients (DM and non-DM) and CHD (DM and non-DM). DESIGN There were two studies: I. Observational design to observe inflammatory responses (hscRP, IL-6, IL-IO, VCAM and ICAM) in DM ACS, non-DM ACS, DM CHD, and non-DM CHD; to evaluate the relationship between metabolic factors (blood fasting glucose, blood glucose 2 hours PP, glyco Hb, total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride) and inflammatory responses (hsCRP, IL-6, IL-lO, VCAM and ICAM) in ACS DM. 2. Interventional study which was a double-blind randomized trial to evaluate the effects of curcumin at escalating doses (Iow dose 3xl5 mg/day, moderate dose 3x30 mg/day and high dose 3x60 mg/dayO on metabolic factors (fasting blood glucose, blood glucose 2 hours PP and glyco Hb) and the effects of curcumin at escalating doses on inflammatory responses (hsCRP, IL-6, VCAM and ICAM) in ACS patients. RESULTS In observational study, as many as 146 subjects were analyzed, consisting of84 ACS patients, 30 DM ACS patients and 54 non-DM ACS, and 62 CHD consisting of 25 DM ACS patients and 37 non-DM ACS patients. The results of the study in the four groups of patients showed: 1. Inflammatory response in DM ACS was higher than in DM CHD (hsCRP, p=O.OO;IL-6, p=O.OO;IL-IO, p=O.OO)and non-DM ACS (ICAM, P=O.03). 2. The ratio of proinflammatory and antiinflammatory cytokines (IL-6IIL-IO) in DM ACS did not differ from that of DM CHD (p=O.21) and non-DM ACS (p=O.5I). 3. There was a relationship between metabolic factors and inflammatory responses in DM ACS: triglyceride and IL-6 (r=0.39, p=O.03) and IL-1O (r=0.37, p=O.04). In interventional study we performed randomization in 75 ACS patients into four groups, consisting of low-dose curcumin group of 15 patients, moderate-dose curcumin group of 15 patients, high-dose curcumin group of 15 patients, and placebo group of 30 patients. The results of the study in these four groups showed: I. Low-dose curcumin showed a decrease in hsCRP in one week of the first month after intervention, there was a significant difference from that of placebo (p=0.04). Low-dose, moderate-dose, high-dose curcumin groups showed a decrease in IL-6, but was not significantly different from placebo. Low- dose, moderate-dose, high-dose curcumin did not show a decrease in VCAM and ICAM after intervention of 2 months. 2. Low-dose curcumin group tended to experience a decrease in glyco Hb level after intervention of 2 months (p=O.06); however, it was not significantly different from that of placebo. 3. There was a tendency that low-dose curcumin reduced total cholesterol and LDL cholesterol; however, it was not significantly different from that of placebo. There was a tendency that low-dose curcumin increased HDL cholesterol; however, it was not significantly different from that of placebo. 4. There was a tendency that the pattern of escalating doses had some effects in inflammatory responses and metabolic factors, in which low-dose curcumin showed the best effects, followed by moderate-dose and finally high- dose curcumin. CONCLUSIONS In this study, inflammatory responses in DM ACS patients were higher than those in DM CHD and non-DM ACS patients. There was no difference in the ratio of proinflammatory and antiinflammatory cytokines (IL-6IIL-IO) in DM ACS compared with DM CHD and non-DM ACS. In addition, the present study identified some of the relationships between metabolic factors and inflammatory responses. Low-dose curcumin reduced hsCRP in one week of the first month after the intervention in ACS patients. There was a tendency that low-dose curcumin reduced glyco Hb level in ACS. KEYWORDS Inflammatory response, metabolic factor, acute coronary syndrome, curcumin.