IntroductionThe cardiovascular heal

Introduction
The cardiovascular health benefits of a diet rich in fish has been known for decades and such benefits have been attributed to the presence of LC n-3 PUFA found in fish [1–4]. The typical Western Diet is relatively deficient in LC n-3 PUFA but enriched in saturated fat and n-6 PUFA [5], leading to chronic LC n-3 PUFA deficiency in the US population. About 70 % of the US population, assessed on the basis of dietary intake, is deficient in LC n-3 PUFA
blood levels [6]. Such deficiency can be determined through the measurement of EPA ?DHA?DPA (docosapentaenoic acid) levels in blood (Omega-Score TM, OS)or of EPA?DHA levels in red blood cells (Omega-3 Index, OI) [7,8]. Although cut-off levels for OS or OI have yet to be defined, LC n-3 PUFA dietary deficiency or insufficiency has been identified as a risk factor attributable to 84,000 all cause deaths per year in the US [9]. In a prospective trial, through analyses of blood samples from the Physicians’ Health Study, the lowest quartile of LC n-3 PUFA has been correlated to about 81 % increased risk of sudden cardiac death among men without prior evidence of CVD [10]. Based upon ‘‘risk quartiles’’ of OS levels, the authors concluded that an OS[6.1 % is strongly associated with a reduced risk for sudden cardiac death. Similar findings were reported earlier where a strong inverse relationship between OI and primary cardiac arrest was
described [11]. More recently, quintiles of individual EPA, DHA,and DPA levels have been shown to be associated with lower cause-specific CVD mortality and their combined levels were associated with a 35 % lower risk [12]. Furthermore, the clinical utility of the OI has been suggested not only as a biomarker of intake but also as an important risk factor for CVD and target for therapy [8,13]. Despite the known beneficial effects of LC n-3 PUFA, a
number of meta-analyses of randomized controlled trials (RCT) have generated controversy for their use as a preventive treatment option for CVD subjects [14–17]. Some of the studies included had study design deficiencies that may have contributed to outcomes. The treatments
employed were often either of low purity with varying ratios of EPA and DHA, and/or doses were suboptimal. Importantly, many studies that employed high purity supplements did not measure OS or OI levels either at pre- or at post-treatment [18–20]. In other studies, either baseline
EPA levels (2.9 % of the total fatty acids) were high [19], or fish consumption increased significantly during the study [21] that may have undermined the beneficial effects of the
treatment. Others have often included patients on concomitant medications (though unavoidable), which can possibly affect the trial outcomes [22–24]. For example, amiodarone, an antiarrhythmic agent, has been shown to be a potent phospholipase inhibitor [25], an enzyme needed for the fatty acid turnover (acylation/de-acylation cycle) in cell membranes. In addition, the choice of placebo employed could also affect placebo-corrected results [26]. The importance of these limitations and emphasis on patient selection, individual patient data meta-analysis,
insufficient dose,and purity of supplement have been emphasized in recent reviews [17, 27, 28]. With the exception of von Schacky and Harris [7, 8, 29, 30] who proposed the OI as an important marker of CVD risk, investigations of the prevalence of LC n-3 PUFA nutritional deficiency and its correction, with health-promoting effects that correlate with increased EPA and DHA intake
are lacking. The primary objective of the present RCT was to investigate the efficacy of a highly pure and a novel 6:1-OM3 formulation to correct LC n-3 PUFA deficiency and
improve lipid profiles in ambulatory CVD subjects. To accommodate suggestions proposed in previous reviews [17, 27, 28], the present study (a) selected the subjects with
LC n-3 PUFA insufficiency (OS6.1 %) with normal and high TG (1.02–5.65 mmol/L, representing 90–500 mg/dL) levels, (b) employed high doses of EPA ?DHA (3.2 g/d) with[90 % purity in a novel 6:1 EPA:DHA formulation, which has been shown to produce maximum and sustained vasodilatory effects in isolated perfused porcine coronary artery rings than other known EPA alone or EPA:DHA
(1.2:1) preparations [31] and finally (c) measured both preand post-treatment OS and OI levels to correlate changes with the trial objectives. Preliminary work of this study has
been presented [32].
Experimental design and methods
This study entitled ‘‘A Placebo-ContRollEd Study of VASCAZEN in Subjects with DEficient Blood LC n-3 FattyAcid Levels’’, the VASCAZEN-REVEAL Trial, was an external contract research organization (CRO)-facilitated study managed by Nutrasource Diagnostics Inc., Guelph, Ontario, Canada, and conducted at two centers in the United States. The CRO was responsible for all trial

Hasil (Bahasa Indonesia) 1:

PendahuluanManfaat kardiovaskular kesehatan diet kaya ikan telah dikenal selama beberapa dekade dan manfaat tersebut telah dikaitkan dengan kehadiran LC n-3 PUFA ditemukan di ikan [1-4]. Diet Western khas relatif kekurangan LC n-3 PUFA tapi diperkaya lemak jenuh dan n-6 PUFA [5], yang mengarah ke kronis LC n-3 PUFA kekurangan dalam populasi Amerika Serikat. Sekitar 70% dari penduduk AS, dinilai berdasarkan asupan makanan, kekurangan LC n-3 PUFAkadar darah [6]. Kekurangan tersebut dapat ditentukan melalui pengukuran EPA?DHA?Tingkat DPA (docosapentaenoic asam) dalam darah (Omega-Skor TM, OS) atau EPA?Tingkat DHA dalam sel darah merah (indeks Omega-3, OI) [7,8]. Meskipun tingkat cut-off untuk OS atau OI belum didefinisikan, LC n-3 PUFA kekurangan makanan atau insufisiensi telah diidentifikasi sebagai faktor risiko berkaitan dengan 84.000 semua menyebabkan kematian per tahun di Amerika Serikat [9]. Dalam sidang calon, melalui analisis sampel darah dari Physicians' Health Study, Kuartil terendah dari LC n-3 PUFA telah berkorelasi sekitar 81% peningkatan risiko kematian jantung mendadak antara laki-laki tanpa bukti sebelumnya CVD [10]. Berdasarkan '' risiko quartiles'' kadar OS, para penulis menyimpulkan bahwa OS [6,1% sangat dikaitkan dengan penurunan risiko untuk kematian jantung mendadak. Temuan serupa dilaporkan sebelumnya mana invers hubungan yang kuat antara OI dan serangan jantung yang utama adalahdescribed [11]. More recently, quintiles of individual EPA, DHA,and DPA levels have been shown to be associated with lower cause-specific CVD mortality and their combined levels were associated with a 35 % lower risk [12]. Furthermore, the clinical utility of the OI has been suggested not only as a biomarker of intake but also as an important risk factor for CVD and target for therapy [8,13]. Despite the known beneficial effects of LC n-3 PUFA, anumber of meta-analyses of randomized controlled trials (RCT) have generated controversy for their use as a preventive treatment option for CVD subjects [14–17]. Some of the studies included had study design deficiencies that may have contributed to outcomes. The treatmentsemployed were often either of low purity with varying ratios of EPA and DHA, and/or doses were suboptimal. Importantly, many studies that employed high purity supplements did not measure OS or OI levels either at pre- or at post-treatment [18–20]. In other studies, either baselineEPA levels (2.9 % of the total fatty acids) were high [19], or fish consumption increased significantly during the study [21] that may have undermined the beneficial effects of thetreatment. Others have often included patients on concomitant medications (though unavoidable), which can possibly affect the trial outcomes [22–24]. For example, amiodarone, an antiarrhythmic agent, has been shown to be a potent phospholipase inhibitor [25], an enzyme needed for the fatty acid turnover (acylation/de-acylation cycle) in cell membranes. In addition, the choice of placebo employed could also affect placebo-corrected results [26]. The importance of these limitations and emphasis on patient selection, individual patient data meta-analysis,insufficient dose,and purity of supplement have been emphasized in recent reviews [17, 27, 28]. With the exception of von Schacky and Harris [7, 8, 29, 30] who proposed the OI as an important marker of CVD risk, investigations of the prevalence of LC n-3 PUFA nutritional deficiency and its correction, with health-promoting effects that correlate with increased EPA and DHA intakeare lacking. The primary objective of the present RCT was to investigate the efficacy of a highly pure and a novel 6:1-OM3 formulation to correct LC n-3 PUFA deficiency andimprove lipid profiles in ambulatory CVD subjects. To accommodate suggestions proposed in previous reviews [17, 27, 28], the present study (a) selected the subjects withLC n-3 PUFA insufficiency (OS6.1 %) with normal and high TG (1.02–5.65 mmol/L, representing 90–500 mg/dL) levels, (b) employed high doses of EPA ?DHA (3.2 g/d) with[90 % purity in a novel 6:1 EPA:DHA formulation, which has been shown to produce maximum and sustained vasodilatory effects in isolated perfused porcine coronary artery rings than other known EPA alone or EPA:DHA(1.2:1) preparations [31] and finally (c) measured both preand post-treatment OS and OI levels to correlate changes with the trial objectives. Preliminary work of this study hasbeen presented [32].Experimental design and methodsThis study entitled ‘‘A Placebo-ContRollEd Study of VASCAZEN in Subjects with DEficient Blood LC n-3 FattyAcid Levels’’, the VASCAZEN-REVEAL Trial, was an external contract research organization (CRO)-facilitated study managed by Nutrasource Diagnostics Inc., Guelph, Ontario, Canada, and conducted at two centers in the United States. The CRO was responsible for all trial

Hasil (Bahasa Indonesia) 2:

Pengantar
Manfaat kesehatan kardiovaskular diet kaya ikan telah dikenal selama puluhan tahun dan manfaat tersebut telah dikaitkan dengan kehadiran LC n-3 PUFA ditemukan pada ikan [1-4]. Khas Diet Barat relatif kekurangan LC n-3 PUFA namun diperkaya dengan lemak jenuh dan n-6 PUFA [5], yang menyebabkan kekurangan LC n-3 PUFA kronis pada populasi Amerika Serikat. Sekitar 70% dari penduduk AS, dinilai berdasarkan asupan makanan, kekurangan dalam LC n-3 PUFA
kadar [6]. Kekurangan tersebut dapat ditentukan melalui pengukuran EPA? DHA? DPA (asam docosapentaenoic) tingkat dalam darah (Omega-Score TM, OS) atau tingkat EPA? DHA dalam sel darah merah (Omega-3 Indeks, OI) [7, 8]. Meskipun tingkat cut-off untuk OS atau OI belum didefinisikan, LC n-3 PUFA kekurangan makanan atau insufisiensi telah diidentifikasi sebagai faktor risiko yang timbul dari 84.000 semua penyebab kematian per tahun di [9] AS. Dalam uji coba prospektif, melalui analisis sampel darah dari Physicians 'Health Study, kuartil terendah LC n-3 PUFA telah berkorelasi dengan sekitar 81% peningkatan risiko kematian jantung mendadak antara laki-laki tanpa bukti sebelum CVD [10]. Berdasarkan '' kuartil risiko '' tingkat OS, penulis menyimpulkan bahwa OS [6,1% sangat terkait dengan penurunan risiko kematian jantung mendadak. Temuan serupa dilaporkan sebelumnya di mana hubungan terbalik yang kuat antara serangan jantung OI dan primer
dijelaskan [11]. Baru-baru ini, kuintil individu tingkat EPA, DHA, dan DPA telah terbukti berhubungan dengan kematian CVD penyebab spesifik yang lebih rendah dan tingkat gabungan mereka dikaitkan dengan risiko 35% lebih rendah [12]. Selain itu, utilitas klinis OI telah disarankan tidak hanya sebagai biomarker asupan tetapi juga sebagai faktor risiko penting untuk CVD dan target terapi [8,13]. Meskipun efek menguntungkan diketahui LC n-3 PUFA, seorang
sejumlah meta-analisis dari percobaan terkontrol acak (RCT) telah dihasilkan kontroversi untuk mereka gunakan sebagai pilihan pengobatan pencegahan untuk mata pelajaran CVD [14-17]. Beberapa studi termasuk memiliki kekurangan desain studi yang mungkin telah berkontribusi terhadap hasil. Perlakuan
yang digunakan adalah sering salah satu dari kemurnian rendah dengan berbagai perbandingan EPA dan DHA, dan / atau dosis yang optimal. Yang penting, banyak penelitian yang digunakan suplemen kemurnian tinggi tidak mengukur OS atau OI tingkat baik pada pra atau pasca perawatan [18-20]. Dalam penelitian lain, baik dasar
tingkat EPA (2,9% dari total asam lemak) yang tinggi [19], atau konsumsi ikan meningkat secara signifikan selama studi [21] yang mungkin telah merusak efek menguntungkan dari
pengobatan. Lain telah sering termasuk pasien pada obat secara bersamaan (meskipun tidak dapat dihindari), yang mungkin dapat mempengaruhi hasil persidangan [22-24]. Sebagai contoh, amiodaron, agen antiarrhythmic, telah terbukti menjadi fosfolipase inhibitor poten [25], enzim yang diperlukan untuk omset asam lemak (siklus asilasi / de-asilasi) di membran sel. Selain itu, pilihan plasebo digunakan juga dapat mempengaruhi plasebo-dikoreksi hasil [26]. Pentingnya keterbatasan ini dan penekanan pada pemilihan pasien, individu data pasien meta-analisis,
dosis cukup, dan kemurnian suplemen telah ditekankan dalam tinjauan baru-baru ini [17, 27, 28]. Dengan pengecualian dari von Schacky dan Harris [7, 8, 29, 30] yang mengusulkan OI sebagai penanda penting risiko CVD, investigasi prevalensi kekurangan gizi LC n-3 PUFA dan koreksi, dengan efek mempromosikan kesehatan yang berkorelasi dengan peningkatan asupan EPA dan DHA
yang kurang. Tujuan utama dari RCT ini adalah untuk menyelidiki efektivitas yang sangat murni dan novel 6: formulasi 1-OM3 untuk memperbaiki LC n-3 PUFA kekurangan dan
meningkatkan profil lipid dalam mata pelajaran CVD rawat jalan. Untuk mengakomodasi saran yang diusulkan dalam tinjauan sebelumnya [17, 27, 28], penelitian ini (a) memilih subyek dengan
LC n-3 PUFA insufisiensi (OS 6,1%) dengan normal dan tinggi TG (1,02-5,65 mmol / L, mewakili 90-500 mg / dL) tingkat, (b) digunakan dosis tinggi EPA DHA (3,2 g / d) dengan [90% kemurnian dalam novel 6: 1 EPA: formulasi DHA, yang telah terbukti untuk menghasilkan maksimum dan efek vasodilatasi berkelanjutan dalam terisolasi perfusi cincin arteri koroner babi daripada dikenal EPA lainnya sendiri atau EPA: DHA
(1,2: 1) persiapan [31] dan akhirnya (c) diukur baik preand pasca perawatan OS dan tingkat OI untuk menghubungkan perubahan dengan tujuan trial . Pekerjaan awal penelitian ini telah
disajikan [32].
Eksperimental desain dan metode
penelitian ini berjudul '' Studi terkontrol plasebo VASCAZEN di Subyek dengan LC Darah kekurangan n-3 FattyAcid Tingkat '', yang VASCAZEN-REVEAL Trial, adalah organisasi penelitian kontrak (CRO) studi -facilitated eksternal dikelola oleh Nutrasource Diagnostics Inc, Guelph, Ontario, Kanada, dan dilakukan di dua pusat di Amerika Serikat. CRO bertanggung jawab atas semua percobaan