University of Groningen

The Clinical Value of HDL Function MeasurementsEbtehaj, Sanam

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CHAPTER 7

Summary

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Chapter 7

Summary Cardiovascular diseases (CVD) are the leading causes of morbidity and mortality worldwide. Dyslipidemia, which is characterized by increased low-density lipoprotein cholesterol (LDL-C) and triacylglycerols, and decreased high-density lipoprotein cholesterol (HDL-C), is an important risk factor for development of CVD. Several epidemiological studies showed an inverse relationship between plasma HDL-C levels and risk of atherosclerosis. However, raising HDL-C levels pharmacologically was reported to be not clinically beneficial and failed to reduce cardiovascular risk. Therefore, Improved HDL functionality was suggested to be a better measure for risk of CVD. HDL protects the blood vessels against the development of atherosclerosis through several mechanisms. Most importantly, HDL mediates cholesterol efflux from lipid-laden macrophages in the arterial wall, which is considered as the initial step in the reverse cholesterol transport (RCT) pathway. This process returns peripheral cholesterol to the liver for its final excretion into the bile and is believed to be the primary anti-atherogenic action of HDL. Several epidemiological studies demonstrated a strong inverse relationship between HDL cholesterol efflux capacity and prevalence as well as incidence of coronary artery disease (CAD). Additional anti-atherogenic functions of HDL include anti-oxidative properties, mediated by HDL’s ability to inhibit the oxidative modification of LDL, and anti-inflammatory properties, referring to the capacity of HDL to reduce cytokine-induced expression of adhesion molecules on endothelial cells. Several studies have indicated that in certain disease conditions, such as renal failure and diabetes, HDL can lose its anti-atherosclerotic functions and may even become pro-atherogenic. However, the relationships between HDL functionality and cardiovascular risk are still poorly understood. Therefore, the research presented in this thesis focused on the importance of HDL functionality measurements for cardiovascular risk. Chapter 2 examined HDL cholesterol efflux capacity as a predictive measure for cardiovascular risk in patients with type 2 diabetes on hemodialysis who participated in the 4D study. It is known that HDL cholesterol efflux capacity inversely correlates with atherosclerotic CVD in individuals with normal kidney function. However, the results of this chapter indicated that HDL cholesterol efflux capacity is not a prognostic predictor of cardiovascular risk in diabetic patients on hemodialysis. In chapter 3, it has been determined whether anti-oxidative activity of HDL would be associated with incident cardiovascular mortality, all-cause mortality, and graft failure in renal transplant recipients (RTR), a population with accelerated development of atherosclerosis. The result of this prospective study demonstrated that anti-oxidative capacity of HDL does not predict cardiovascular or all-cause mortality in RTR. However, HDL’s anti-oxidative function was associated with graft failure, which was lost when adjusting for renal function and inflammatory load. In chapter 4, the anti-inflammatory function of HDL was studied in type 2 diabetes and factors that may potentially impact this metric of HDL functionality were explored. The results of this chapter showed that HDL anti-inflammatory capacity is substantially impaired in T2DM, partly attributed to hyperglycemia, decreased PON-1 activity, and low-grade chronic inflammation. Decreased anti-inflammatory capacity of HDL may contribute to increased risk of

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Summary

atherosclerosis in patients with type 2 diabetes. The study described in chapter 5 tested associations between individual or combined HDL functionalities with PROCAM-risk, intima media thickness, and Agatston score as risk measures of CVD in patients with high estimated cardiovascular risk. The results of this cross-sectional study revealed that no association exists between these measures of HDL function and PROCAM risk in this patient population. Finally, chapter 6 summarizes and discusses the highlights of our studies in this thesis. Taken together, important information may be obtained by looking into alternative ways to measure HDL functionality beside plasma levels of HDL cholesterol.

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Chapter 7

هصلاخ

لماــشیمدــیپیلســید.ددرــگیــمبوــسحمناــھجرــسارسردیناــسنارــیموگرــمیلــصاتــلعیــقورعیــبلقیراــمیبیرــت،LDLلورتــسلکنازــیمنتــفرلااــببــجومھــکتــساھیــبرچزاــسوتخوــسردللاتــخازایــفلتخمعاوــنایــمقورــعهراوــیدندــشتخــسویــگنتببــسللاتــخانــیا.دوــشیــمHDLلورتــسلکنازــیمشھاــکواھدیرــسیلگ .تساCVDھعسوتردرطخلماوعنیرتمھمزایکیھکدوشرداــھنیئتورپوــپیلطــسوتلــیلدنیــمھھــبھــکدــشابیــمنوــخردلــحلــباقرــیغیــبرچمــھمعاوــنازایــکیلورتــسلکدــشابداــیزنیئتورپوــپیلنــیانازــیمرــگاودنوــشیمهدــناوخLDLلاــگچمــکیاــھنیئتورپوــپیل.دنوــشیــممــھنوــخ .دوشیماھنآدادسناثعابوهدرکبوسراھگرهرادجHDL.دــنکیــمدیدــشتاریــبلقیاــھیراــمیبرــطخیرــنورکیاــھگرصوــصخھــباــھگرردیــبرچبوــسر.دــنربیمدــبکھــبعــفدلــمعیارــبوهدرــکروداــھلولــسزااریــبرچھــکدنــشابیــملااــبیلاــگچاــبییاــھنیئتورپوپیلدراددوــجوزورلکــسورتآرــطخوHDLلورتــسلکنیــبیــسوکعمھــطبارھــکهدادناــشنیکیژولویمدــیپاتاــعلاطمنــیااــب.تــسایدــیفمشوریــبلقیاــھیراــمیبرــطخیــنیبشیــپردنوــخردنآلورتــسلکحطــسیریگهزادــناویراــمیبھــبلاتــبارــطخشھاــکھــبوتــسیندــیفمینیلاــبظاــحلزایــیورادرــظنزاHDLلورتــسلکشیازــفا،لاــحیارــبرــتھبیراــیعمناوــنعھــبHDLدرــکلمعیریگهزادــنا،ًارــیخانیارــباــنب.دــنکیــمنکــمکیــقورعویــبلق.تساهدشحرطمCVDھبلاتبارطخینیبشیپ

HDLزابوــسرلورتــسلکردگراــھیریگوــلجیــمدــنکویــتحثــعابفذــحنآزاهراوــیدگراــھیــمدوــشویراــمیبرــباربرداــھنآیگدــننکتــظفاحممــسیناکمنــیاودوــشیــمماــجنامــسیناکمنیدــنچقــیرطزادرــکلمعنــیانوردیاـــھژافورکامزالورتـــسلکســـکلافیا،HDLدرـــکلمعمـــسیناکمنیرـــتھم.دـــشابیـــمیـــقورعویـــبلقیاـــھنــیارد.دوــشیــمھتخانــشRCTسوــکعملورتــسلکلاــقتناریــسمردھــیلواماــگناوــنعھــبھــکتــساینایرــشهراوــید .دنادرگیمزابدبکھب،ارفصھبییاھنعفدروظنمھباریطیحملورتسلک،HDLدنیارفزورــبوعویــشوHDLســکلافیالورتــسلکنیــبیوــقسوــکعمھــطبارھــکدــھدیمناــشنکیژولویمدــیپاتاــعلاطمھــکتــساویتادیــسکادــضیــگژیو،HDLیاــھدرــکلمعرــگیدزا.دراددوــجوCADرــنورکقورــعیاــھیراــمیبیباــھتلادــضیــگژیویرــگیدودوــشیمھــتفگLDLندــشهدیــسکازایریگوــلجوندرــکراــھمیارــبنآییاــناوت .تسالایلتودنایاھلولسرباھنیکوتیسیفنمرثاشھاکروظنمھبنآییاناوتھکتسایــمHDLتــبایدوھــیلکییاــسراندــننامیــصاخطیارــشردھــکدــناهدادناــشنیددــعتمتاــعلاطم،رــگیدیوــسزا.دــھدشیازــفاارزورلکــسورتآرــطختــسانــکممیــتحودــھدبتــسدزااردوــخزورلکــسورتآدــضدرــکلمعدــناوتنــیارباــنبوتــساهدــشنھــعلاطملــماکروــطبزوــنھیــقورعویــبلقرــطخوHDLدرــکلمعنیــبھــطبارلاــحنــیااــبزــکرمتیــقورعویــبلقرــطخیارــبHDLدرــکلمعوییاــناوتیرــیگهزادــناتــیمھاھــبھــمانناــیاپنــیایاــھشھوژــپ.درادیــبلقیراــمیبهدــننکیــنیبشیــپناوــنعھــبلورتــسلکســکلافیایارــبHDLییاــناوت،ھــمانناــیاپنــیازامودلــصفردیــسرربدروــم،دنتــشادتکرــش4Dھــعلاطمردھــکزیلاــیدومھو٢عوــنتــبایدھــبلاتــبمناراــمیبردیــقورعوCVDاــبسوــکعمطاــبترا،HDLلورتــسلکســکلافیاییاــناوت،ھــیلکیــعیبطدرــکلمعاــبدارــفارد.تــساھــتفرگرارــق،HDLلورتــسلکســکلافیاییاــناوتھــکتــساهدادناــشنلــصفنــیاجیاــتنلاــحنــیااــب،درادسیزورلکــسورتآیاــھ.تسینزیلایدومھهارمھھبیتبایدنارامیبردیقورعویبلقیرامیبرطخیاربیقیقدیهدننکینیبشیپیتفاــیردناراــمیبردھــیلکدــنویپییاــسرانورــیموگرــمعویــشاــبHDLویتادیــسکادــضییاــناوتموــسلــصفرددــضییاــناوتھــکتــساهدادناــشنرگنهدــنیآھــعلاطمنــیاجیاــتن.تــساھــتفرگرارــقیــسرربدروــمھــیلکدــنویپاــب.دــھدناــشنھــیلکدــنویپناراــمیبرداریــقورعویــبلقیراــمیبزایــشانرــیموگرــمدــناوتیمنHDLویتادیــسکادرــکلمعنتفرــگرــظنرداــبھــکتــشاددوــجوھــیلکدــنویپندزســپاــبHDLدرــکلمعنــیانیــبیاھــطبار،لاــحنــیا.تفرنیبزاھطبارنیایباھتلایاھروتکافوھیلکدرکلمعراــیعمنــیارــبرثوــملــماوعو٢عوــنتــبایدناراــمیبردHDLیباــھتلادــضدرــکلمع،مراــھچلــصفردیاھــظحلاملــباقروــطھــبHDLیباــھتلادــضدرــکلمعھــکدادناــشنلــصفنــیاجیاــتن.تــفرگرارــقیــسرربدروــمباـــھتلاوPON1شھاـــک،یمـــسیلگرپیھشیازـــفاھـــبنآزایـــشخبھـــکتـــسافیعـــض٢عوـــنتـــبایدناراـــمیبردھـــبلاتـــبارـــطخشیازـــفاھـــبتـــسانـــکممHDLیباـــھتلادـــضییاـــناوتشھاـــکنـــیا.دـــشابیـــمطوـــبرمنمزـــم

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Summary

.دوشرجنم٢عونتبایدھبلاتبمنارامیبردزورلکسورتآرــطخصخاــشاــبیــبیکرتتروــصھــباــیوھــناگادجروــطھــبHDLمــھمدرــکلمعھــسنیــبطاــبترا،مجنــپلــصفرد

PROCAMتماخـــضوایدـــمایمیتنیاوبیرـــضنوتـــستاگآدروـــمیـــسرربرارـــقجیاـــتن .تـــفرگلـــصاحزانـــیا .درادندوجوPROCAMرطخوHDLدرکلمعیاھصخاشنیبیطابتراچیھھکدادناشنیعطقمھعلاطمروــطب.دــھدیــمناــشنھــمانناــیاپنــیاردارتاــعلاطممــھموھتــسجربتاــکنزایاھــصلاخمــششلــصف،ماجنارــسحطــسیرــیگهزادــناهارــمھھــبHDLدرــکلمعیریگهزادــنایارــبییاــھراکھارندوزــفاوندرــکنیزگیاــجاــبیــلک.دروآتسدھباریعیسوومھمتاعلاطادناوتیمنآلورتسلک

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