The inflammable truth of atherosclerosis - Chapter 1: General introduction and outline of the thesis

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The inflammable truth of atherosclerosis

Verweij, S.L.

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2018

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Verweij, S. L. (2018). The inflammable truth of atherosclerosis.

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'ĞŶĞƌĂůŝŶƚƌŽĚƵĐƟŽŶĂŶĚ 





outline of the thesis

^ŝŵŽŶĞ>͘sĞƌǁĞŝũ Adapted from: sĞƌǁĞŝũ^>͕ǀĂŶĚĞƌsĂůŬ&D͕^ƚƌŽĞƐ^͘ EŽǀĞůĚŝƌĞĐƟŽŶƐŽĨŝŶŇĂŵŵĂƟŽŶĂƐĂƚŚĞƌĂƉĞƵƟĐƚĂƌŐĞƚŝŶ atherosclerosis. ƵƌƌKƉŝŶ>ŝƉŝĚŽů͘ϮϬϭϱ͖Ϯϲ;ϲͿ͗ϱϴϬͲϱ͘

Chapter 1 10

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ƚŚĞƌŽƐĐůĞƌŽƐŝƐ ŝƐ Ă ĐŚƌŽŶŝĐ ĚŝƐĞĂƐĞ ŽĨ ƚŚĞ ĂƌƚĞƌŝĂů ǁĂůů͕ ƵŶĚĞƌůLJŝŶŐ ƚŚĞ ŵĂũŽƌŝƚLJ ŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĞǀĞŶƚƐ͘ /Ŷ ƚŚĞ ƚǁĞŶƟĞƚŚ ĐĞŶƚƵƌLJ͕ ƚŚĞ ĐĂƵƐĂů ƌŽůĞ ĨŽƌ >> ĐŚŽůĞƐƚĞƌŽů ŝŶ ƚŚĞ ĚĞǀĞůŽƉŵĞŶƚ ŽĨ ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ ǁĂƐ ĮƌŵůLJ ĞƐƚĂďůŝƐŚĞĚ ƵƐŝŶŐ Ă ŐĞŶĞƟĐ ĂƉƉƌŽĂĐŚ1_͕ ĐŽŵƉůĞŵĞŶƚĞĚ ďLJ ƐĞƌŝĞƐ ŽĨ ƌĂŶĚŽŵŝnjĞĚ ĐůŝŶŝĐĂů ƚƌŝĂůƐ͕ ĐŽŶƐŝƐƚĞŶƚůLJ ƐŚŽǁŝŶŐ ƚŚĂƚ >> ĐŚŽůĞƐƚĞƌŽů ůŽǁĞƌŝŶŐ ƚŚĞƌĂƉŝĞƐ ƌĞĚƵĐĞĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚŝƐĞĂƐĞ ;sͿ ƌĞůĂƚĞĚ ŵŽƌďŝĚŝƚLJ ĂŶĚ ŵŽƌƚĂůŝƚLJ2_{͘ KǀĞƌ ƚŚĞ LJĞĂƌƐ͕ ƚŚĞƌĂƉĞƵƟĐ ŽƉƟŽŶƐ ƚŽ ůŽǁĞƌ >> ĐŚŽůĞƐƚĞƌŽů ŚĂǀĞ} ĞdžƉĂŶĚĞĚ͕ ǁŝƚŚ W^<ϵ ŝŶŚŝďŝƚŽƌƐ ĂƐ ƚŚĞ ŵŽƐƚ ƌĞĐĞŶƚůLJ ĂƉƉƌŽǀĞĚ ƚƌĞĂƚŵĞŶƚ͕ ůĞĂĚŝŶŐ ƚŽ ĂƉƉƌŽdžŝŵĂƚĞůLJ ϲϬй ůŽǁĞƌŝŶŐ ŽĨ >> ĐŚŽůĞƐƚĞƌŽů ŽŶ ƚŽƉ ŽĨ ƐƚĂƟŶ ƚƌĞĂƚŵĞŶƚ ĂŶĚ Ă ĨƵƌƚŚĞƌ ƌĞĚƵĐƟŽŶ ŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ƌŝƐŬ3_{͘ ĞƐƉŝƚĞ ƚŚĞƐĞ ŝŵƉƌĞƐƐŝǀĞ ĂĐŚŝĞǀĞŵĞŶƚƐ͕ ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ} ĐŽŶƟŶƵĞƐƚŽďĞĂůĞĂĚŝŶŐĐĂƵƐĞŽĨŵŽƌƚĂůŝƚLJ͕ǁŝƚŚϭϳ͘ϭŵŝůůŝŽŶĞƐƟŵĂƚĞĚĚĞĂƚŚƐƉĞƌLJĞĂƌ4_. ƚ ƚŚĞ ďĞŐŝŶŶŝŶŐ ŽĨ ƚŚĞ ƚǁĞŶƚLJͲĮƌƐƚ ĐĞŶƚƵƌLJ͕ ƚŚĞ ůŝƉŝĚͲĐĞŶƚĞƌĞĚ ǀŝĞǁ ŽŶ ĂƚŚĞƌŽŐĞŶĞƐŝƐ ƐŚŝŌĞĚ͕ ĂƐ ǁĞ ƐƚĂƌƚĞĚ ƚŽ ĂĐŬŶŽǁůĞĚŐĞ ŝƚƐ ŵƵůƟĨĂĐƚŽƌŝĂů ŶĂƚƵƌĞ ǁŚŝĐŚ ŝƐ ĐŚĂƌĂĐƚĞƌŝnjĞĚ ďLJ Ă ĐŚƌŽŶŝĐ ůŽǁͲŐƌĂĚĞ ŝŶŇĂŵŵĂƟŽŶ ƚŚƌŽƵŐŚŽƵƚ Ăůů ƐƚĂŐĞƐ ŽĨ ƚŚĞ ĂƚŚĞƌŽƐĐůĞƌŽƟĐ ƉƌŽĐĞƐƐϱ͕ϲ_. /Ŷ ƌĞĐŽŐŶŝƟŽŶ ŽĨ ƚŚŝƐ ƉĂƌĂĚŝŐŵ ƐŚŝŌ͕ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ƌŝƐŬ ĂŌĞƌ ŽƉƟŵĂů ůŽǁĞƌŝŶŐ ŽĨ >> ĐŚŽůĞƐƚĞƌŽů ŵĂLJ ďĞ ĚƌŝǀĞŶ ďLJ ƌĞƐŝĚƵĂů ͚ŝŶŇĂŵŵĂƚŽƌLJ͛ ƌŝƐŬ͘ ZĞĐĞŶƚůLJ͕ ƚŚĞ ŝŶŇĂŵŵĂƟŽŶͲ ŚLJƉŽƚŚĞƐŝƐǁĂƐǀĂůŝĚĂƚĞĚďLJďŽƚŚĂDĞŶĚĞůŝĂŶZĂŶĚŽŵŝƐĂƟŽŶƐƚƵĚLJ;ĐLJƚŽŬŝŶĞ/>ͲϲĂƐĐĂƵƐĂů ƌŝƐŬĨĂĐƚŽƌĨŽƌsͿ7_{ĂƐǁĞůůĂƐĂƌĂŶĚŽŵŝnjĞĚĐŽŶƚƌŽůƚƌŝĂů;ƚŚĞEdK^ƚƌŝĂůͿ͕ǁŚŝĐŚƐŚŽǁĞĚ} ĨŽƌ ƚŚĞ ĮƌƐƚ ƟŵĞ Ă ƌĞĚƵĐƟŽŶ ŝŶ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĞǀĞŶƚƐ ŝŶ ƉĂƟĞŶƚƐ ǁŝƚŚ ŬŶŽǁŶ s ƵƉŽŶ ƚƌĞĂƚŵĞŶƚǁŝƚŚĂŶƟͲŝŶŇĂŵŵĂƚŽƌLJƚŚĞƌĂƉLJ;ƚĂƌŐĞƟŶŐ/>ͲϭɴͿ8_. DƵůƟͲůĞǀĞůĐĞůůƵůĂƌŝŵŵƵŶĞƌĞƐƉŽŶƐĞĂŶĚĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ dŚĞŝŶŇĂŵŵĂƟŽŶͲŚLJƉŽƚŚĞƐŝƐŝŶsŝƐďĂƐĞĚŽŶƚŚĞĮŶĚŝŶŐŽĨŝŵŵƵŶĞĐĞůůƐ͕ƉĂƌƟĐƵůĂƌůLJ ŵLJĞůŽŝĚ ůŝŶĞĂŐĞ ŵĂĐƌŽƉŚĂŐĞƐ͕ ŝŶ ĂƚŚĞƌŽƐĐůĞƌŽƟĐ ƉůĂƋƵĞƐ9_{͘ /Ŷ ŵŽƌĞ ƉƌŽŐƌĞƐƐŝǀĞ ƉůĂƋƵĞƐ͕} Ă ŚŝŐŚĞƌ ĂŵŽƵŶƚ ŽĨ ŝŵŵƵŶĞ ĐĞůůƐ ŝƐ ĨŽƵŶĚ͕ ŝŶĚƵĐŝŶŐ ƉůĂƋƵĞ ǀƵůŶĞƌĂďŝůŝƚLJ͘ ZĞĐƌƵŝƚŵĞŶƚ ŽĨ ĐŝƌĐƵůĂƟŶŐŵŽŶŽĐLJƚĞƐ;ŵĂĐƌŽƉŚĂŐĞƉƌĞĐƵƌƐŽƌƐͿƚŽƚŚĞĂƚŚĞƌŽƐĐůĞƌŽƟĐƉůĂƋƵĞŝƐĨĂĐŝůŝƚĂƚĞĚ ďLJ ĂĚŚĞƐŝŽŶ ŽĨ ŵŽŶŽĐLJƚĞƐ ƚŽ ĞŶĚŽƚŚĞůŝĂů ĐĞůůƐ͕ ǁŚŝĐŚ ŝƐ ĨŽůůŽǁĞĚ ďLJ ŵŝŐƌĂƟŽŶ ŝŶƚŽ ƚŚĞ arterial wall10_{͘ /Ŷ ƚŚĞ ĂƌƚĞƌŝĂů ǁĂůů͕ ŵŽŶŽĐLJƚĞƐ ĚŝīĞƌĞŶƟĂƚĞ ŝŶƚŽ ŵĂĐƌŽƉŚĂŐĞƐ͕ ĞŶŐƵůĮŶŐ} ůŝƉŝĚƐ͕ ƌĞƐƵůƟŶŐ ŝŶ ĨŽĂŵ ĐĞůůƐ͘ dŚĞƐĞ ŵŽŶŽĐLJƚĞƐͬŵĂĐƌŽƉŚĂŐĞƐ ĞdžƉƌĞƐƐ ƉƌŽͲŝŶŇĂŵŵĂƚŽƌLJ ĐLJƚŽŬŝŶĞƐ͕ŝŶĚƵĐŝŶŐĂŶĚŵĂŝŶƚĂŝŶŝŶŐŝŶŇĂŵŵĂƚŽƌLJĂĐƟǀŝƚLJŝŶĂƚŚĞƌŽƐĐůĞƌŽƟĐůĞƐŝŽŶƐŝŶĂůů stages of atherogenesis11_{͘ ƵƌŝŶŐ ƐƚĞĂĚLJ ƐƚĂƚĞ ĐŽŶĚŝƟŽŶƐ͕ ŵLJĞůŽŝĚ ĐĞůůƐ ĂƌĞ ƉƌŽĚƵĐĞĚ ďLJ} ŚĞŵĂƚŽƉŽŝĞƟĐƐƚĞŵĂŶĚƉƌŽŐĞŶŝƚŽƌĐĞůůƐ;,^WƐͿŝŶƚŚĞďŽŶĞŵĂƌƌŽǁ͘KƚŚĞƌůLJŵƉŚŽŝĚŽƌŐĂŶƐ͕ ƐƵĐŚĂƐƚŚĞƐƉůĞĞŶ͕ĐŽŶƚƌŝďƵƚĞƚŽŵLJĞůŽŝĚĐĞůůƉƌŽĚƵĐƟŽŶĚƵƌŝŶŐŝŶŇĂŵŵĂƚŽƌLJĐŽŶĚŝƟŽŶƐ12_. /Ŷ ƌĞĐĞŶƚ LJĞĂƌƐ ŝƚ ŚĂƐ ďĞĞŶ ƌĞĐŽŐŶŝnjĞĚ ƚŚĂƚ ĚLJƐƌĞŐƵůĂƟŽŶ ŽĨ ƚŚĞ ŚĂĞŵĂƚŽƉŽŝĞƟĐ ŽƌŐĂŶƐ ĐĂŶďĞŝŶĚƵĐĞĚďLJŚŝŐŚĐŚŽůĞƐƚĞƌŽůůĞǀĞůƐ13_{͘&ƵƌƚŚĞƌŵŽƌĞ͕ĐŝƌĐƵůĂƟŶŐŵŽŶŽĐLJƚĞƐĐĂŶƐŚŽǁ} ĂŵŽƌĞƉƌŽͲŝŶŇĂŵŵĂƚŽƌLJƉŚĞŶŽƚLJƉĞ͘dŚŝƐĂůůĐŽŶƚƌŝďƵƚĞƐƐŝŐŶŝĮĐĂŶƚůLJƚŽĂƚŚĞƌŽŐĞŶĞƐŝƐ͘/Ŷ ƐƵŵŵĂƌLJ͕ ĂƚŚĞƌŽƐĐůĞƌŽƐŝƐ ŝƐ ŵĞĚŝĂƚĞĚ ďLJ Ă ŵƵůƟͲůĞǀĞů ĐĞůůƵůĂƌ ŝŵŵƵŶĞ ƌĞƐƉŽŶƐĞ͕ ĚƌŝǀĞŶ

1

ďLJ ŵŝŐƌĂƟŽŶ ŽĨ ƉƌŽͲŝŶŇĂŵŵĂƚŽƌLJ ŵŽŶŽĐLJƚĞƐ͕ ƉƌŽĚƵĐĞĚ ďLJ ŚĞŵĂƚŽƉŽŝĞƟĐ ŽƌŐĂŶƐ͕ ŝŶƚŽ ĂƚŚĞƌŽƐĐůĞƌŽƟĐƉůĂƋƵĞƐ͕ŝŶĚƵĐŝŶŐĂƌƚĞƌŝĂůǁĂůůŝŶŇĂŵŵĂƟŽŶ͘ /ŵĂŐŝŶŐŽĨŝŶŇĂŵŵĂƟŽŶ dŚĞ ŝŶŇĂŵŵĂƚŽƌLJ ƌĞƐƉŽŶƐĞ ĐĂŶ ďĞ ǀŝƐƵĂůŝnjĞĚ ƵƐŝŶŐ 18_{&ͲŇƵŽƌĚĞŽdžLJŐůƵĐŽƐĞ ;}18_&Ͳ&'Ϳ ƉŽƐŝƚƌŽŶ ĞŵŝƐƐŝŽŶ ƚŽŵŽŐƌĂƉŚLJͬĐŽŵƉƵƚĞĚ ƚŽŵŽŐƌĂƉŚLJ ;WdͲdͿ14_{͘ Wdͬd ŝƐ Ă ŶƵĐůĞĂƌ} ŝŵĂŐŝŶŐƚĞĐŚŶŝƋƵĞƵƐŝŶŐƌĂĚŝŽĂĐƟǀĞƚƌĂĐĞƌƐ͕ƐƵĐŚĂƐ18_{&ͲŇƵŽƌĚĞŽdžLJŐůƵĐŽƐĞ;}18_{&Ͳ&'Ϳ͘&'} ŝƐ Ă ŐůƵĐŽƐĞ ĂŶĂůŽŐƵĞ͕ ƚŚƵƐ ƌĞŇĞĐƟŶŐ ŵĞƚĂďŽůŝĐ ĂĐƟǀŝƚLJ ŽĨ ĐĞůůƐ ;ŝŶ ƚŚĞ ĂƌƚĞƌŝĂů ǁĂůů ĂŶĚ ŚĞŵĂƚŽƉŽŝĞƟĐ ŽƌŐĂŶƐͿ͘ dŚĞ ƵƐĞ ŽĨ18_{&Ͳ&' Wdͬd ƚŽ ƋƵĂŶƟĨLJ ĂƌƚĞƌŝĂů ǁĂůů ŝŶŇĂŵŵĂƟŽŶ} ŝƐďĂƐĞĚŽŶƐƚƵĚŝĞƐĞdžĂŵŝŶŝŶŐŚŝƐƚŽůŽŐLJϭϱ͕ϭϲ_{ĂŶĚŐĞŶĞĞdžƉƌĞƐƐŝŽŶ}ϭϳ͕ϭϴ_{ŝŶƉůĂƋƵĞŵĂƚĞƌŝĂůŽĨ} ŚƵŵĂŶ ĐĂƌŽƟĚƐ͘ &ƵƌƚŚĞƌŵŽƌĞ͕18_{&Ͳ&' ƵƉƚĂŬĞ ŝƐ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ ŵĂĐƌŽƉŚĂŐĞ ĐŽŶƚĞŶƚ ŝŶ} ƚŚĞƉůĂƋƵĞƐ15_{͘&ŝŶĂůůLJ͕ƌĞůĞǀĂŶĐĞŽĨƚŚĞƐĞĮŶĚŝŶŐƐǁĂƐƉƌŽǀĞŶŝŶĂůĂƌŐĞƐƚƵĚLJƐŚŽǁŝŶŐƚŚĂƚ} increased 18_{&Ͳ&'ƵƉƚĂŬĞŝŶƚŚĞĂƌƚĞƌŝĂůǁĂůůƉƌĞĚŝĐƚƐĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ}19_. dĂƌŐĞƟŶŐŽĨŝŶŇĂŵŵĂƚŽƌLJƉĂƚŚǁĂLJƐ ƐƚŚĞEdK^ƚƌŝĂůƐŚŽǁĞĚƚŚĂƚƚƌĞĂƚŵĞŶƚǁŝƚŚĂŶƟͲŝŶŇĂŵŵĂƚŽƌLJƚŚĞƌĂƉLJŝŶsƉĂƟĞŶƚƐ ƌĞƐƵůƚƐŝŶĂƌĞĚƵĐƟŽŶŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ8_{͕ƚŚĞŝŶŇĂŵŵĂƚŽƌLJƉĂƚŚǁĂLJŝƐŝŶĐƌĞĂƐŝŶŐůLJ} ďĞŝŶŐ ĐŽŶƐŝĚĞƌĞĚ ĂƐ ĂŶ ĂƩƌĂĐƟǀĞ ƚĂƌŐĞƚ ĨŽƌ ĂŶƟͲŝŶŇĂŵŵĂƚŽƌLJ ƚŚĞƌĂƉŝĞƐ ƚŽ ĨƵƌƚŚĞƌ ƌĞĚƵĐĞ ƚŚĞ ƌĞƐŝĚƵĂů ŝŶŇĂŵŵĂƚŽƌLJ ƌŝƐŬ͘18_{&Ͳ&' Wdͬd ĐŽƵůĚ ďĞ ƵƐĞĚ ƚŽ ĞǀĂůƵĂƚĞ ŶĞǁ} ƚŚĞƌĂƉŝĞƐƚĂƌŐĞƟŶŐĂƚŚĞƌŽƐĐůĞƌŽƐŝƐĂŶĚƚŚĞƌĞďLJŝĚĞŶƟĨLJŝŶŐƚŚĞŵŽƐƚƉƌŽŵŝƐŝŶŐƚƌĞĂƚŵĞŶƚ ŽƉƉŽƌƚƵŶŝƟĞƐ͘,ŽǁĞǀĞƌ͕ĚƵĞƚŽƚŚĞĐŽŵƉůĞdžƌŽůĞŽĨŝŵŵƵŶĞĐĞůůƐŝŶĂƚŚĞƌŽŐĞŶĞƐŝƐ͕ďĞƩĞƌ ƵŶĚĞƌƐƚĂŶĚŝŶŐŽĨƚŚĞŵƵůƟͲůĞǀĞůŝŶŇĂŵŵĂƚŽƌLJƌĞƐƉŽŶƐĞĂŶĚƚŚĞŵĞĚŝĂƚŽƌƐŽĨƚŚŝƐƌĞƐƉŽŶƐĞ ŝŶĂƚŚĞƌŽƐĐůĞƌŽƐŝƐŝƐŶĞĞĚĞĚƚŽĚĞǀĞůŽƉƐƉĞĐŝĮĐĂŶƟͲŝŶŇĂŵŵĂƚŽƌLJƚŚĞƌĂƉŝĞƐŝŶƚŚĞĨƵƚƵƌĞ͘

Chapter 1

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OUTLINE OF THIS THESIS

/Ŷ ƚŚŝƐ ƚŚĞƐŝƐ ǁĞ Ăŝŵ ƚŽ ǀŝƐƵĂůŝnjĞ ƚŚĞ ŵƵůƟͲůĞǀĞů ŝŶŇĂŵŵĂƚŽƌLJ ƌĞƐƉŽŶƐĞ ŝŶ s ĂŶĚ ƚŽ ŝĚĞŶƟĨLJŵĞĚŝĂƚŽƌƐŽĨƚŚŝƐƌĞƐƉŽŶƐĞ͘Part IŽĨƚŚŝƐƚŚĞƐŝƐĐŽŶĐĞƌŶƐŝŵĂŐŝŶŐŽĨŝŶŇĂŵŵĂƟŽŶ͘ /ŶƚŚĞĮƌƐƚĐŚĂƉƚĞƌǁĞůŽŽŬĂƚ18_{&Ͳ&'WdͬdĂƐĂŶŝŵĂŐŝŶŐƚĞĐŚŶŝƋƵĞƚŽƋƵĂŶƟĨLJĂƌƚĞƌŝĂů} ǁĂůůŝŶŇĂŵŵĂƟŽŶŝŶǀĂƌŝŽƵƐƉĂƟĞŶƚŐƌŽƵƉƐ;ĐŚĂƉƚĞƌϮͿ͘/ŶĐŚĂƉƚĞƌϯ͕ǁĞŝŶǀĞƐƟŐĂƚĞ the ĐŚƌŽŶŝĐŵƵůƟͲůĞǀĞůŝŶŇĂŵŵĂƚŽƌLJƌĞƐƉŽŶƐĞŝŶƉĂƟĞŶƚƐǁŝƚŚŬŶŽǁŶs͕ƵƐŝŶŐ18_&Ͳ&'Wdͬ d͘/ŶĐŚĂƉƚĞƌϰǁĞĞdžƉůŽƌĞƚŚĞĞīĞĐƚŽĨĂŶĂĐƵƚĞĐŽƌŽŶĂƌLJƐLJŶĚƌŽŵĞŽŶƚŚĞŵƵůƟͲůĞǀĞů ŝŶŇĂŵŵĂƚŽƌLJƌĞƐƉŽŶƐĞ͕ƵƐŝŶŐĂWdƚƌĂĐĞƌŵŽƌĞƐƉĞĐŝĮĐĨŽƌŵLJĞůŽŝĚĐĞůůƐ͗18_{&ͲWͲϳϭϰ͘/Ŷ} ĐŚĂƉƚĞƌϱwe ĞƐƚĂďůŝƐŚƚŚĞƌĞůĂƟŽŶďĞƚǁĞĞŶŵŽŶŽĐLJƚĞƉŚĞŶŽƚLJƉĞĂŶĚŝŶŇĂŵŵĂƚŽƌLJĂĐƟǀŝƚLJ ŝŶƚŚĞĂƌƚĞƌŝĂůǁĂůůŝŶƉĂƟĞŶƚƐĂƚŝŶĐƌĞĂƐĞĚsƌŝƐŬ͘ Part II ĨŽĐƵƐƐĞƐ ŽŶ ŵĞĚŝĂƚŽƌƐ ŽĨ ƚŚĞ ŝŶŇĂŵŵĂƚŽƌLJ ƌĞƐƉŽŶƐĞ͕ ďŽƚŚ ůŝƉŝĚ ĚƌŝǀĞŶ ĂƐ ǁĞůů ĂƐ ŶŽŶͲůŝƉŝĚ ĚƌŝǀĞŶ͘ >> ĐŚŽůĞƐƚĞƌŽů ŝƐ ŶŽƚ ƚŚĞ ŽŶůLJ ĂƚŚĞƌŽŐĞŶŝĐ ůŝƉŽƉƌŽƚĞŝŶ͖ ĂůƐŽ ŽƚŚĞƌ ůŝƉŽƉƌŽƚĞŝŶƐ ĂƌĞ ĂƐƐŽĐŝĂƚĞĚ ǁŝƚŚ ŝŶĐƌĞĂƐĞĚ sͲƌŝƐŬ͘ ŚĂƉƚĞƌ ϲ looks at the role of ƌĞŵŶĂŶƚ ĐŚŽůĞƐƚĞƌŽů͕ Ă ƚƌŝŐůLJĐĞƌŝĚĞͲƌŝĐŚ ůŝƉŽƉƌŽƚĞŝŶ͕ ŽŶ ƚŚĞ ŝŶŇĂŵŵĂƚŽƌLJ ƌĞƐƉŽŶƐĞ͘ In ĐŚĂƉƚĞƌ ϳ͕ ǁĞ ŝŶǀĞƐƟŐĂƚĞ ƚŚĞ ĐŽŶƚƌŝďƵƟŽŶ ŽĨ ůŝƉŽƉƌŽƚĞŝŶ ;ĂͿ ƚŽ ĂƚŚĞƌŽƐĐůĞƌŽƟĐ ďƵƌĚĞŶ ŝŶ ĂƐLJŵƉƚŽŵĂƟĐ ŝŶĚŝǀŝĚƵĂůƐ ǁŝƚŚ Ă ĨĂŵŝůLJ ŚŝƐƚŽƌLJ ŽĨ ƉƌĞŵĂƚƵƌĞ s͘ WĂƟĞŶƚƐǁŝƚŚŶŽŶͲůŝƉŝĚĚƌŝǀĞŶƌŝƐŬĨĂĐƚŽƌƐĨŽƌsĂƌĞƐƚƵĚŝĞĚŝŶĐŚĂƉƚĞƌϴĂŶĚϵ͘/ŶĐŚĂƉƚĞƌϴ͕ ǁĞĞdžƉůŽƌĞŝŶƉĂƟĞŶƚƐǁŝƚŚĐŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ͕ǁŚŽĂƌĞĂƚŝŶĐƌĞĂƐĞĚsƌŝƐŬ͕ǁŚĞƚŚĞƌ ĂŶĚƚŽǁŚĂƚĞdžƚĞŶƚĂŶŝŶĐƌĞĂƐĞĚŝŶŇĂŵŵĂƚŽƌLJƐƚĂƚĞĐŽƵůĚďĞĚĞƚĞĐƚĞĚ͘/ŶƚŚĞůĂƐƚĐŚĂƉƚĞƌ͕ ĐŚĂƉƚĞƌϵ͕ǁĞĂƐƐĞƐƐƚŚĞĞīĞĐƚŽĨƐĞĐƵŬŝŶƵŵĂďƚƌĞĂƚŵĞŶƚ;/>ͲϭϳŝŶŚŝďŝƟŽŶͿŽŶĂƌƚĞƌŝĂůǁĂůů ŝŶŇĂŵŵĂƟŽŶŝŶƉĂƟĞŶƚƐǁŝƚŚƐƉŽŶĚLJůŽĂƌƚŚƌŝƟƐ͕ǁŚŽĂƌĞŚĂůůŵĂƌŬĞĚďLJŝŶĐƌĞĂƐĞĚsƌŝƐŬ͘

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ϭϵ͘ &ŝŐƵĞƌŽĂ>͕ďĚĞůďĂŬLJ͕dƌƵŽŶŐYĞƚĂů͘ DĞĂƐƵƌĞŵĞŶƚŽĨĂƌƚĞƌŝĂůĂĐƟǀŝƚLJŽŶƌŽƵƟŶĞ &'WdͬdŝŵĂŐĞƐŝŵƉƌŽǀĞƐƉƌĞĚŝĐƟŽŶŽĨ risk of future CV events. JACC Cardiovasc