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(1)Cover Page. The handle http://hdl.handle.net/1887/72625 holds various files of this Leiden University dissertation. Author: Hensen, L.C.R. Title: Cardiac mechanics in chronic kidney disease Issue Date: 2019-05-15.

(2) Chapter 1 GENER AL INTRODUC TION AND OUTLINE OF THE THESIS.

(3) Chapter 1. GENERAL INTRODUCTION AND OUTLINE OF THE THESIS Introduction. Àœ˜ˆVŽˆ`˜iÞ`ˆÃi>Ãi­ 

(4) ®ˆÃ>ܜÀ`܈`i}ÀœÜˆ˜}i«ˆ`i“ˆV>ÃÜVˆ>Ìi`ÜˆÌ  an increased risk of cardiovascular morbidity and mortality.1-4 Heart failure is particularly frequent among patients with CKD.2 Pressure and volume overload >˜`˜œ˜‡ i“œ`ޘ>“ˆVv>V̜ÀÃ>ÃÜVˆ>Ìi`ÜˆÌ  

(5) ˆ˜`ÕViivÌÛi˜ÌÀˆVՏ>À­6® Þ«iÀÌÀœ« Þ]Ài`ÕViV>«ˆ>ÀÞ`i˜ÃˆÌÞ>˜`ˆ˜VÀi>Ãi“ÞœV>À`ˆ>wLÀœÃˆÃÌ >̏i>` ̜6`ˆ>Ã̜ˆV>˜`ÃÞÃ̜ˆV`ÞÃv՘V̈œ˜°5 These processes have been proposed as important determinants of increased mortality in this population.5 The most frequent cause of death in patients with advanced CKD is sudden cardiac death; there is an enhanced arrhythmogenicity due to an increased «ÀiÛ>i˜ViœvV>À`ˆ>VÀˆÃŽv>V̜ÀÃÃÕV >ÃVœÀœ˜>ÀÞ>ÀÌiÀÞ`ˆÃi>Ãi]6 Þ«iÀÌÀœ« Þ >˜`“ÞœV>À`ˆ>wLÀœÃˆÃ]>ÃÜi>Øœ˜‡V>À`ˆ>V­ 

(6) ‡Ã«iVˆwV®ÀˆÃŽv>V̜ÀÃÃÕV  as electrolyte alterations, sympathetic hyperactivity, uremia and anemia. 2,6 Patients with CKD also have an increased risk for developing valvular heart disease due to hemodynamic factors and metabolic pathways that promote Û>ÛՏ>À V>VˆwV>̈œ˜] V>À`ˆ>V `ˆ>Ì>̈œ˜ >˜` ˆ˜viV̈Ûi i˜`œV>À`ˆÌˆÃ°7,8 Finally, >ÌÀˆ>wLÀˆ>̈œ˜ˆÃ«>À̈VՏ>ÀÞvÀiµÕi˜Ìˆ˜«>̈i˜ÌÃÜˆÌ >`Û>˜Vi` 

(7) `Õi̜ electrical and structural remodeling of the atrial myocardium as a consequence of hemodynamic and metabolic disturbances.9-13 Left ventricular systolic dysfunction in patients with chronic kidney disease 6iiV̈œ˜vÀ>V̈œ˜­6 ®]V>VՏ>Ìi`vÀœ“Ìܜ‡`ˆ“i˜Ãˆœ˜>iV œV>À`ˆœ}À>« Þ] ˆÃÌ i“œÃÌvÀiµÕi˜ÌÞÕÃi`«>À>“iÌiÀ̜`iw˜i6ÃÞÃ̜ˆV­`ÞÇ®v՘V̈œ˜14, and is strongly associated with HF and increased mortality in patients with CKD.15,16 œÜiÛiÀ]6  >ÃLii˜à œÜ˜À>Ì iÀˆ˜Ãi˜ÃˆÌˆÛi̜Ì i`iÌiV̈œ˜œv6ÃÞÃ̜ˆV `ÞÃv՘V̈œ˜]«>À̈VՏ>ÀÞˆ˜«>̈i˜ÌÃÜˆÌ  

(8) °˜Ì iÃi«>̈i˜ÌÃ]6 Þ«iÀÌÀœ« Þ >˜` V >˜}ià ˆ˜ Ì i 6 ÃÌÀÕVÌÕÀi “>Þ i>` ̜ ÃÕL̏i 6 ÃÞÃ̜ˆV `ÞÃv՘V̈œ˜ `iëˆÌi«ÀiÃiÀÛi`6 °17 In the last years, several advances in echocardiography ÀiÃՏÌi`ˆ˜˜œÛiˆ˜`ˆViȘœÀ`iÀ̜ˆ“«ÀœÛiV >À>VÌiÀˆâ>̈œ˜œv6v՘V̈œ˜°/ܜ‡ dimensional speckle tracking echocardiography provides more insight in cardiac “iV >˜ˆVÃ>˜`6«iÀvœÀ“>˜Vi°6}œL>œ˜}ˆÌÕ`ˆ˜>ÃÌÀ>ˆ˜­-®]>ÃÃiÃÃi`ÜˆÌ  two-dimensional speckle tracking echocardiography, may provide more detailed ˆ˜vœÀ“>̈œ˜œ˜6ÃÞÃ̜ˆVv՘V̈œ˜°18 9iÌ]`>Ì>œ˜Ì i«ÀiÛ>i˜ViœvÃÕL̏i6 ÃÞÃ̜ˆV`ÞÃv՘V̈œ˜]>VVœÀ`ˆ˜}̜6-ˆ˜«>̈i˜ÌÃÜˆÌ  

(9) >˜`«ÀiÃiÀÛi`. 10.

(10) General Introduction. 6  >Ûi˜œÌLii˜iÝ«œÀi`̜`>Ìi°/ iˆ˜VÀi“i˜Ì>«Àœ}˜œÃ̈VÛ>Õiœv6 -œÛiÀ6  >ÃLii˜`i“œ˜ÃÌÀ>Ìi`ˆ˜«>̈i˜ÌÃÜˆÌ Û>ÀˆœÕÃV>À`ˆœÛ>ÃVՏ>À `ˆÃi>Ãià ­ˆÃV i“ˆV i>ÀÌ `ˆÃi>Ãi] Û>ÛՏ>À i>ÀÌ `ˆÃi>Ãi >˜` i>ÀÌ v>ˆÕÀi®°19 œÜiÛiÀ]ˆÌ̏iˆÃŽ˜œÜ˜>LœÕÌÌ i>ÃÜVˆ>̈œ˜LiÌÜii˜6->˜`ÃÕÀۈÛ>ˆ˜ patients with CKD.19 6 “iV >˜ˆV> `ˆÃ«iÀȜ˜ Ài«ÀiÃi˜Ìà 6 “iV >˜ˆV> `ÞÃÃޘV Àœ˜Þ >˜` ˆÃ “i>ÃÕÀi`ÜˆÌ Ìܜ‡`ˆ“i˜Ãˆœ˜>ëiVŽiÌÀ>VŽˆ˜}iV œV>À`ˆœ}À>« Þ°6->˜` 6“iV >˜ˆV>`ˆÃ«iÀȜ˜>Ài«œÌi˜Ìˆ>ÀˆÃŽ“>ÀŽiÀÃœvÛi˜ÌÀˆVՏ>À>ÀÀ ÞÌ “ˆ>Ș «>̈i˜ÌÃÜˆÌ  

(11) °*>̈i˜ÌÃÜˆÌ >`Û>˜Vi` 

(12) “>ÞLi˜iwÌvÀœ“>˜ˆ“«>˜Ì>Li V>À`ˆœÛiÀÌiÀ`iwLÀˆ>̜À­

(13) ®vœÀ«ÀiÛi˜Ìˆœ˜œvÃÕ``i˜V>À`ˆ>V`i>Ì °œÜiÛiÀ] they also show an increased risk of ICD-related complications.20-22 Therefore, Ì iÀi ˆÃ >˜ ՘“iÌ ˜ii` vœÀ >VVÕÀ>Ìi ÀˆÃŽ ÃÌÀ>̈wV>̈œ˜ ̜œÃ ̜ ˆ`i˜ÌˆvÞ 

(14)  patients at risk of ventricular arrhythmias and sudden cardiac death. Valvular heart disease in patients with chronic kidney disease Patients with CKD have an increased risk for developing valvular heart disease, however they are often denied or not referred to surgery due to the increased operative risk.23,24/ i«Àœ}˜œÃ̈Vˆ“«ˆV>̈œ˜Ãœv՘ÌÀi>Ìi`ÃiÛiÀi6

(15) ˆ˜Ì i }i˜iÀ>«œ«Õ>̈œ˜>ÀiÜiŽ˜œÜ˜]LÕÌ >Ûi˜œÌLii˜ÃÌÕ`ˆi`iÝÌi˜ÃˆÛiÞˆ˜ patients with CKD.25 Underscoring the need of additional studies regarding the prevalence of valvular heart disease in patients with CKD and the frequency of referral for surgical or transcatheter valve intervention. In CKD patients, valvular calcium is an important underlying mechanism œvÛ>Ûi`ÞÃv՘V̈œ˜°6>ÛՏ>ÀV>VˆÕ“ˆÃ>ÃÜVˆ>Ìi`ÜˆÌ >˜ˆ˜VÀi>Ãi`ÀˆÃŽœv all-cause mortality in patients with end-stage renal disease.26,27 However, the prognostic implications of left-sided valve calcium in patients with stage 2 and Î 

(16) ­i,œvÈä‡n™“ɓˆ˜É£°ÇΓÔ>˜`Îä‡x™“ɓˆ˜É£°ÇΓÔÀiëiV̈ÛiÞ® are unknown. #VTKCNƂDTKNNCVKQPKPRCVKGPVUYKVJEJTQPKEMKFPG[FKUGCUG ƂÌÀˆ>wLÀˆ>̈œ˜ˆÃÛiÀÞVœ““œ˜ˆ˜i˜`‡ÃÌ>}iÀi˜>`ˆÃi>Ãi«>̈i˜ÌÃ>˜`Ì i ˆ˜Vˆ`i˜Viœv˜i܏Þ`ˆ>}˜œÃi`>ÌÀˆ>wLÀˆ>̈œ˜ˆ˜œ`iÀ«>̈i˜ÌȘˆÌˆ>̈˜}`ˆ>ÞÈà is 5-fold higher than in the general population.9-11 Electrical and structural Ài“œ`iˆ˜}œvÌ i>ÌÀˆ>“ÞœV>À`ˆÕ“ÃiÀÛiÃ>Ã>ÃÕLÃÌÀ>ÌivœÀ>ÌÀˆ>wLÀˆ>̈œ˜°12 In patients with end-stage renal disease, the metabolic and hemodynamic `ˆÃÌÕÀL>˜ViÃ>ÃÜVˆ>Ìi`ÜˆÌ `ˆ>ÞÈÓ>Þ“œ`Տ>ÌiÌ i>ÌÀˆ>wLÀˆ>̈œ˜ÃÕLÃÌÀ>Ìi. 11.

(17) Chapter 1. Vœ˜ÌÀˆLṎ˜}̜Ì i ˆ} ˆ˜Vˆ`i˜Viœv>ÌÀˆ>wLÀˆ>̈œ˜°13 To date, the structural Ài“œ`iˆ˜}œvÌ iivÌ>ÌÀˆÕ“ >ØœÌLii˜V >À>VÌiÀˆâi`ˆ˜Ì ˆÃ}ÀœÕ«œv«>̈i˜Ìð Outline of the thesis The aim of this thesis was to evaluate cardiac mechanics using two-dimensional ­Ã«iVŽi ÌÀ>VŽˆ˜}® iV œV>À`ˆœ}À>« Þ >˜` VœÀœ˜>ÀÞ Vœ“«ÕÌi` ̜“œ}À>« Þ >˜}ˆœ}À>« Þ ˆ˜ «>̈i˜ÌÃ ÜˆÌ  

(18)  ̜ `iw˜i Ì i «ÀiÛ>i˜Vi >˜` «Àœ}˜œÃ̈V implications of cardiovascular diseases. In Part 1 the value of two-dimensional speckle tracking echocardiography was ˆ˜ÛiÃ̈}>Ìi`vœÀ>ÃÃiÃȘ}6->˜`6“iV >˜ˆV>`ˆÃ«iÀȜ˜ˆ˜«>̈i˜ÌÃÜˆÌ  CKD and its prognostic implications. Chapter 2 >˜>ÞÃiÃ6-]>ÃÃiÃÃi`LÞ two-dimensional speckle tracking echocardiography, in pre-dialysis and dialysis «>̈i˜ÌÃÜˆÌ «ÀiÃiÀÛi`6 °Chapter 3 evaluates the prognostic implications œv6-ˆ˜«Ài‡`ˆ>ÞÈÃ>˜``ˆ>ÞÈë>̈i˜ÌðChapter 4 discusses the value of 6“iV >˜ˆV>`ˆÃ«iÀȜ˜>˜`6->ÃÀˆÃŽ“>ÀŽiÀÃœvÛi˜ÌÀˆVՏ>À>ÀÀ ÞÌ “ˆ>à in pre-dialysis and dialysis patients. Part II focuses on the prevalence and prognostic implications of valvular heart disease and mitral and aortic valve calcium in patients with CKD. Chapter 5 investigates the prevalence and prognostic value of valvular heart disease in pre-dialysis and dialysis patients. Chapter 6 describes the prevalence and prognostic implications of mitral and aortic valve calcium in patients with CKD. Part III vœVÕÃiÃœ˜>ÌÀˆ>wLÀˆ>̈œ˜ˆ˜«>̈i˜ÌÃÜˆÌ i˜`‡ÃÌ>}iÀi˜>`ˆÃi>Ãi° Chapter 7 provides more insight on the echocardiographic associates of atrial wLÀˆ>̈œ˜ˆ˜«>̈i˜ÌÃÜˆÌ i˜`‡ÃÌ>}iÀi˜>`ˆÃi>Ãi°. 12.

(19) General Introduction. REFERENCES £° œƂ-] iÀ̜Ü]>˜

(20) ]V ՏœV  CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular iÛi˜ÌÃ]>˜` œÃ«ˆÌ>ˆâ>̈œ˜°N Engl J Med 2004;351:1296-1305. 2. United States Renal Data System. 2016 USRDS annual data repor t: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2016. ΰ 7i˜ *] i˜}/9]/Ã>ˆ] >˜}9 ] Chan HT, Tsai SP, Chiang PH, Hsu CC, -՘}*]ÃÕ9]7i˜-°Ƃ‡V>ÕÃi mortality attributable to chronic kidney disease: a prospective cohort study based on 462 293 adults in Taiwan. Lancet 2008;371:2173-2182. {° >`L>˜ -] Àˆ}>˜Ìˆ ] iÀÀ *]

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(23) ]

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(25) iœ>V --]*՘*],ˆÌâ ° Cardiovascular disease in chronic kidney disease. A clinical update from Kidney

(26) ˆÃi>Ãi\“«ÀœÛˆ˜}œL>"ÕÌVœ“ià ­

(27) "®°Kidney Int 2011;80:572-586. È° œÀˆ>˜ˆ]->ÛiˆiÛ>]

(28) >˜Ƃ]

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(32) Chapter 1 Cardiovasc Res 2002;54:230-246. £Î°œÀ>˜Ì✫œÕœÃ*]œŽŽœÀˆÃ-]ˆÕ/] *ÀœÌœ«Ã>ÌˆÃ]ˆ]œÕ`iÛi˜œÃƂ° ƂÌÀˆ> wLÀˆ>̈œ˜ ˆ˜ i˜`‡ÃÌ>}i Ài˜> disease. Pacing Clin Electrophysiol 2007;30:1391-1397. £{°>˜},] >`>˜œ*]œÀ‡Ƃۈ6]Ƃw>œ ]ƂÀ“ÃÌÀœ˜}Ƃ] À˜>˜`i]>V Î>“«v Ƃ]œÃÌiÀ ]œ`ÃÌiˆ˜-Ƃ]Õâ˜iÌÜÛ> T, Lancellotti P, Muraru D, Picard MH, ,ˆiÌâÃV i ,],Õ`Έ]-«i˜ViÀ/] /Ã>˜}7]6œˆ}Ì1°,iVœ““i˜`>̈œ˜Ã for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233-270. £x°*>ޘi]- >À“>-]

(33) iiœ˜

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(35) ]i˜Ì ]ÕÀÀ>Þ

(36) ] >ÀÀi* °"ÕÌVœ“i and risk factors for left ventricular disorders in chronic uraemia. Nephrol Dial Transplant 1996;11:1277-1285. 17. Unger ED, Dubin RF, Deo R, Daruwalla 6]Àˆi`“>˜]i`ˆ˜> ] iÕÃȘŽ ]Àii` ]- > -°ƂÃÜVˆ>̈œ˜œv chronic kidney disease with abnormal cardiac mechanic s and adverse outcomes in patients with heart failure and preserved ejection fraction. Eur J Heart Fail 2016;18:103-112. £n°/œ«Ã]

(37) i}>`œ6]>ÀÃ>˜ Ƃ] >Ý. 14. °ޜV>À`ˆ>ÃÌÀ>ˆ˜̜`iÌiVÌÃÕL̏i left ventricular systolic dysfunction. Eur J Heart Fail 2017;19:307-313. £™°>>“ ] "Ì> > *] >À ܈VŽ /° *Àœ}˜œÃ̈Vˆ“«ˆV>̈œ˜Ãœv}œL>6 dysfunction: a systematic review and meta-analysis of global longitudinal strain and ejection fraction. Heart 2014;100:1673-1680. Óä°ÀiÞLi ] ââi``ˆ˜i ,] i`ˆ ] >ÀÀˆ˜}̜˜7] >â>â,]>˜â]>ˆ˜ -] }ÜÕ"]œ˜`œ˜ ]->L>-°,i˜> ˆ˜ÃÕvwVˆi˜VÞ«Ài`ˆVÌÃÌ ï“i̜wÀÃÌ >««Àœ«Àˆ>Ìi `iwLÀˆ>̜À à œVŽ° Am Heart J 2006;151:852-856. 21. Makki N, Swaminathan PD, Hanmer ] "Ã >˜ÃŽÞ °

(38) œ ˆ“«>˜Ì>Li cardioverter defibrillators improve survival in patients with chronic kidney disease at high risk of sudden cardiac death? A meta-analysis of observational studies. Europace 2014;16:55-62. ÓÓ° ՈÌi˜ -]

(39) i ˆi ] 6>˜

(40) iÀ iˆ`i˜Ƃ ],œÌ“>˜Ã] œœÌÓ>] >ÀVÀœi˜iÛi`]7œÌiÀLiiŽ,] ,>Liˆ˜Ž/]Վi“>7]-V >ˆ]6>˜ Erven L. Chronic kidney disease and ˆ“«>˜Ì>LiV>À`ˆœÛiÀÌiÀ`iwLÀˆ>̜À related complications: 16 years of iÝ«iÀˆi˜Vi°J Cardiovasc Electrophysiol 2014;25:998-1004. Óΰ՘} ] >Àœ˜] ÕÌV >ÀÌ ]

(41) i> >Þi ] œ Ži‡ >Àܜv ] iÛ>˜} "7] /œÀ˜œÃ*]6>˜œÛiÀÃV i`i]6iÀ“iiÀ ] œiÀÓ> ],>Û>Õ`*]6> >˜ˆ>˜Ƃ° A prospective survey of patients with valvular heart disease in Europe: The ÕÀœi>ÀÌ-ÕÀÛiÞœ˜6>ÛՏ>Ài>ÀÌ Disease. Eur Heart J 2003;24:1231-1243. Ó{°iÀâœ} Ƃ]><] œˆ˜ÃƂ°œ˜}‡ÌiÀ“ survival of dialysis patients in the United.

(42) General Introduction States with prosthetic heart valves: à œÕ`Ƃ. ÉƂƂ«À>V̈Vi}Ո`iˆ˜iÃœ˜ Û>ÛiÃiiV̈œ˜Li“œ`ˆwi`¶Circulation 2002;105:1336-1341. Óx° ˆÃ ˆ“ÕÀ>,Ƃ]"Ì̜ ] œ˜œÜ,"]. >À>Liœ Ƃ] À܈˜*]ÎÀ`]ÕÞ̜˜,Ƃ] "½>À>*/],Ոâ ]-ŽÕL>à ]-œÀ>>*] -՘`Ì/]ÎÀ`]/ œ“>Ã

(43) °Óä£{ƂƂÉ ACC guideline for the management of patients with valvular heart disease: a report of the American College of. >À`ˆœœ}ÞÉƂ“iÀˆV>˜i>ÀÌƂÃÜVˆ>̈œ˜ />ÎœÀViœ˜*À>V̈ViՈ`iˆ˜iðJ Am Coll Cardiol 2014;63:e57-185. ÓÈ°,>}}ˆ*] i>ÈƂ]>“Lœ> ]iÀÀ>“œÃV> ],>Ì̈ ] œVŽƂ]՘̘iÀ*°Ƃ‡ cause mortality in hemodialysis patients ÜˆÌ  i>ÀÌÛ>ÛiV>VˆwV>̈œ˜°Clin J Am Soc Nephrol 2011;6:1990-1995. 27. Takahashi H, Ishii H, Aoyama T, Kamoi D, Kasuga H, Ito Y, Yasuda K, Tanaka M, Yoshikawa D, Maruyama S, Matsuo -]ÕÀœ >À>/]9Õâ>Ü>9°ƂÃÜVˆ>̈œ˜ œvV>À`ˆ>VÛ>ÛՏ>ÀV>VˆwV>̈œ˜Ã>˜` C-reactive protein with cardiovascular mortality in incident hemodialysis «>̈i˜ÌÃ\>>«>˜iÃiVœ œÀÌÃÌÕ`Þ°Am J Kidney Dis 2013;61:254-261.. 15.

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