A number of studies demonstrate that coronary collaterals were increased in coronary artery disease patients with high EPC numbers. Conversely, inadequate coronary collateral development was associated with reduced numbers of circulating EPCs and impaired pro-angiogenic activity, as determined by the low values of EC-CFUs and tube formation in culture [30, 31]. Moreover, increased circulating EPC levels were also associated with collateral formation in patients with NSTEMI [32]. Furthermore, reduced circulating EPC numbers also predicted future cardiovascular events, emphasizing the clinical importance of endogenous vascular repair [30, 31, 33]. Therefore, circulating EPC numbers might represent a good prognostic marker for the outcomes in the clinical context of acute coronary syndrome [20].

Interestingly in OSA patients with total coronary occlusion, collateral development was significantly higher than in non-OSA patients with the same coronary occlusion (Rentrop score 2.4 ± 0.7 vs. 1.61 ± 1.2, *p* = 0.02, respectively) [34]. Similar finding supporting increased coronary collaterals in inaugural AMI patients with OSA was also reported more recently [35].

#### **5. Interindividual responses to hypoxic conditions**

Interindividual differences are fundamental to the development of personalized medicine. Different individuals respond in a distinctively different manner to an identical hypoxic stimulus. Such diverse responses can result from a number of reasons. Specifically, however, genetic variations in the expression of oxygenregulated genes are of a particular interest in this growing field of personalized and regenerative medicine, as EPCs and their proliferative and angiogenic functions are [3]. For instance, the expression of the transcription factor HIF-1α and some of its downstream genes as VEGF and aldolase C was determined in lymphocytes from healthy adults exposed to eight different hypoxic treatments ranging from 0.1 to 20% oxygen. The sensitivity of HIF-1α expression to hypoxia varied considerably between individuals. HIF expression in the "low responders" was upregulated at 0.1% oxygen, whereas "high responders" upregulated HIF already at 5% oxygen. Moreover, also the HIF-regulated downstream genes responded in the same manner in each individual, suggesting that the source of this variation resides within the HIF system itself [36]. Furthermore, in patients with ischemic heart disease, DNA was genotyped for singlenucleotide polymorphism (C or T changes at residue 582 of HIF-1α, from proline to serine). HIF-1α polymorphism was associated with the development of collaterals in those patients and was dependent on the frequency of the T alleles. Its frequency was higher in patients without collaterals than in patients with collaterals (the presence of CT or TT was a negative predictor). Thus, variations in HIF-1α genotype may influence the development of collaterals in patients with significant coronary artery disease perhaps regardless of the severity of the ischemia they encounter [37]. In an earlier study, interindividual responses to hypoxia were also shown in coronary artery disease patients undergoing angiography. Their monocytes were harvested and exposed to an identical hypoxic stimulus. Then, mRNA levels of VEGF were determined and correlated with the presence of collaterals. Patients with no collaterals had significantly lower hypoxic induction of mRNA VEGF levels, whereas high mRNA VEGF levels were correlated with high collateral formation [38]. Collectively, these latter studies emphasize the heterogenic responses observed between different individuals exposed to an identical hypoxic stimulus, due to a different genetic background. Moreover, the significance of collateral development in the context of individual responses and clinical outcomes is further emphasized.

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

used as a surrogate marker to assess clinical outcomes.

lial cells in culture [26].

In AMI patients, EPCs were shown to home at the ischemic myocardium and participate in vascular and cardiac repair, basically acting as an internal pool of endothelial cells (ECs). EPCs contribute up to 25% of ECs in newly developed vessels at ischemic sites. Hence, they promote coronary collateral formation while improving endothelial functions by integrating into newly developing capillaries or into injured blood vessels [20, 23]. Of note, low EPC numbers were shown to correlate with endothelial dysfunction, atherosclerosis, and poor cardiovascular outcome. Thus, they are currently considered in many studies to represent an independent predictor of endothelial dysfunction and long-term prognosis in patients with coronary artery disease [21, 24]. Therefore, circulating EPC levels might be

In most of the studies published thus far, EPCs were primarily identified by CD34 (primitive hematopoietic progenitors) and VEGF-R2 (a VEGF receptor) expressions [20]. Their proliferative and angiogenic capacities were demonstrated in vitro by two widely used assays: (1) the formation of endothelial colonies in culture—termed endothelial cell colony-forming units (EC-CFUs) [25]—and (2) the determination of the paracrine effects of these developed colonies on endothe-

Growing EPCs on fibronectin in vitro can induce proliferation and differentiation into EC-CFUs which are characterized by a central core of round angiogenic T cells and outgrowing spindle-shaped cells. These colonies secret angiogenic growth factors such as VEGF inducing endothelial tube formation via paracrine pathways. Moreover, in AMI patients the expression of circulating EPCs (CD34+/VEGF-R2) was positively correlated with mean endothelial tube formation [27]. Also, EC-CFUs were shown to negatively correlate with the Framingham risk score, thus adequately representing circulating EPCs [25]. Both these two in vitro measures—the formation of EC-CFUs in culture and their paracrine effects on endothelial tube formation might be considered as good surrogate markers for circulating EPCs [25, 27].

**3.1 Endothelial progenitor cells and their proliferative and angiogenic**

Acute MI can be a devastating I/R event and a frequent cause of sudden death. Sleep apnea is highly prevalent in AMI patients, ranging in various studies from 22 to 69%. However, in the setting of AMI, the presence of OSA is frequently not considered and therefore under diagnosed [28]. Evaluating circulating EPCs in patients diagnosed with OSA while recovering from an AMI revealed significantly higher EPC numbers than in AMI patients without OSA. Also the intracellular VEGF expression, EC-CFU numbers, and their angiogenic T cells in culture, and endothelial tube formation, were all significantly higher than those in AMI patients without OSA [27]. These findings suggest that the IH associated with OSA might have a crucial role in promoting these protective functions of EPCs in the setting of AMI. Subsequently, the development of EC-CFUs and their paracrine functions in healthy individuals were determined by exposure to IH in vitro. Indeed, the proliferative and paracrine abilities of EC-CFUs and endothelial tube formation were increased by IH, as compared to those that developed under normoxic conditions [27, 29]. Moreover, IH in vitro increased NADPH oxidase-dependent ROS production, protein carbonylation, and VEGF expression in EC-CFUs. Both EC-CFU numbers and endothelial tube formation in culture were increased by ROS-dependent mechanisms. Accordingly, ROS scavengers and NADPH oxidase inhibitors attenuated or completely abolished the formation of EC-CFUs treated by IH in vitro. It is therefore likely that IH and ROS are crucial contributors to increased EPC numbers

**properties in AMI patients with OSA**

and their proliferative and angiogenic functions [29].

**22**

#### **Figure 2.**

*Individual and mean EC-CFU numbers were determined on the 7th day in culture in 15 healthy donors. Cells were exposed to intermittent hypoxia (IH) and to sustained hypoxia (SH) and compared to normoxia (Norm). Each symbol represents a different donor. The horizontal black bar represents the average value for each treatment. (IH 12.7 ± 10.0 vs. Norm 5.0 ± 3.3 EC-CFUs/well, p < 0.017; SH 5.4 ± 4.7 vs. Norm EC-CFUs/ well, p = NS). These data were published in Avezov et al. [29].*

Since high levels of EC-CFUs and endothelial tube formation were correlated with high collateral formation [30, 31], we investigated the effects on EC-CFUs, endothelial tube formation, and VEGF levels in young healthy adults by applying IH in vitro. As aforementioned, IH increased the formation of EC-CFUs and their paracrine activity by increasing endothelial tube formation via higher VEGF expression in culture [29]. However, there was also a significant variation within the cellular responses to the hypoxic stimuli between individuals as depicted in **Figure 2**. This latter finding emphasizes again the importance of the interindividual heterogeneity observed in the hypoxic responses to a specific stimulus as described earlier for the HIF system and the downstream genes in cardiovascular patients as well as in healthy individuals [36–38].

#### **6. Conclusions**

Intermittent hypoxia is the hallmark of obstructive sleep apnea. However, many of the molecular pathways activated in OSA and in response to IH in vivo and in vitro resemble pathways activated by ischemia and reperfusion (I/R). This is evident in injurious as well as in protective mechanisms. IH, similar to I/R, promotes fundamentally injurious mechanisms as oxidative stress and inflammation which invoke atherosclerotic processes rendering OSA a major risk factor for cardio- and cerebrovascular disease. Yet, not all OSA patients develop these morbidities. Importantly, also, similar to I/R, some OSA patients with concomitant acute MI respond to the harsh effects of IH by activating akin molecular pathways

**25**

**Author details**

**Acknowledgements**

their generous support.

**Conflict of interest**

None to declare.

Lena Lavie

provided the original work is properly cited.

Institute of Technology, Haifa, Israel

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

The Lloyd Rigler Sleep Apnea Research Laboratory, Unit of Anatomy and Cell Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel

tion of acute MI patients with low or unfavorable HIF polymorphism.

Drs. Slava Berger and Katia Avezov are gratefully acknowledged for their insightful findings. The Guzik Foundation, USA, is gratefully acknowledged for

*Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses…*

which promote protective mechanisms as ischemic preconditioning. It is therefore likely that OSA promotes IPC in some instances as well. This is particularly evident

Both IH and ROS were shown to play a major role in increasing EPC and EC-CFU numbers and angiogenic functions. All in all, circulating EPC numbers and their angiogenic functions were shown to represent a good surrogate marker as well as a prognostic marker to assess the outcomes in the clinical context of acute MI. This is emphasized by their association and significance to collateral development and clinical outcome. Moreover, the heterogenic responses observed between individuals, implicating a specific personal response to a given particular stimulus, based on genetic variants, might be considered as the foundation for developing personalized medicine for acute MI patients. Thus, IH might be considered as a new modality for the upregulation of angiogenic processes to induce collateral formation in the clinical setting. However, the severity, the frequency, and the chronicity of the IH paradigms should be determined in order to identify and harness IH patterns possessing protective effects. Collectively, based on the studies presented in this review, it is clearly evident that determination of collateral formation, EPC numbers (and possibly their proliferative and angiogenic properties), HIF polymorphism, downstream genes as VEGF, and additional markers, yet to be unraveled, represent an important tool to identify patients at higher or lower risk for outcomes of acute coronary syndromes. However, no less important is the identification of IH patterns possessing protective effects toward elevating EPC numbers in the circula-

*DOI: http://dx.doi.org/10.5772/intechopen.86117*

in patients recovering from AMI.

*Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses… DOI: http://dx.doi.org/10.5772/intechopen.86117*

which promote protective mechanisms as ischemic preconditioning. It is therefore likely that OSA promotes IPC in some instances as well. This is particularly evident in patients recovering from AMI.

Both IH and ROS were shown to play a major role in increasing EPC and EC-CFU numbers and angiogenic functions. All in all, circulating EPC numbers and their angiogenic functions were shown to represent a good surrogate marker as well as a prognostic marker to assess the outcomes in the clinical context of acute MI. This is emphasized by their association and significance to collateral development and clinical outcome. Moreover, the heterogenic responses observed between individuals, implicating a specific personal response to a given particular stimulus, based on genetic variants, might be considered as the foundation for developing personalized medicine for acute MI patients. Thus, IH might be considered as a new modality for the upregulation of angiogenic processes to induce collateral formation in the clinical setting. However, the severity, the frequency, and the chronicity of the IH paradigms should be determined in order to identify and harness IH patterns possessing protective effects. Collectively, based on the studies presented in this review, it is clearly evident that determination of collateral formation, EPC numbers (and possibly their proliferative and angiogenic properties), HIF polymorphism, downstream genes as VEGF, and additional markers, yet to be unraveled, represent an important tool to identify patients at higher or lower risk for outcomes of acute coronary syndromes. However, no less important is the identification of IH patterns possessing protective effects toward elevating EPC numbers in the circulation of acute MI patients with low or unfavorable HIF polymorphism.

#### **Acknowledgements**

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

Since high levels of EC-CFUs and endothelial tube formation were correlated with high collateral formation [30, 31], we investigated the effects on EC-CFUs, endothelial tube formation, and VEGF levels in young healthy adults by applying IH in vitro. As aforementioned, IH increased the formation of EC-CFUs and their paracrine activity by increasing endothelial tube formation via higher VEGF expression in culture [29]. However, there was also a significant variation within the cellular responses to the hypoxic stimuli between individuals as depicted in **Figure 2**. This latter finding emphasizes again the importance of the interindividual heterogeneity observed in the hypoxic responses to a specific stimulus as described earlier for the HIF system and the downstream genes in cardiovascular patients as

*Individual and mean EC-CFU numbers were determined on the 7th day in culture in 15 healthy donors. Cells were exposed to intermittent hypoxia (IH) and to sustained hypoxia (SH) and compared to normoxia (Norm). Each symbol represents a different donor. The horizontal black bar represents the average value for each treatment. (IH 12.7 ± 10.0 vs. Norm 5.0 ± 3.3 EC-CFUs/well, p < 0.017; SH 5.4 ± 4.7 vs. Norm EC-CFUs/*

Intermittent hypoxia is the hallmark of obstructive sleep apnea. However, many of the molecular pathways activated in OSA and in response to IH in vivo and in vitro resemble pathways activated by ischemia and reperfusion (I/R). This is evident in injurious as well as in protective mechanisms. IH, similar to I/R, promotes fundamentally injurious mechanisms as oxidative stress and inflammation which invoke atherosclerotic processes rendering OSA a major risk factor for cardio- and cerebrovascular disease. Yet, not all OSA patients develop these morbidities. Importantly, also, similar to I/R, some OSA patients with concomitant acute MI respond to the harsh effects of IH by activating akin molecular pathways

**24**

well as in healthy individuals [36–38].

*well, p = NS). These data were published in Avezov et al. [29].*

**6. Conclusions**

**Figure 2.**

Drs. Slava Berger and Katia Avezov are gratefully acknowledged for their insightful findings. The Guzik Foundation, USA, is gratefully acknowledged for their generous support.

#### **Conflict of interest**

None to declare.

#### **Author details**

Lena Lavie

The Lloyd Rigler Sleep Apnea Research Laboratory, Unit of Anatomy and Cell Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[14] Belaidi E, Beguin PC, Levy P, Ribuot C, Godin-Ribuot D. Prevention of HIF-1 activation and iNOS gene targeting by low-dose cadmium results in loss of myocardial hypoxic preconditioning in the rat. American Journal of Physiology. Heart and Circulatory Physiology. 2008;**294**:H901-H908. DOI: 10.1152/ ajpheart.00715.2007

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*Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses…*

[22] Cuadrado-Godia E, Regueiro A, Nunez J, Diaz-Ricard M, Novella S, Oliveras A, et al. Endothelial progenitor cells predict cardiovascular events after atherothrombotic stroke and acute myocardial infarction. A PROCELL substudy. PLoS One. 2015;**10**:e0132415. DOI: 10.1371/journal.pone.0132415

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Shwiri T, Mutlak M, Lavie P,

Schenke WH, Waclawiw MA, Quyyumi AA, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. The New England Journal of Medicine. 2003;**348**:593-600.

[26] Bauer J, Margolis M, Schreiner C, Edgell CJ, Azizkhan J, Lazarowski E, et al. In vitro model of angiogenesis using a human endothelium-derived permanent cell line: Contributions of induced gene expression, G-proteins, and integrins. Journal of Cellular Physiology. 1992;**153**:437-449. DOI:

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[17] Ludka O, Stepanova R, Sert-Kuniyoshi F, Spinar J, Somers VK, Kara T. Differential likelihood of NSTEMI vs STEMI in patients with sleep apnea. International Journal of Cardiology. 2017;**248**:64-68. DOI: 10.1016/j.

[18] Festic N, Alejos D, Bansal V, Mooney L, Fredrickson PA, Castillo PR, et al. Sleep apnea in patients hospitalized with acute ischemic stroke: Underrecognition and associated clinical outcomes. Journal of Clinical Sleep Medicine. 2018;**14**:75-80. DOI: 10.5664/jcsm.6884

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[20] Leal V, Ribeiro CF, Oliveiros B, Antonio N, Silva S. Intrinsic vascular repair by endothelial progenitor cells in acute coronary syndromes: An update overview. Stem Cell Reviews. 2018;**15**:35-47. DOI: 10.1007/

[21] Rigato M, Avogaro A, Fadini GP. Levels of circulating progenitor cells, cardiovascular outcomes and death: A meta-analysis of prospective observational studies. Circulation Research. 2016;**118**:1930-1939. DOI: 10.1161/CIRCRESAHA.116.308366

s12015-018-9857-2

chest.2017.06.046

ijcard.2017.06.034

*Intermittent Hypoxia and Obstructive Sleep Apnea: Mechanisms, Interindividual Responses… DOI: http://dx.doi.org/10.5772/intechopen.86117*

[15] Jackman KA, Zhou P, Faraco G, Peixoto PM, Coleman C, Voss HU, et al. Dichotomous effects of chronic intermittent hypoxia on focal cerebral ischemic injury. Stroke. 2014;**45**:1460-1467. DOI: 10.1161/ STROKEAHA.114.004816

[16] Sanchez-de-la-Torre A, Soler X, Barbe F, Flores M, Maisel A, Malhotra A, et al. Cardiac troponin values in patients with acute coronary syndrome and sleep apnea: A pilot study. Chest. 2018;**153**:329-338. DOI: 10.1016/j. chest.2017.06.046

[17] Ludka O, Stepanova R, Sert-Kuniyoshi F, Spinar J, Somers VK, Kara T. Differential likelihood of NSTEMI vs STEMI in patients with sleep apnea. International Journal of Cardiology. 2017;**248**:64-68. DOI: 10.1016/j. ijcard.2017.06.034

[18] Festic N, Alejos D, Bansal V, Mooney L, Fredrickson PA, Castillo PR, et al. Sleep apnea in patients hospitalized with acute ischemic stroke: Underrecognition and associated clinical outcomes. Journal of Clinical Sleep Medicine. 2018;**14**:75-80. DOI: 10.5664/jcsm.6884

[19] Alejos D, Festic E, Guru P, Moss JE. Neurological outcomes of patients with history of obstructive sleep apnea after a cardiac arrest. Resuscitation. 2017;**119**:13-17. DOI: 10.1016/j. resuscitation.2017.07.027

[20] Leal V, Ribeiro CF, Oliveiros B, Antonio N, Silva S. Intrinsic vascular repair by endothelial progenitor cells in acute coronary syndromes: An update overview. Stem Cell Reviews. 2018;**15**:35-47. DOI: 10.1007/ s12015-018-9857-2

[21] Rigato M, Avogaro A, Fadini GP. Levels of circulating progenitor cells, cardiovascular outcomes and death: A meta-analysis of prospective observational studies. Circulation Research. 2016;**118**:1930-1939. DOI: 10.1161/CIRCRESAHA.116.308366

[22] Cuadrado-Godia E, Regueiro A, Nunez J, Diaz-Ricard M, Novella S, Oliveras A, et al. Endothelial progenitor cells predict cardiovascular events after atherothrombotic stroke and acute myocardial infarction. A PROCELL substudy. PLoS One. 2015;**10**:e0132415. DOI: 10.1371/journal.pone.0132415

[23] Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. The EMBO Journal. 1999;**18**: 3964-3972. DOI: 10.1093/emboj/18.14.3964

[24] Werner N, Wassmann S, Ahlers P, Schiegl T, Kosiol S, Link A, et al. Endothelial progenitor cells correlate with endothelial function in patients with coronary artery disease. Basic Research in Cardiology. 2007;**102**: 565-571. DOI: 10.1007/s00395-007-0680-1

[25] Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. The New England Journal of Medicine. 2003;**348**:593-600. DOI: 10.1056/NEJMoa022287

[26] Bauer J, Margolis M, Schreiner C, Edgell CJ, Azizkhan J, Lazarowski E, et al. In vitro model of angiogenesis using a human endothelium-derived permanent cell line: Contributions of induced gene expression, G-proteins, and integrins. Journal of Cellular Physiology. 1992;**153**:437-449. DOI: 10.1002/jcp.1041530302

[27] Berger S, Aronson D, Lavie P, Lavie L. Endothelial progenitor cells in acute myocardial infarction and sleep-disordered breathing. American Journal of Respiratory and Critical Care Medicine. 2013;**187**:90-98. DOI: 10.1164/rccm.201206-1144OC

[28] Aronson D, Nakhleh M, Zeidan-Shwiri T, Mutlak M, Lavie P,

**26**

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

[1] Levy P, Kohler M, McNicholas WT, Barbe F, McEvoy RD, Somers VK, et al. Obstructive sleep apnoea syndrome. Nature Reviews. Disease Primers. 2015;**1**:15015. DOI: 10.1038/nrdp.2015.15 [8] Lavie L. Obstructive sleep apnoea syndrome—An oxidative stress disorder. Sleep Medicine Reviews. 2003;**7**:35-51.

DOI: 10.1053/smrv.2002.0261

[9] Hausenloy DJ, Yellon DM. The therapeutic potential of ischemic conditioning: An update. Nature Reviews Cardiology. 2011;**8**:619-629. DOI: DOI 10.1038/nrcardio.2011.85

[10] Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation. 1986;**74**: 1124-1136. https://doi.org/10.1161/01.

[11] Stokfisz K, Ledakowicz-Polak A, Zagorski M, Zielinska M. Ischaemic preconditioning—Current knowledge and potential future applications after 30 years of experience. Advances in Medical Sciences. 2017;**62**:307-316. DOI:

10.1016/j.advms.2016.11.006

japplphysiol.00056.2005

ajpheart.00715.2007

[12] Heusch G. Molecular basis of cardioprotection: Signal transduction in ischemic pre-, post-, and remote conditioning. Circulation Research. 2015;**116**:674-699. DOI: 10.1161/ CIRCRESAHA.116.305348

[13] Beguin PC, Joyeux-Faure M, Godin-Ribuot D, Levy P, Ribuot C. Acute intermittent hypoxia improves rat myocardium tolerance to ischemia. Journal of Applied Physiology. 2005;**99**:1064-1069. DOI: 10.1152/

[14] Belaidi E, Beguin PC, Levy P, Ribuot C, Godin-Ribuot D. Prevention of HIF-1 activation and iNOS gene targeting by low-dose cadmium results in loss of myocardial hypoxic preconditioning in the rat. American Journal of Physiology. Heart and Circulatory Physiology. 2008;**294**:H901-H908. DOI: 10.1152/

CIR.74.5.1124

[2] Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proceedings of the American Thoracic Society. 2008;**5**:136-143. DOI: 10.1513/

[3] Lavie L. Oxidative stress in

obstructive sleep apnea and intermittent hypoxia—Revisited—The bad ugly and good: Implications to the heart and brain. Sleep Medicine Reviews. 2015;**20**:27-45. DOI: 10.1016/j.

[4] Eltzschig HK, Eckle T. Ischemia and reperfusion—From mechanism to translation. Nature Medicine. 2011;**17**:1391-1401. DOI: 10.1038/

[5] Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. American Journal of Respiratory and Critical Care Medicine.

2002;**165**:934-939. DOI: 10.1164/

[6] Dyugovskaya L, Lavie P, Lavie L. Phenotypic and functional

2003;**168**:242-249. DOI: 10.1164/

characterization of blood gammadelta T cells in sleep apnea. American Journal of Respiratory and Critical Care Medicine.

[7] Dyugovskaya L, Polyakov A, Cohen-Kaplan V, Lavie P, Lavie L. Bax/Mcl-1 balance affects neutrophil survival in intermittent hypoxia and obstructive sleep apnea: Effects of p38MAPK and ERK1/2 signaling. Journal of Translational Medicine. 2012;**10**:211. DOI: 10.1186/1479-5876-10-211

ajrccm.165.7.2104126

rccm.200210-1226OC

pats.200709-155MG

smrv.2014.07.003

nm.2507

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[29] Avezov K, Aizenbud D, Lavie L. Intermittent hypoxia induced formation of "Endothelial Cell-Colony Forming Units (EC-CFUs)" is affected by ROS and oxidative stress. Frontiers in Neurology. 2018;**9**:447. DOI: 10.3389/ fneur.2018.00447

[30] Lambiase PD, Edwards RJ, Anthopoulos P, Rahman S, Meng YG, Bucknall CA, et al. Circulating humoral factors and endothelial progenitor cells in patients with differing coronary collateral support. Circulation. 2004;**109**:2986-2992. DOI: 10.1161/01. CIR.0000130639.97284.EC

[31] Matsuo Y, Imanishi T, Hayashi Y, Tomobuchi Y, Kubo T, Hano T, et al. The effect of endothelial progenitor cells on the development of collateral formation in patients with coronary artery disease. Internal Medicine. 2008;**47**:127-134. DOI: JST.JSTAGE/ internalmedicine/47.0284

[32] Lev EI, Kleiman NS, Birnbaum Y, Harris D, Korbling M, Estrov Z. Circulating endothelial progenitor cells and coronary collaterals in patients with non-ST segment elevation myocardial infarction. Journal of Vascular Research. 2005;**42**:408-414. DOI: 10.1159/000087370

[33] Schmidt-Lucke C, Rossig L, Fichtlscherer S, Vasa M, Britten M, Kamper U, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: Proof of concept for the clinical importance of endogenous vascular repair. Circulation. 2005;**111**:2981-2987. DOI: 10.1161/ CIRCULATIONAHA.104.504340

[34] Steiner S, Schueller PO, Schulze V, Strauer BE. Occurrence of coronary collateral vessels in patients with sleep apnea and total coronary occlusion. Chest. 2010;**137**:516-520. DOI: 10.1378/ chest.09-1136

[35] Ben Ahmed H, Boussaid H, Longo S, Tlili R, Fazaa S, Baccar H, et al. Impact of obstructive sleep apnea in recruitment of coronary collaterality during inaugural acute myocardial infarction. Annales de Cardiologie et d'Angéiologie. 2015;**64**:273-278. DOI: 10.1016/j.ancard.2015.01.014

[36] Brooks JT, Elvidge GP, Glenny L, Gleadle JM, Liu C, Ragoussis J, et al. Variations within oxygen-regulated gene expression in humans. Journal of Applied Physiology (Bethesda, MD: 1985). 2009;**106**:212-220. DOI: 10.1152/ japplphysiol.90578.2008

[37] Resar JR, Roguin A, Voner J, Nasir K, Hennebry TA, Miller JM, et al. Hypoxia-inducible factor 1alpha polymorphism and coronary collaterals in patients with ischemic heart disease. Chest. 2005;**128**:787-791. DOI: 10.1378/ chest.128.2.787

[38] Schultz A, Lavie L, Hochberg I, Beyar R, Stone T, Skorecki K, et al. Interindividual heterogeneity in the hypoxic regulation of VEGF: Significance for the development of the coronary artery collateral circulation. Circulation. 1999;**100**:547-552

**29**

**Chapter 4**

**Abstract**

rheumatic diseases.

**1. Introduction**

therapy

Atherosclerosis in Rheumatology:

Cardiovascular diseases are the leading cause of morbidity and mortality in general population worldwide. There is an increasing significance of cardiovascular risk in the field of rheumatology, and accordingly, the evidence on the relation between immune system disorders and atherosclerosis has been substantially growing especially in last decades. Since novel immune and metabolic factors are considered to participate in pathogenesis of atherosclerosis and increased cardiovascular risk in rheumatic patients, they are getting to the forefront of the research. Since novel therapeutic approaches have improved survival of rheumatic patients, and decreased morbidity caused by rheumatic disease activity and damage, the significance of other comorbidities leading to premature mortality has arisen. Nevertheless, appropriate recommendations for the management of cardiovascular risk are still lacking. Recently, European League Against Rheumatism (EULAR) recommendations for management of the cardiovascular risk and comorbidities in patients with inflammatory arthropathies have been published. However, the cardiovascular management of these patients is still suboptimal. In addition, the situation in other orphan diseases such as idiopathic inflammatory myopathies, systemic sclerosis and others is even more uncertain and strongly requires further research. This chapter provides an overview of epidemiology, pathogenesis, clinical manifestations, screening and management of atherosclerosis in patients with

**Keywords:** atherosclerosis, rheumatic diseases, metabolic risk factors, management,

Cardiovascular diseases (CVDs) are estimated to be the leading cause of mortality and morbidity worldwide and are responsible for one-third of world's population mortality [1]. Atherosclerosis (ATS), as the main cause of CVD, starts to develop early in the life and presents later with clinical manifestations depending on other circumstances. ATS is a multifactorial disease, in which the immune system and impairment of vascular system play a significant role. Inflammation, which can be triggered by infectious agents or by autoimmune reaction, worsens and promotes atherogenesis by several mechanisms [2]. In addition to the immune system, other factors significantly participate in atherogenesis by facilitating the vascular damage, initiating the formation, progression and the rupture of atherosclerotic plaques leading to consequent clinical manifestation of ATS. So-called traditional risk factors include dysregulation of lipid and glucose

Old and New Insights

*Sabina Oreska and Michal Tomcik*

#### **Chapter 4**

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

collateral vessels in patients with sleep apnea and total coronary occlusion. Chest. 2010;**137**:516-520. DOI: 10.1378/

[35] Ben Ahmed H, Boussaid H, Longo S, Tlili R, Fazaa S, Baccar H, et al. Impact of obstructive sleep apnea in recruitment of coronary collaterality during inaugural acute myocardial infarction. Annales de Cardiologie et d'Angéiologie. 2015;**64**:273-278. DOI:

10.1016/j.ancard.2015.01.014

japplphysiol.90578.2008

chest.128.2.787

[37] Resar JR, Roguin A, Voner J, Nasir K, Hennebry TA, Miller JM, et al. Hypoxia-inducible factor 1alpha polymorphism and coronary collaterals in patients with ischemic heart disease. Chest. 2005;**128**:787-791. DOI: 10.1378/

[38] Schultz A, Lavie L, Hochberg I, Beyar R, Stone T, Skorecki K, et al. Interindividual heterogeneity in the hypoxic regulation of VEGF: Significance for the development of the coronary artery collateral circulation.

Circulation. 1999;**100**:547-552

[36] Brooks JT, Elvidge GP, Glenny L, Gleadle JM, Liu C, Ragoussis J, et al. Variations within oxygen-regulated gene expression in humans. Journal of Applied Physiology (Bethesda, MD: 1985). 2009;**106**:212-220. DOI: 10.1152/

chest.09-1136

Lavie L. Clinical implications of sleep disordered breathing in acute myocardial infarction. PLoS One. 2014;**9**:e88878. DOI: 10.1371/journal.

[29] Avezov K, Aizenbud D, Lavie L. Intermittent hypoxia induced formation of "Endothelial Cell-Colony Forming Units (EC-CFUs)" is affected by ROS and oxidative stress. Frontiers in Neurology. 2018;**9**:447. DOI: 10.3389/

[30] Lambiase PD, Edwards RJ, Anthopoulos P, Rahman S, Meng YG, Bucknall CA, et al. Circulating humoral factors and endothelial progenitor cells in patients with differing coronary collateral support. Circulation. 2004;**109**:2986-2992. DOI: 10.1161/01.

CIR.0000130639.97284.EC

internalmedicine/47.0284

DOI: 10.1159/000087370

[33] Schmidt-Lucke C, Rossig L, Fichtlscherer S, Vasa M, Britten M, Kamper U, et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: Proof of concept for the clinical importance of endogenous vascular repair. Circulation. 2005;**111**:2981-2987. DOI: 10.1161/ CIRCULATIONAHA.104.504340

[34] Steiner S, Schueller PO, Schulze V, Strauer BE. Occurrence of coronary

[31] Matsuo Y, Imanishi T, Hayashi Y, Tomobuchi Y, Kubo T, Hano T, et al. The effect of endothelial progenitor cells on the development of collateral formation in patients with coronary artery disease. Internal Medicine. 2008;**47**:127-134. DOI: JST.JSTAGE/

[32] Lev EI, Kleiman NS, Birnbaum Y, Harris D, Korbling M, Estrov Z. Circulating endothelial progenitor cells and coronary collaterals in

patients with non-ST segment elevation myocardial infarction. Journal of Vascular Research. 2005;**42**:408-414.

pone.0088878

fneur.2018.00447

**28**

## Atherosclerosis in Rheumatology: Old and New Insights

*Sabina Oreska and Michal Tomcik*

#### **Abstract**

Cardiovascular diseases are the leading cause of morbidity and mortality in general population worldwide. There is an increasing significance of cardiovascular risk in the field of rheumatology, and accordingly, the evidence on the relation between immune system disorders and atherosclerosis has been substantially growing especially in last decades. Since novel immune and metabolic factors are considered to participate in pathogenesis of atherosclerosis and increased cardiovascular risk in rheumatic patients, they are getting to the forefront of the research. Since novel therapeutic approaches have improved survival of rheumatic patients, and decreased morbidity caused by rheumatic disease activity and damage, the significance of other comorbidities leading to premature mortality has arisen. Nevertheless, appropriate recommendations for the management of cardiovascular risk are still lacking. Recently, European League Against Rheumatism (EULAR) recommendations for management of the cardiovascular risk and comorbidities in patients with inflammatory arthropathies have been published. However, the cardiovascular management of these patients is still suboptimal. In addition, the situation in other orphan diseases such as idiopathic inflammatory myopathies, systemic sclerosis and others is even more uncertain and strongly requires further research. This chapter provides an overview of epidemiology, pathogenesis, clinical manifestations, screening and management of atherosclerosis in patients with rheumatic diseases.

**Keywords:** atherosclerosis, rheumatic diseases, metabolic risk factors, management, therapy

#### **1. Introduction**

Cardiovascular diseases (CVDs) are estimated to be the leading cause of mortality and morbidity worldwide and are responsible for one-third of world's population mortality [1]. Atherosclerosis (ATS), as the main cause of CVD, starts to develop early in the life and presents later with clinical manifestations depending on other circumstances. ATS is a multifactorial disease, in which the immune system and impairment of vascular system play a significant role. Inflammation, which can be triggered by infectious agents or by autoimmune reaction, worsens and promotes atherogenesis by several mechanisms [2]. In addition to the immune system, other factors significantly participate in atherogenesis by facilitating the vascular damage, initiating the formation, progression and the rupture of atherosclerotic plaques leading to consequent clinical manifestation of ATS. So-called traditional risk factors include dysregulation of lipid and glucose

metabolism, arterial hypertension, and degeneration of vascular tissue caused by aging, smoking and hormonal factors [3].

It is well known that autoimmune diseases are accompanied by increased CV morbidity and mortality, caused by exacerbation of atherogenesis [2]. Traditional risk factors of ATS in general population such as dyslipidemia, glucose intolerance, arterial hypertension, etc. can explain only about 75% of CV manifestations in rheumatic patients [4]. In these patients, non-traditional risk factors associated with the systemic inflammatory disease apply [5].

Despite the significant improvement of the therapy of rheumatic diseases, the incidence of CVD in rheumatic patients remains increased compared to that in general population [6]. Both the CV risk and CVD manifestations differ among rheumatic diseases according to the characteristic pathogenetic mechanism, inflammation activity and other specific features of the rheumatic diseases [7]. CV risk in the more prevalent rheumatic diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) is relatively best described. On the other hand, the situation is less clear in orphan connective tissue diseases such as systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), primary Sjögren's syndrome (pSS) and others.

The aim of this review chapter is to provide an overview and sum up the current knowledge on CV risk factors and the treatment options of ATS-related comorbidities in rheumatic diseases.

#### **2. Cardiovascular risks in rheumatic diseases**

Traditional CV risk factors play two roles in rheumatic patients: the first one as a trigger, the second as a consequence of the rheumatic disease activity [3]. Non-traditional risk factors are given by genetic and epigenetic factors, concurrent autoimmune inflammatory disorder and the specific features of each particular rheumatic disease (age of onset, duration, activity and the type of the disease) and other comorbidities, among others depression [8–10].

#### **2.1 Metabolic syndrome and its association with immune disorders**

Metabolic syndrome (MetS) is defined as a cluster of comorbidities and risk factors leading to CVDs and increasing the CV mortality and morbidity. MetS includes obesity and visceral adiposity, diabetes and insulin resistance (IR), arterial hypertension (AH) and dyslipidemia [11]. The matter of mutual interactions and cross-talk of immune and metabolic system has become the object of many studies in recent years. Immune-metabolic interactions are regulated by genetic factors, nutritional status and by intestinal microbiome. The imbalance of the immune and metabolic interactions contributes to the occurrence and manifestation of rheumatic diseases [12].

The prevalence of MetS in general population is estimated to be 24–44% depending on the exact definition of the MetS and the studied population [11, 13], and increases in rheumatic patients and gout to as much as 36–42%, as was reported in studies comparing rheumatic patients to the healthy control population [13].

Different immune mechanisms have been reported to be implemented in the pathogenesis of MetS, including pro-inflammatory cytokines, namely interleukin (IL)-1 and IL-12 family. These cytokines are included in the regulation of immune response and atherogenic damage, and in the differentiation of T helper cells (Th), which participate in the pathogenesis of both autoimmune disorders and CVDs [14, 15]. Cytokines of IL-23/IL-17 signaling pathway are increased in rheumatic diseases, and significantly participate in atherogenesis [16]. MetS is associated with increased oxidative stress,

**31**

*Atherosclerosis in Rheumatology: Old and New Insights DOI: http://dx.doi.org/10.5772/intechopen.88605*

and activity [13].

values higher than 30 kg/m<sup>2</sup>

immune diseases [22, 25].

autoimmune disorders [13].

contributes to pathogenesis of autoimmune disorders [13].

which, among others, leads to the formation of oxidized phospholipids (oxPL) and

IR is not only closely related to MetS, but is also considered to act as a key pathogenic factor in MetS [13]. The definition describes IR as a decreased sensitivity and responsiveness of target organs to the action of insulin resulting in hyperinsulinemia [17]. As consequence, this metabolic disorder leads to glucotoxicity, lipotoxicity and inflammation, all of which participate in endothelial damage and dysfunction [18]. The visceral fat tissue is considered to be the major locus of these unfavorable changes. Of note, CVDs, MetS and autoimmune disorders share common pathogenic mechanisms and mediators of inflammation

In recent years, study of microbiome has come to the forefront of interest. An imbalance of intestinal microbiota (dysbiosis) is characterized by a decrease of the number of beneficial intestinal bacteria and the overgrowth of potentially pathogenic bacteria. This phenomenon accompanies metabolic disorders and contributes to the emergence of MetS, obesity and type 2 diabetes mellitus (T2DM) [19]. Impaired balance of the intestinal flora may also contribute to the development of autoimmune disorders. Several studies have demonstrated onset of inflammation induced by alterations in the gut microbiome. This could explain the relationship

The definition of obesity is mostly based on the body mass index (BMI—

Adipose tissue not only consists of adipocytes and connective tissue cells, but also contains immune cells as well (T cells, eosinophils, B regulatory cells and macrophages) [26–28]. In individuals with normal BMI, the immune cells interact with adipocytes and maintain a non-inflammatory environment by production of anti-inflammatory cytokines (IL-10, IL-4, IL-13) [27]. On the contrary, predominance of pro-inflammatory T helper (Th) type 1 and 17 cells and proinflammatory type of macrophages has been found in increased adipose tissue mass of obese individuals [27, 29, 30]. These changes result in the production of pro-inflammatory molecules such as tumor necrosis factor (TNF) and IL-6, which are one of the crucial cytokines involved in the pathogenesis of several rheumatic diseases. Moreover, obesity leads to an altered expression of adipokines, multifunctional molecules produced by white adipose tissue cells and involved in the regulation of inflammatory and autoimmune processes [31, 32]. The MetS and secretion of pro-inflammatory adipokines can be associated with CVDs and

Thus, obesity is not only a passive comorbidity, but can actively participate in the inflammatory process. According to the current evidence, obesity can negatively

especially in developed countries. The prevalence has been constantly growing over the years and to date, it is estimated to be almost 40% in the general population [21, 22]. Nevertheless, the association of obesity and CVDs in the general population is not clear [23]. Some evidence even suggests better prognosis for people with higher value of BMI [24]. However, there is a well-known correlation of obesity and increased risk of T2DM and coronary arterial disease (CAD), as well as a negative impact of obesity on other comorbidities including rheumatic diseases [23]. The immunomodulatory potential of adipose tissue and its ability to create an inflammatory environment of moderate activity could explain the effect of obesity as a risk factor for the development of some auto-

). Obesity, as well as MetS, is a global health problem

between the microbiome and systemic inflammatory response [20].

**2.2 Obesity as an active contributor to inflammation**

*Atherosclerosis in Rheumatology: Old and New Insights DOI: http://dx.doi.org/10.5772/intechopen.88605*

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

aging, smoking and hormonal factors [3].

syndrome (pSS) and others.

ties in rheumatic diseases.

with the systemic inflammatory disease apply [5].

**2. Cardiovascular risks in rheumatic diseases**

other comorbidities, among others depression [8–10].

**2.1 Metabolic syndrome and its association with immune disorders**

metabolism, arterial hypertension, and degeneration of vascular tissue caused by

It is well known that autoimmune diseases are accompanied by increased CV morbidity and mortality, caused by exacerbation of atherogenesis [2]. Traditional risk factors of ATS in general population such as dyslipidemia, glucose intolerance, arterial hypertension, etc. can explain only about 75% of CV manifestations in rheumatic patients [4]. In these patients, non-traditional risk factors associated

Despite the significant improvement of the therapy of rheumatic diseases, the incidence of CVD in rheumatic patients remains increased compared to that in general population [6]. Both the CV risk and CVD manifestations differ among rheumatic diseases according to the characteristic pathogenetic mechanism, inflammation activity and other specific features of the rheumatic diseases [7]. CV risk in the more prevalent rheumatic diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) is relatively best described. On the other hand, the situation is less clear in orphan connective tissue diseases such as systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIM), primary Sjögren's

The aim of this review chapter is to provide an overview and sum up the current knowledge on CV risk factors and the treatment options of ATS-related comorbidi-

Traditional CV risk factors play two roles in rheumatic patients: the first one as a trigger, the second as a consequence of the rheumatic disease activity [3]. Non-traditional risk factors are given by genetic and epigenetic factors, concurrent autoimmune inflammatory disorder and the specific features of each particular rheumatic disease (age of onset, duration, activity and the type of the disease) and

Metabolic syndrome (MetS) is defined as a cluster of comorbidities and risk factors leading to CVDs and increasing the CV mortality and morbidity. MetS includes obesity and visceral adiposity, diabetes and insulin resistance (IR), arterial hypertension (AH) and dyslipidemia [11]. The matter of mutual interactions and cross-talk of immune and metabolic system has become the object of many studies in recent years. Immune-metabolic interactions are regulated by genetic factors, nutritional status and by intestinal microbiome. The imbalance of the immune and metabolic interactions contributes to the occurrence and manifestation of rheumatic diseases [12]. The prevalence of MetS in general population is estimated to be 24–44% depending on the exact definition of the MetS and the studied population [11, 13], and increases in rheumatic patients and gout to as much as 36–42%, as was reported in studies comparing rheumatic patients to the healthy control population [13].

Different immune mechanisms have been reported to be implemented in the pathogenesis of MetS, including pro-inflammatory cytokines, namely interleukin (IL)-1 and IL-12 family. These cytokines are included in the regulation of immune response and atherogenic damage, and in the differentiation of T helper cells (Th), which participate in the pathogenesis of both autoimmune disorders and CVDs [14, 15]. Cytokines of IL-23/IL-17 signaling pathway are increased in rheumatic diseases, and significantly participate in atherogenesis [16]. MetS is associated with increased oxidative stress,

**30**

which, among others, leads to the formation of oxidized phospholipids (oxPL) and contributes to pathogenesis of autoimmune disorders [13].

IR is not only closely related to MetS, but is also considered to act as a key pathogenic factor in MetS [13]. The definition describes IR as a decreased sensitivity and responsiveness of target organs to the action of insulin resulting in hyperinsulinemia [17]. As consequence, this metabolic disorder leads to glucotoxicity, lipotoxicity and inflammation, all of which participate in endothelial damage and dysfunction [18]. The visceral fat tissue is considered to be the major locus of these unfavorable changes. Of note, CVDs, MetS and autoimmune disorders share common pathogenic mechanisms and mediators of inflammation and activity [13].

In recent years, study of microbiome has come to the forefront of interest. An imbalance of intestinal microbiota (dysbiosis) is characterized by a decrease of the number of beneficial intestinal bacteria and the overgrowth of potentially pathogenic bacteria. This phenomenon accompanies metabolic disorders and contributes to the emergence of MetS, obesity and type 2 diabetes mellitus (T2DM) [19]. Impaired balance of the intestinal flora may also contribute to the development of autoimmune disorders. Several studies have demonstrated onset of inflammation induced by alterations in the gut microbiome. This could explain the relationship between the microbiome and systemic inflammatory response [20].

#### **2.2 Obesity as an active contributor to inflammation**

The definition of obesity is mostly based on the body mass index (BMI values higher than 30 kg/m<sup>2</sup> ). Obesity, as well as MetS, is a global health problem especially in developed countries. The prevalence has been constantly growing over the years and to date, it is estimated to be almost 40% in the general population [21, 22]. Nevertheless, the association of obesity and CVDs in the general population is not clear [23]. Some evidence even suggests better prognosis for people with higher value of BMI [24]. However, there is a well-known correlation of obesity and increased risk of T2DM and coronary arterial disease (CAD), as well as a negative impact of obesity on other comorbidities including rheumatic diseases [23]. The immunomodulatory potential of adipose tissue and its ability to create an inflammatory environment of moderate activity could explain the effect of obesity as a risk factor for the development of some autoimmune diseases [22, 25].

Adipose tissue not only consists of adipocytes and connective tissue cells, but also contains immune cells as well (T cells, eosinophils, B regulatory cells and macrophages) [26–28]. In individuals with normal BMI, the immune cells interact with adipocytes and maintain a non-inflammatory environment by production of anti-inflammatory cytokines (IL-10, IL-4, IL-13) [27]. On the contrary, predominance of pro-inflammatory T helper (Th) type 1 and 17 cells and proinflammatory type of macrophages has been found in increased adipose tissue mass of obese individuals [27, 29, 30]. These changes result in the production of pro-inflammatory molecules such as tumor necrosis factor (TNF) and IL-6, which are one of the crucial cytokines involved in the pathogenesis of several rheumatic diseases. Moreover, obesity leads to an altered expression of adipokines, multifunctional molecules produced by white adipose tissue cells and involved in the regulation of inflammatory and autoimmune processes [31, 32]. The MetS and secretion of pro-inflammatory adipokines can be associated with CVDs and autoimmune disorders [13].

Thus, obesity is not only a passive comorbidity, but can actively participate in the inflammatory process. According to the current evidence, obesity can negatively affect the course of most rheumatic diseases, functional disability, quality of life and the overall prognosis [21, 22].

#### **2.3 Dyslipidemia in autoimmune disorders**

Dyslipidemia is one of the most common forms of metabolic disease in the general population and also a significant risk factor for atherogenic CVD. In the general population, dyslipidemia is characterized by an increased level of total cholesterol (TC), low-density lipoproteins (LDLs), triglycerides (TGs) and a decreased level of highdensity lipoproteins (HDLs) [33]. Under normal circumstances, HDL (in normal serum levels) exerts an anti-atherogenic effect: it removes cholesterol particles from cells (especially macrophages in the artery wall) and from circulation; inhibits the migration of macrophages and the binding of monocytes to the endothelium, oxidation of LDL; promotes endothelial repair and improves endothelial function, and also exerts antiinflammatory and anti-apoptotic effects [34–36]. In systemic inflammation, HDL is converted into a dysfunctional form due to loss of anti-inflammatory and anti-oxidative proteins. The modification of apolipoprotein A1 (apo-A1) results in the inability of HDL to uptake LDL from macrophages and in the activation of pro-inflammatory pathways leading to increased risk of coronary artery involvement [35, 37].

Moreover, quantitative changes of lipidogram related to disease activity are often seen in rheumatic diseases. In RA patients, the levels of TC and LDL are lower than in general population. This so-called lipid paradox, best described in RA, is associated with an increased CV risk [37]. Decrease in levels of TC and LDL has been found to precede clinical manifestation of RA. Later, TC and LDL levels tend to increase after the initiation of immunosuppressive therapy and on the contrary, decline during the relapse of RA [38]. Therefore, the low levels of TC and LDL can be misinterpreted as a low CV risk factor when evaluated according to the scoring tools (e.g., Framingham risk score, Reynolds risk score, Systemic Coronary Risk Evaluation—SCORE) [39–41].

A small study in early RA patients reported non-significant, beneficial effect of methotrexate similar to that of tumor necrosis factor inhibitors (anti-TNF) on lipidogram [42]. On the other hand, higher levels of TC, LDL and TG were described in patients with ankylosing spondylitis (AS) treated by anti-TNF compared to AS patients on nonsteroidal anti-inflammatory drug (NSAID) therapy. Nevertheless, results reported in a cross-sectional study do not allow for a generalized assessment of the influence of long-term anti-TNF therapy on lipidogram in AS [43].

Dyslipidemia is found in almost half of SLE patients, characterized by elevated levels of very-low density lipoprotein (VLDL) and TG. Increased levels of TC and TG are associated with two times increased risk of CVD [44]. In SSc, dyslipidemia is characterized by increased levels of lipoprotein A (LpA) and LDL and decreased levels of HDL and TC [45].

#### **2.4 Role of immune system and autoantibodies in atherogenesis**

The presence of immune cells in atherosclerotic plaques proves the participation of immune system in atherogenesis [46, 47]. These infiltrating immune cells are responsible for the promotion and exacerbation of ATS [48]. All the components of immune system are included in atherogenesis, while TNF and IL-1β are the most significant pro-inflammatory cytokines and mediators [1].

Damage of endothelium is the first step in atherogenesis. Particles circulating in the blood penetrate the damaged endothelial barrier into subendothelial layer via the interaction with adhesion molecules on the surface of endothelium. These

**33**

*Atherosclerosis in Rheumatology: Old and New Insights DOI: http://dx.doi.org/10.5772/intechopen.88605*

protective role of anti-oxLDL antibodies in pSS [52].

manifested ATS in non-rheumatic population, as well [56].

**2.5 Immunosuppressive therapy and its effect on CV risk**

relatively safest drug from this group [58].

check the reasons to continue glucocorticoid therapy [59].

reactions lead to activation of endothelium and attraction of immune cells [1]. Penetrating particles consist mainly of LDL, which are one of the targets of oxidation and form oxLDL (oxidized LDL). oxLDLs are taken up by macrophages, which subsequently transform into the foam cells. Specific autoantibodies against oxLDL (anti-oxLDL) were detected in the sera of individuals from the general population as well as in rheumatic patients [49]. Furthermore, in rheumatic patients, the levels of anti-oxLDL are increased compared to those in the general population [49, 50]. The presence of these antibodies can predict the peripheral vascular involvement and even the severity of ATS [51]. On the other hand, increased levels of anti-oxLDL antibodies in patients with pSS were paradoxically associated with decreased occurrence of plaques (unlike in RA or SLE), which suggests a possible

Many autoantibodies have been described to have a relation to higher risk of ATS and its clinical manifestations [2]. These include the antibodies against heat shock proteins (HSPs), which are expressed on the surface of endothelial cells exposed to stress, and to β-2-glycoprotein I (β2GPI), which are abundantly expressed within the subendothelial layer and intima-media borders of plaques [46, 53]. Furthermore, antinuclear antibodies (ANAs) are more frequently detected in patients with symptomatic angina pectoris and the three-vessel disease compared to individuals without coronary artery involvement [54]. Moreover, ANA positivity is associated with an increased risk of myocardial infarction (MI) in non-rheumatic individuals [55]. Specific anti-endothelial cell antibodies (AECAs) are associated with subclinical or

Immunosuppressive therapy of rheumatic diseases has a potential effect on CV morbidity and mortality in two ways: on the one hand, it suppresses the inflammatory activity and thus decreases the CV risk; on the other hand, the adverse effect of some drugs can worsen the CV risk [9, 57]. NSAIDs and coxibs (selective blockers of cyclooxygenase-2) mostly used in inflammatory arthropathies exert pro-thrombotic effect and have a negative impact on the CV risk. Due to this fact, benefit-risk ratio should be evaluated individually in every case. Naproxen is considered as the

Corticosteroids (CSs) suppress the inflammatory activity, hence dampen the CV risk [59, 60]. On the other hand, CSs cause or worsen the traditional CV risk factors [61]. Meta-analysis evaluating CS therapy in RA reported that a long-term therapy with prednisone or prednisone-equivalents in high doses (above 7.5 mg per day) is associated with an increased risk of CV mortality [62]. The effect of lower doses (7.5–10 mg a day) is uncertain [63]. Duration and the cumulative dose of CS are considered as CV risk factors in SLE. Nevertheless, current evidence regarding the CS therapy in SLE is not conclusive [44]. European League Against Rheumatism (EULAR) recommends, especially in inflammatory arthropathies, to keep the glucocorticoid dosage to a minimum and to taper glucocorticoids in case of remission or low disease activity and to regularly

The group of disease-modifying anti-rheumatic drugs (DMARDs) is a heterogeneous entity of medicaments with immunosuppressive effects of various specificity: less specific conventional synthetic DMARDs (csDMARD), or more specific biologic (bDMARDs), biosimilar (bsDMARDs) or targeted synthetic molecules (tsDMARDs). The side effects differ within the whole group. csDMARDs have a potential to reduce atherogenesis and progression of ATS [64]. Thus, the early initiation of therapy with scDMARDs can prevent development of CVDs [65].

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

**2.3 Dyslipidemia in autoimmune disorders**

leading to increased risk of coronary artery involvement [35, 37].

and the overall prognosis [21, 22].

Evaluation—SCORE) [39–41].

levels of HDL and TC [45].

affect the course of most rheumatic diseases, functional disability, quality of life

Dyslipidemia is one of the most common forms of metabolic disease in the general population and also a significant risk factor for atherogenic CVD. In the general population, dyslipidemia is characterized by an increased level of total cholesterol (TC), low-density lipoproteins (LDLs), triglycerides (TGs) and a decreased level of highdensity lipoproteins (HDLs) [33]. Under normal circumstances, HDL (in normal serum levels) exerts an anti-atherogenic effect: it removes cholesterol particles from cells (especially macrophages in the artery wall) and from circulation; inhibits the migration of macrophages and the binding of monocytes to the endothelium, oxidation of LDL; promotes endothelial repair and improves endothelial function, and also exerts antiinflammatory and anti-apoptotic effects [34–36]. In systemic inflammation, HDL is converted into a dysfunctional form due to loss of anti-inflammatory and anti-oxidative proteins. The modification of apolipoprotein A1 (apo-A1) results in the inability of HDL to uptake LDL from macrophages and in the activation of pro-inflammatory pathways

Moreover, quantitative changes of lipidogram related to disease activity are often seen in rheumatic diseases. In RA patients, the levels of TC and LDL are lower than in general population. This so-called lipid paradox, best described in RA, is associated with an increased CV risk [37]. Decrease in levels of TC and LDL has been found to precede clinical manifestation of RA. Later, TC and LDL levels tend to increase after the initiation of immunosuppressive therapy and on the contrary, decline during the relapse of RA [38]. Therefore, the low levels of TC and LDL can be misinterpreted as a low CV risk factor when evaluated according to the scoring tools (e.g., Framingham risk score, Reynolds risk score, Systemic Coronary Risk

A small study in early RA patients reported non-significant, beneficial effect of methotrexate similar to that of tumor necrosis factor inhibitors (anti-TNF) on lipidogram [42]. On the other hand, higher levels of TC, LDL and TG were described in patients with ankylosing spondylitis (AS) treated by anti-TNF compared to AS patients on nonsteroidal anti-inflammatory drug (NSAID) therapy. Nevertheless, results reported in a cross-sectional study do not allow for a generalized assessment

Dyslipidemia is found in almost half of SLE patients, characterized by elevated levels of very-low density lipoprotein (VLDL) and TG. Increased levels of TC and TG are associated with two times increased risk of CVD [44]. In SSc, dyslipidemia is characterized by increased levels of lipoprotein A (LpA) and LDL and decreased

The presence of immune cells in atherosclerotic plaques proves the participation of immune system in atherogenesis [46, 47]. These infiltrating immune cells are responsible for the promotion and exacerbation of ATS [48]. All the components of immune system are included in atherogenesis, while TNF and IL-1β are the most

Damage of endothelium is the first step in atherogenesis. Particles circulating in the blood penetrate the damaged endothelial barrier into subendothelial layer via the interaction with adhesion molecules on the surface of endothelium. These

of the influence of long-term anti-TNF therapy on lipidogram in AS [43].

**2.4 Role of immune system and autoantibodies in atherogenesis**

significant pro-inflammatory cytokines and mediators [1].

**32**

reactions lead to activation of endothelium and attraction of immune cells [1]. Penetrating particles consist mainly of LDL, which are one of the targets of oxidation and form oxLDL (oxidized LDL). oxLDLs are taken up by macrophages, which subsequently transform into the foam cells. Specific autoantibodies against oxLDL (anti-oxLDL) were detected in the sera of individuals from the general population as well as in rheumatic patients [49]. Furthermore, in rheumatic patients, the levels of anti-oxLDL are increased compared to those in the general population [49, 50]. The presence of these antibodies can predict the peripheral vascular involvement and even the severity of ATS [51]. On the other hand, increased levels of anti-oxLDL antibodies in patients with pSS were paradoxically associated with decreased occurrence of plaques (unlike in RA or SLE), which suggests a possible protective role of anti-oxLDL antibodies in pSS [52].

Many autoantibodies have been described to have a relation to higher risk of ATS and its clinical manifestations [2]. These include the antibodies against heat shock proteins (HSPs), which are expressed on the surface of endothelial cells exposed to stress, and to β-2-glycoprotein I (β2GPI), which are abundantly expressed within the subendothelial layer and intima-media borders of plaques [46, 53]. Furthermore, antinuclear antibodies (ANAs) are more frequently detected in patients with symptomatic angina pectoris and the three-vessel disease compared to individuals without coronary artery involvement [54]. Moreover, ANA positivity is associated with an increased risk of myocardial infarction (MI) in non-rheumatic individuals [55]. Specific anti-endothelial cell antibodies (AECAs) are associated with subclinical or manifested ATS in non-rheumatic population, as well [56].

#### **2.5 Immunosuppressive therapy and its effect on CV risk**

Immunosuppressive therapy of rheumatic diseases has a potential effect on CV morbidity and mortality in two ways: on the one hand, it suppresses the inflammatory activity and thus decreases the CV risk; on the other hand, the adverse effect of some drugs can worsen the CV risk [9, 57]. NSAIDs and coxibs (selective blockers of cyclooxygenase-2) mostly used in inflammatory arthropathies exert pro-thrombotic effect and have a negative impact on the CV risk. Due to this fact, benefit-risk ratio should be evaluated individually in every case. Naproxen is considered as the relatively safest drug from this group [58].

Corticosteroids (CSs) suppress the inflammatory activity, hence dampen the CV risk [59, 60]. On the other hand, CSs cause or worsen the traditional CV risk factors [61]. Meta-analysis evaluating CS therapy in RA reported that a long-term therapy with prednisone or prednisone-equivalents in high doses (above 7.5 mg per day) is associated with an increased risk of CV mortality [62]. The effect of lower doses (7.5–10 mg a day) is uncertain [63]. Duration and the cumulative dose of CS are considered as CV risk factors in SLE. Nevertheless, current evidence regarding the CS therapy in SLE is not conclusive [44]. European League Against Rheumatism (EULAR) recommends, especially in inflammatory arthropathies, to keep the glucocorticoid dosage to a minimum and to taper glucocorticoids in case of remission or low disease activity and to regularly check the reasons to continue glucocorticoid therapy [59].

The group of disease-modifying anti-rheumatic drugs (DMARDs) is a heterogeneous entity of medicaments with immunosuppressive effects of various specificity: less specific conventional synthetic DMARDs (csDMARD), or more specific biologic (bDMARDs), biosimilar (bsDMARDs) or targeted synthetic molecules (tsDMARDs). The side effects differ within the whole group. csDMARDs have a potential to reduce atherogenesis and progression of ATS [64]. Thus, the early initiation of therapy with scDMARDs can prevent development of CVDs [65].

Antimalarial drugs have been reported to act favorably on lipid and glucose metabolism, and in SLE patients, they have been described to reduce hypercholesterolemia, ATS and the risk of thrombosis [44, 66, 67]. In addition, hydroxychloroquine (HCQ ) influences the production of cytokines, activation of T cells and monocytes via interaction with Toll-like receptor (TLR) signaling pathway, and attenuates the oxidative stress and endothelial dysfunction [68].

The effects of methotrexate (MTX) on the CV risk have been best studied in RA, in which the potential to reduce the risk of heart failure by half was demonstrated [69]. Moreover, MTX can decrease the mortality of RA patients caused by CVDs by 30% [70]. The data suggest that MTX should be considered cardioprotective in rheumatic diseases, although the exact mechanism of this effect is not known yet [71]. A possible link with anti-inflammatory effect has been proposed [72]. On the other hand, according to the results of a recent randomized controlled trial in patients with carotid artery disease or history of MI and concurrent T2DM or MetS, no protective effect of MTX in low doses (15–20 mg weekly) on future risk of CVD was described [73]. Data in other DMARDs are insufficient and, therefore, the effect on CV risk is not clear.

bDMARDs are targeting selectively specific pro-inflammatory molecules, which significantly participate in both pathogenesis of inflammatory diseases and atherogenesis (e.g., TNF, IL-1r, IL-6 and others) [74]. In this group, TNF inhibitors (anti-TNFs) are the best-studied drugs regarding the possible effect on the CV risk. On the one hand, they exert anti-inflammatory and anti-atherogenic effect; on the other hand, they have been demonstrated to worsen the cardiac insufficiency in a couple of first published studies [3, 8]. Their benefit was proven in several randomized controlled trials (RCTs) with more or less significantly beneficial effect when compared to MTX [72, 75–77]. Anti-TNFa influences particularly the level of HDL and restores its anti-atherogenic potential [78]. The results of RCTs in RA, PsA and psoriasis show a beneficial effect of anti-TNF therapy on glucose metabolism and MetS [79]. Anti-TNFs also reduce the risk of T2DM manifestation and prevent endothelial damage due to specific inhibition of TNF [74, 80]. Overall, current data support the beneficial effect of anti-TNF therapy on CV risk and CVD incidence that is probably related to the attenuation of inflammation and thus also of atherogenesis rather than to the effect on lipidogram (which can change as a consequence of changes in disease activity as well). Published studies have reported the potential of anti-TNF to reduce intima-media thickness and the number of unstable plaques [81]. Nevertheless, anti-TNF therapy is not recommended in patients with congestive heart failure [82]. Not only no positive effect, but even a negative effect of anti-TNF on chronic heart failure has been described. Experts therefore suggest performing a baseline echocardiography examination in patients at risk before the commencement of anti-TNF therapy [81].

Higher IL-6 levels are associated with an increased CV risk, therefore therapeutic blockade of tocilizumab (inhibitor of IL-6 receptor) has a protective potential [83]. Recently published RCT with tocilizumab and etanercept (anti-TNF) reported very similar effect of both drugs on CV risk [84]. Inhibition of the IL-6 receptor by tocilizumab is assumed to influence lipid metabolism in a favorable manner due to blockade of the mobilization of fatty acids to peripheral tissues mediated by IL-6 [84]. On the contrary, anti-IL-6r therapy is known to cause a significant increase in the levels of HDL, TC, LDL and TG [85].

Rituximab (RTX, anti-CD20) is supposed to have a beneficial effect on CV risk due to inhibition of B cells and release of (auto)antibodies, which participate in the vasoconstriction, activation of thrombocytes and promote rupture of atherosclerotic plaques [74]. In SLE patients, the RTX therapy was associated with improvement of lipidogram [86]. The overall effect of RTX on CV risk is not clear, due to limited data

**35**

*Atherosclerosis in Rheumatology: Old and New Insights DOI: http://dx.doi.org/10.5772/intechopen.88605*

large cohorts of rheumatic patients.

comparable to the risk in diabetes [93].

**3.2 Ankylosing spondylitis**

**3.1 Rheumatoid arthritis**

and lack of SLE patients treated by RTX [44]. To date, studies with RTX have not shown any long-term adverse cardiovascular effects or cardiotoxicity [74, 87]. The recent study CANTOS (Canacinumab Antiinflammatory Thrombosis Outcome Study) has proven the ability of anti-IL-1b (canacinumab) to reduce the CV events and stroke in non-rheumatic patients with history of MI [88]. The effect of bDMARDs, including the latest bsDMARDs and tsDMARDs, on the CV risk needs to be closely monitored and evaluated in long-term studies with sufficiently

**3. Atherosclerosis and its manifestation in rheumatic diseases**

RA is relatively the most common autoimmune disease with prevalence of 1%, which primarily affects joints and can also manifest by extra-articular involvement. The most frequent occurrence of RA is in middle-aged women. It can shorten the life expectancy by up to 2.5 years [89, 90]. In addition, there is up to three times higher mortality in RA patients compared to the general population [91]. CV involvement and complications, including asymptomatic heart failure or silent MI and sudden death, are the leading death causes in RA patients and occur in RA patients 1.5 times more often than in the general population [2, 92]. CV risk in RA is

The underlying mechanism of increased CV mortality in RA is not completely understood [94]. The main cause of death in RA is ischemic heart disease (IHD), often asymptomatic and underdiagnosed [91, 95, 96]. Up to three times increased risk of IHD in RA patients with positivity of anti-cyclic citrullinated peptide (aCCP) antibodies and rheumatoid factor (RF) has been reported [69, 97].

In fact, RA itself can act as an independent risk factor for development of CVD [98]. The relation between an increase in the CV risk and the disease duration of RA patients is partly attributable to a higher prevalence of hypertension and smoking [99]. In RA, CV risk is also significantly related to traditional risk factors [100]. Smoking has a negative impact on the course of RA and stimulates the production of RF and aCCP nevertheless, the direct role in the increase of CV risk was not proved [98, 101].

Systemic inflammation accompanying the activity of RA significantly contributes to the atherogenesis and CV mortality [102]. The reduction of CV risk was observed during the DMARD therapy (namely HCQ, MTX, anti-TNFs). According to available studies and their meta-analysis, CV risk is most increased by CS therapy (up to 47%) and NSAIDs, in particular by coxibs (by 36%), and, on the contrary, is

AS is a chronic inflammatory disease, which primarily affects the joints in the site of enthesis. It belongs to the group of diagnostic entity called spondyloarthropathies, which typically manifest in HLA-B27 positive patients. Similar to RA, AS can also manifest with extra-articular manifestations, such as gastrointestinal, ocular and cardiac involvement. The prevalence of AS in the population is about 0.1% (the overall prevalence of spondyloarthritis is around 1%) and, unlike most rheumatic

Similar to RA, an increased CV risk has been reported in AS patients [104, 105]. However, views on the close association of ATS and AS are divergent, in particular, due to the small evidence and conflicting results of studies [106]. Regarding the evidence

decreased by MTX (by 28%) or anti-TNF therapy (by about 30%) [72].

diseases, occurs more frequently in men (up to three times) [103].

and lack of SLE patients treated by RTX [44]. To date, studies with RTX have not shown any long-term adverse cardiovascular effects or cardiotoxicity [74, 87].

The recent study CANTOS (Canacinumab Antiinflammatory Thrombosis Outcome Study) has proven the ability of anti-IL-1b (canacinumab) to reduce the CV events and stroke in non-rheumatic patients with history of MI [88]. The effect of bDMARDs, including the latest bsDMARDs and tsDMARDs, on the CV risk needs to be closely monitored and evaluated in long-term studies with sufficiently large cohorts of rheumatic patients.

#### **3. Atherosclerosis and its manifestation in rheumatic diseases**

#### **3.1 Rheumatoid arthritis**

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

effect on CV risk is not clear.

Antimalarial drugs have been reported to act favorably on lipid and glucose metabolism, and in SLE patients, they have been described to reduce hypercholesterolemia, ATS and the risk of thrombosis [44, 66, 67]. In addition, hydroxychloroquine (HCQ ) influences the production of cytokines, activation of T cells and monocytes via interaction with Toll-like receptor (TLR) signaling pathway, and

The effects of methotrexate (MTX) on the CV risk have been best studied in RA, in which the potential to reduce the risk of heart failure by half was demonstrated [69]. Moreover, MTX can decrease the mortality of RA patients caused by CVDs by 30% [70]. The data suggest that MTX should be considered cardioprotective in rheumatic diseases, although the exact mechanism of this effect is not known yet [71]. A possible link with anti-inflammatory effect has been proposed [72]. On the other hand, according to the results of a recent randomized controlled trial in patients with carotid artery disease or history of MI and concurrent T2DM or MetS, no protective effect of MTX in low doses (15–20 mg weekly) on future risk of CVD was described [73]. Data in other DMARDs are insufficient and, therefore, the

bDMARDs are targeting selectively specific pro-inflammatory molecules, which significantly participate in both pathogenesis of inflammatory diseases and atherogenesis (e.g., TNF, IL-1r, IL-6 and others) [74]. In this group, TNF inhibitors (anti-TNFs) are the best-studied drugs regarding the possible effect on the CV risk. On the one hand, they exert anti-inflammatory and anti-atherogenic effect; on the other hand, they have been demonstrated to worsen the cardiac insufficiency in a couple of first published studies [3, 8]. Their benefit was proven in several randomized controlled trials (RCTs) with more or less significantly beneficial effect when compared to MTX [72, 75–77]. Anti-TNFa influences particularly the level of HDL and restores its anti-atherogenic potential [78]. The results of RCTs in RA, PsA and psoriasis show a beneficial effect of anti-TNF therapy on glucose metabolism and MetS [79]. Anti-TNFs also reduce the risk of T2DM manifestation and prevent endothelial damage due to specific inhibition of TNF [74, 80]. Overall, current data support the beneficial effect of anti-TNF therapy on CV risk and CVD incidence that is probably related to the attenuation of inflammation and thus also of atherogenesis rather than to the effect on lipidogram (which can change as a consequence of changes in disease activity as well). Published studies have reported the potential of anti-TNF to reduce intima-media thickness and the number of unstable plaques [81]. Nevertheless, anti-TNF therapy is not recommended in patients with congestive heart failure [82]. Not only no positive effect, but even a negative effect of anti-TNF on chronic heart failure has been described. Experts therefore suggest performing a baseline echocardiography examination in

patients at risk before the commencement of anti-TNF therapy [81].

the levels of HDL, TC, LDL and TG [85].

Higher IL-6 levels are associated with an increased CV risk, therefore therapeutic blockade of tocilizumab (inhibitor of IL-6 receptor) has a protective potential [83]. Recently published RCT with tocilizumab and etanercept (anti-TNF) reported very similar effect of both drugs on CV risk [84]. Inhibition of the IL-6 receptor by tocilizumab is assumed to influence lipid metabolism in a favorable manner due to blockade of the mobilization of fatty acids to peripheral tissues mediated by IL-6 [84]. On the contrary, anti-IL-6r therapy is known to cause a significant increase in

Rituximab (RTX, anti-CD20) is supposed to have a beneficial effect on CV risk due to inhibition of B cells and release of (auto)antibodies, which participate in the vasoconstriction, activation of thrombocytes and promote rupture of atherosclerotic plaques [74]. In SLE patients, the RTX therapy was associated with improvement of lipidogram [86]. The overall effect of RTX on CV risk is not clear, due to limited data

attenuates the oxidative stress and endothelial dysfunction [68].

**34**

RA is relatively the most common autoimmune disease with prevalence of 1%, which primarily affects joints and can also manifest by extra-articular involvement. The most frequent occurrence of RA is in middle-aged women. It can shorten the life expectancy by up to 2.5 years [89, 90]. In addition, there is up to three times higher mortality in RA patients compared to the general population [91]. CV involvement and complications, including asymptomatic heart failure or silent MI and sudden death, are the leading death causes in RA patients and occur in RA patients 1.5 times more often than in the general population [2, 92]. CV risk in RA is comparable to the risk in diabetes [93].

The underlying mechanism of increased CV mortality in RA is not completely understood [94]. The main cause of death in RA is ischemic heart disease (IHD), often asymptomatic and underdiagnosed [91, 95, 96]. Up to three times increased risk of IHD in RA patients with positivity of anti-cyclic citrullinated peptide (aCCP) antibodies and rheumatoid factor (RF) has been reported [69, 97].

In fact, RA itself can act as an independent risk factor for development of CVD [98]. The relation between an increase in the CV risk and the disease duration of RA patients is partly attributable to a higher prevalence of hypertension and smoking [99]. In RA, CV risk is also significantly related to traditional risk factors [100]. Smoking has a negative impact on the course of RA and stimulates the production of RF and aCCP nevertheless, the direct role in the increase of CV risk was not proved [98, 101].

Systemic inflammation accompanying the activity of RA significantly contributes to the atherogenesis and CV mortality [102]. The reduction of CV risk was observed during the DMARD therapy (namely HCQ, MTX, anti-TNFs). According to available studies and their meta-analysis, CV risk is most increased by CS therapy (up to 47%) and NSAIDs, in particular by coxibs (by 36%), and, on the contrary, is decreased by MTX (by 28%) or anti-TNF therapy (by about 30%) [72].

#### **3.2 Ankylosing spondylitis**

AS is a chronic inflammatory disease, which primarily affects the joints in the site of enthesis. It belongs to the group of diagnostic entity called spondyloarthropathies, which typically manifest in HLA-B27 positive patients. Similar to RA, AS can also manifest with extra-articular manifestations, such as gastrointestinal, ocular and cardiac involvement. The prevalence of AS in the population is about 0.1% (the overall prevalence of spondyloarthritis is around 1%) and, unlike most rheumatic diseases, occurs more frequently in men (up to three times) [103].

Similar to RA, an increased CV risk has been reported in AS patients [104, 105]. However, views on the close association of ATS and AS are divergent, in particular, due to the small evidence and conflicting results of studies [106]. Regarding the evidence

on CV events in AS, the situation is similarly unsatisfactory and inconclusive [107–109]. Recently published meta-analysis has reported an increased risk of MI (RR = 1.6) and cerebrovascular events (RR = 1.5) compared to the general population [110].

There are several risk factors in AS, which participate in CV comorbidities. Since laboratory markers of inflammation are not elevated in many patients, CV risk is likely related to the risk profile of a typical patient with AS: a smoker with arterial hypertension and dyslipidemia, in whom low levels of HDL and TC accompany the disease activity [105, 110]. In addition, extra-articular cardiac manifestations of AS (e.g., conduction disorders, aortic valve insufficiency, left ventricular dysfunction) contribute to CV morbidity and mortality [105]. Levels of C-reactive protein (CRP), therapy with NSAIDs and work disability are considered significant predictive factors of CV mortality in AS [111, 112]. NSAIDs as the first-line therapy with the highest safety profile should be prescribed for the shortest time period possible [110]. On the other hand, anti-TNFs have a favorable effect on the endothelial function and a decrease of the CV risk [105, 113].

#### **3.3 Psoriatic arthritis**

PsA is a systemic inflammatory disease from the spondyloarthritis spectrum, associated with psoriasis [114]. The prevalence is 0.05–0.25% in the general population, but rises to 15–30% in patients with psoriasis [115]. The relative risk of CV involvement in psoriasis is reported to be 1.4, but the relative risk in PsA is less studied and the data are conflicting [116–119]. Meta-analysis demonstrated a 1.43 fold higher CV risk in PsA patients compared to the general population. The incidence of MI, cerebrovascular events and heart failure has been reported to be increased (1.68, 1.22 and 1.31, respectively) [120].

According to the current evidence, various manifestations of ATS in PsA have been described, from subclinical involvement to symptomatic manifestations [121–125]. PsA is considered to be an additional independent CV risk factor, as proved by findings of more severe subclinical ATS compared to the general population and the association of plaque development with the inflammatory activity of PsA [120].

PsA is typically associated with high prevalence of MetS, which is two or three times more common than in other rheumatic diseases and the general population [126]. During the active inflammatory phase, there are characteristic alterations of lipidogram with a decrease of HDL and LDL, which consequently rises in remission of the disease [9]. The suggested mechanism, which causes changes of HDL levels, is the uptake of apoA-1 in the tissue affected by inflammation: particles of HDL penetrate from the circulation due to increased endothelial permeability. The consequent decline of serum HDL concentrations increases the CV risk in PsA in a similar manner as in RA [127].

The presence of subclinical ATS and its correlation with inflammatory markers and the effect of immunosuppressive therapy are questionable [9, 128]. Anti-TFN therapy seems to have a beneficial effect on CV risk in PsA, as well as in AS [129].

#### **3.4 Systemic lupus erythematosus**

SLE is characterized by a wide spectrum of clinical manifestations and involvement of different organs. The prevalence is 0.03% in Caucasian population, while SLE affects predominantly women in reproductive years, in whom the clinically significant ATS is not usually found under normal circumstances [130]. Although the survival of SLE has significantly improved, thanks to new therapeutic options, it still remains 5–10 years shorter compared to the general population [131]. The rate of SLE-associated mortality has declined, but the rate

**37**

*Atherosclerosis in Rheumatology: Old and New Insights DOI: http://dx.doi.org/10.5772/intechopen.88605*

from the CV manifestations [132].

bodies play significant role in ATS [2].

than in the general population [136, 137].

the general population [138].

**3.5 Systemic sclerosis**

of CV complications, which are considered to be the leading cause of mortality in SLE nowadays and are responsible for 30% of deaths, has risen [131]. The bimodal mortality pattern describes two peaks of mortality in SLE population: the first peak represents death early in the course of the disease related to the disease activity and infectious complications, and the second peak refers to late death

The prevalence of traditional risk factors is higher in SLE compared to the general population [133]. In addition, SLE-related risk factors, including renal involvement, apply in CV morbidity. The presence of SLE itself increases the risk of heart failure up to three times [134]. The clinical manifestation of ATS in SLE is predicted particularly by higher age at the onset of SLE, presence of arterial hypertension and hypercholesterolemia. Among others, the cumulative dose and the duration of CS therapy, long duration of SLE, and activity of immune system including autoanti-

Due to their pathophysiologic mechanism both SLE and vasculitis predispose to the atherosclerotic involvement of coronary circulation [135]. Coronary artery disease affects 6–10% of SLE patients and the incidence is four to eight times higher

Risk of heart failure in SLE significantly rises immediately after the first manifestation of the autoimmune disorder, mostly at a young age. The relative risk of heart failure is therefore most increased in young patients in the age between 20 and 30 years, and decreases with a higher age. However, the incidence of CV diseases and heart failure is continually increasing in positive correlation with the increasing age of patients [134]. SLE patients are at 5–10 times higher risk, and young SLE women at age around 40 years are even at 50 times higher risk of MI compared to

Concerning the risk of a stroke in SLE, the ischemic stroke is estimated to be two times, hemorrhagic stroke three times and subarachnoid hemorrhage four times more common in SLE than in the general population [139]. In case of a stroke, young patients are more threatened due to accelerated ATS during the high activity of inflammation. The relation between disease activity and the risk of a stroke was described also in other diseases. Immunosuppressive therapy and other comorbidities (e.g., vasculitis, antiphospholipid syndrome, arterial hypertension) take part in this increased risk, as well [139]. Accompanying factors such as antiphospholipid syndrome, Liebman-Sacks endocarditis and formation of immune complexes of antibodies with antigens predispose patients to thrombotic complications and ischemic stroke, while endothelial dysfunction and interrupted endothelial layer integrity can lead to hemorrhagic stroke. Subarachnoid hemorrhage in SLE probably results from intracerebral vasculitis and concurrent arterial hypertension [139]. Atherosclerotic plaques have been detected in 17–65% of SLE patients using ultrasound examination. The age seems to play a major role in prediction of atherosclerosis and its manifestations in SLE. Some experts suggest a role of consequences of the disease activity and side effects of therapy in older patients with SLE [2].

SSc belongs to orphan connective tissue diseases with the prevalence of 0.003– 0.06%, and is less understood, concerning the CV risk. The key pathologies leading to CV involvement are vasculopathy, inflammation and tissue fibrosis, which can also affect the heart. In addition to pathognomic microvasculopathy, macrovascular

To date, the relative risk of CV diseases in SSc in not known. Survival of SSc patients is about 16–34 years shorter compared to the general population with about

involvement is getting more attention in the last years [45].

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

the CV risk [105, 113].

**3.3 Psoriatic arthritis**

similar manner as in RA [127].

**3.4 Systemic lupus erythematosus**

on CV events in AS, the situation is similarly unsatisfactory and inconclusive [107–109]. Recently published meta-analysis has reported an increased risk of MI (RR = 1.6) and

There are several risk factors in AS, which participate in CV comorbidities. Since laboratory markers of inflammation are not elevated in many patients, CV risk is likely related to the risk profile of a typical patient with AS: a smoker with arterial hypertension and dyslipidemia, in whom low levels of HDL and TC accompany the disease activity [105, 110]. In addition, extra-articular cardiac manifestations of AS (e.g., conduction disorders, aortic valve insufficiency, left ventricular dysfunction) contribute to CV morbidity and mortality [105]. Levels of C-reactive protein (CRP), therapy with NSAIDs and work disability are considered significant predictive factors of CV mortality in AS [111, 112]. NSAIDs as the first-line therapy with the highest safety profile should be prescribed for the shortest time period possible [110]. On the other hand, anti-TNFs have a favorable effect on the endothelial function and a decrease of

PsA is a systemic inflammatory disease from the spondyloarthritis spectrum,

According to the current evidence, various manifestations of ATS in PsA have been described, from subclinical involvement to symptomatic manifestations [121–125]. PsA is considered to be an additional independent CV risk factor, as proved by findings of more severe subclinical ATS compared to the general population and the association

PsA is typically associated with high prevalence of MetS, which is two or three times more common than in other rheumatic diseases and the general population [126]. During the active inflammatory phase, there are characteristic alterations of lipidogram with a decrease of HDL and LDL, which consequently rises in remission of the disease [9]. The suggested mechanism, which causes changes of HDL levels, is the uptake of apoA-1 in the tissue affected by inflammation: particles of HDL penetrate from the circulation due to increased endothelial permeability. The consequent decline of serum HDL concentrations increases the CV risk in PsA in a

The presence of subclinical ATS and its correlation with inflammatory markers and the effect of immunosuppressive therapy are questionable [9, 128]. Anti-TFN therapy seems to have a beneficial effect on CV risk in PsA, as well as in AS [129].

SLE is characterized by a wide spectrum of clinical manifestations and involvement of different organs. The prevalence is 0.03% in Caucasian population, while SLE affects predominantly women in reproductive years, in whom the clinically significant ATS is not usually found under normal circumstances [130]. Although the survival of SLE has significantly improved, thanks to new therapeutic options, it still remains 5–10 years shorter compared to the general population [131]. The rate of SLE-associated mortality has declined, but the rate

associated with psoriasis [114]. The prevalence is 0.05–0.25% in the general population, but rises to 15–30% in patients with psoriasis [115]. The relative risk of CV involvement in psoriasis is reported to be 1.4, but the relative risk in PsA is less studied and the data are conflicting [116–119]. Meta-analysis demonstrated a 1.43 fold higher CV risk in PsA patients compared to the general population. The incidence of MI, cerebrovascular events and heart failure has been reported to be

increased (1.68, 1.22 and 1.31, respectively) [120].

of plaque development with the inflammatory activity of PsA [120].

cerebrovascular events (RR = 1.5) compared to the general population [110].

**36**

of CV complications, which are considered to be the leading cause of mortality in SLE nowadays and are responsible for 30% of deaths, has risen [131]. The bimodal mortality pattern describes two peaks of mortality in SLE population: the first peak represents death early in the course of the disease related to the disease activity and infectious complications, and the second peak refers to late death from the CV manifestations [132].

The prevalence of traditional risk factors is higher in SLE compared to the general population [133]. In addition, SLE-related risk factors, including renal involvement, apply in CV morbidity. The presence of SLE itself increases the risk of heart failure up to three times [134]. The clinical manifestation of ATS in SLE is predicted particularly by higher age at the onset of SLE, presence of arterial hypertension and hypercholesterolemia. Among others, the cumulative dose and the duration of CS therapy, long duration of SLE, and activity of immune system including autoantibodies play significant role in ATS [2].

Due to their pathophysiologic mechanism both SLE and vasculitis predispose to the atherosclerotic involvement of coronary circulation [135]. Coronary artery disease affects 6–10% of SLE patients and the incidence is four to eight times higher than in the general population [136, 137].

Risk of heart failure in SLE significantly rises immediately after the first manifestation of the autoimmune disorder, mostly at a young age. The relative risk of heart failure is therefore most increased in young patients in the age between 20 and 30 years, and decreases with a higher age. However, the incidence of CV diseases and heart failure is continually increasing in positive correlation with the increasing age of patients [134]. SLE patients are at 5–10 times higher risk, and young SLE women at age around 40 years are even at 50 times higher risk of MI compared to the general population [138].

Concerning the risk of a stroke in SLE, the ischemic stroke is estimated to be two times, hemorrhagic stroke three times and subarachnoid hemorrhage four times more common in SLE than in the general population [139]. In case of a stroke, young patients are more threatened due to accelerated ATS during the high activity of inflammation. The relation between disease activity and the risk of a stroke was described also in other diseases. Immunosuppressive therapy and other comorbidities (e.g., vasculitis, antiphospholipid syndrome, arterial hypertension) take part in this increased risk, as well [139]. Accompanying factors such as antiphospholipid syndrome, Liebman-Sacks endocarditis and formation of immune complexes of antibodies with antigens predispose patients to thrombotic complications and ischemic stroke, while endothelial dysfunction and interrupted endothelial layer integrity can lead to hemorrhagic stroke. Subarachnoid hemorrhage in SLE probably results from intracerebral vasculitis and concurrent arterial hypertension [139].

Atherosclerotic plaques have been detected in 17–65% of SLE patients using ultrasound examination. The age seems to play a major role in prediction of atherosclerosis and its manifestations in SLE. Some experts suggest a role of consequences of the disease activity and side effects of therapy in older patients with SLE [2].

#### **3.5 Systemic sclerosis**

SSc belongs to orphan connective tissue diseases with the prevalence of 0.003– 0.06%, and is less understood, concerning the CV risk. The key pathologies leading to CV involvement are vasculopathy, inflammation and tissue fibrosis, which can also affect the heart. In addition to pathognomic microvasculopathy, macrovascular involvement is getting more attention in the last years [45].

To date, the relative risk of CV diseases in SSc in not known. Survival of SSc patients is about 16–34 years shorter compared to the general population with about 3.5 times higher mortality [140]. Due to advances in therapy of scleroderma renal crisis (SRC) and pulmonary arterial hypertension (PAH), new causes of death have got to the front, and the prevalence of ATS in SSc has risen [141]. Cardiac causes account for a quarter of the overall mortality in SSc patients [142]. The prevalence of traditional CV risk does not seem to differ from the general population. SScassociated factors, which participate in endothelial damage, include inflammation and ischemia-reperfusion injury caused by impaired vasodilation [45]. The level of inflammation in SSc is lower than in RA or SLE, which indicates lower rate of acceleration of ATS. Impaired vasodilation characteristic for both SSc and ATS precedes the clinical manifestation of SSc. It is accompanied by the mechanisms typical for both of these pathologies: imbalance between vasodilators (e.g., nitric oxide, NO) and vasoconstrictors (e.g., endothelin), defective angiogenesis caused by the increased expression of VEGF, the presence of AECA and others. The main clinical manifestations of microvascular impairment, Raynaud's phenomenon, PAH and SRC, probably predict macrovascular impairment in SSc [45].

Reports on the prevalence of ATS and its clinical manifestations in SSc differ in various studies. Among others, the reason is asymptomatic subclinical cardiac involvement. Increased risk of CV events is attributed both to ATS and the pathogenesis of SSc and its consequences (impaired microcirculation, myocardial fibrosis, arrhythmia, etc.), and last but not least, secondary deterioration of cardiac function due to renal vasculopathy, interstitial lung disease (ILD) and PAH [143].

The risk of MI is almost 2.5 times higher compared to the general population, while the impact of SSc itself outweighs the effect of hypertension or diabetes on the risk of MI. Ischemic injury of myocardium can be caused by occlusive vasculopathy and intermittent vasospasm (so-called myocardial Raynaud's phenomenon) [144].

It is not clear whether the prevalence of subclinical ATS in SSc is higher compared to the general population. Nussinovitch and Shoenfeld reported carotid involvement in more than 60% of SSc patients, where the findings were described to be more frequent and more severe than in a control group from the general population [143].

Cerebrovascular involvement in SSc patients is 1.3 times more common than in the general population. SSc as an independent risk factor increases the risk of ischemic stroke by up to 43%. There are several pathologic mechanisms in SSc playing a role in the manifestation of a stroke, including vasospasm of cerebral arteries corresponding to the Raynaud's phenomenon, which can manifest as a transient ischemic attack or a focal neurologic deficit [145].

#### **3.6 Idiopathic inflammatory myopathies**

IIM is a heterogeneous group of diseases, which primary affect the skeletal muscles as the common pathologic mechanism. The most prevalent subtypes are dermatomyositis (DM) and polymyositis (PM) [146, 147]. IIM belongs to orphan rheumatologic diseases and occurs in approximately 0.02% of population [148]. The mortality in IIM is almost four times higher than in the general population, with CV involvement as the leading cause [149]. The main pathology responsible for the cardiac involvement in IIM is myocarditis and accelerated ATS in coronary arteries [150]. Other mechanisms have not been sufficiently studied. Resulting structural alterations in myocardium can lead to disturbed function, arrhythmia and other, mostly asymptomatic, rarely fatal manifestations [151].

Data on cardiovascular disability in IIM are insufficient. Meta-analysis of studies in IIM reported 2.24 times higher CV risk compared to the general population [152]. With regard to the prevalence of MI in IIM, there are only limited data. A retrospective study by Rai et al. in more than 700 IIM patients described

**39**

*Atherosclerosis in Rheumatology: Old and New Insights DOI: http://dx.doi.org/10.5772/intechopen.88605*

the onset of IIM [153].

**3.7 Primary Sjögren's syndrome**

due to CV causes (RR = 1.48) [155].

**4. Examination and estimation of the CV risk**

normal CFR [160].

tially females at the age of 40–60 years [154].

an increased risk of MI, but not of a stroke. The risk of MI has been increased in PM almost four times and in DM three times compared to the general population. Patients were most threatened by these complications during the first years after

Traditional risk factors in IIM are specifically related to the specific features of the disease, particularly muscle involvement resulting in impaired physical activity and CS therapy. The prevailing effect of CS in IIM, whether anti-inflammatory or

Primary Sjögren's syndrome is another relatively rare rheumatic disease with a prevalence of 0.06%. It is characterized by lymphocytic infiltration of exocrine glands (especially lacrimal and salivary) leading to dryness of the mucous membranes (sicca syndrome) and hyperactivity of B lymphocytes. pSS affects preferen-

The situation in terms of the CV risk in pSS is similarly unclear as in the above-mentioned rare systemic connective tissue diseases [155]. There is a lack of studies concerning the CV risk in pSS, moreover, the results are conflicting. CVD-associated mortality accounts for 30% of deaths. According to the recent meta-analysis including 14 studies in pSS, the CV risk is significantly increased compared to the general population: the relative risk of coronary artery disease is 1.34, cerebrovascular events 1.46, heart failure 2.54 and thromboembolism 1.78. This meta-analysis has not demonstrated a significantly increased risk of mortality

Similar results have been reported in a population study that also described higher prevalence of arterial hypertension and hypercholesterolemia in pSS patients, and, in addition, suggested pSS as an independent CV risk factor [156]. On the other hand, some studies did not confirm the increased CV risk in pSS [157, 158]. One study has reported subclinical atherosclerotic involvement in pSS patients detected by coronary flow reserve (CFR) and pulse wave velocity (PWV), while the echocardiography showed no pathology [159]. Impaired PWV is thus suggested as a marker of endothelial dysfunction even in patients with

Available data rather suggest higher CV risk in pSS patients compared to the general population, and the need of preventive screening and appropriate management, eventually including consultation and monitoring by a cardiologist [155].

Chronic inflammatory condition can skew the results of the examination, which have otherwise good reliability in the general population [3]. For example, ultrasound imaging of clinically insignificant atherosclerotic lesions or plaques cannot reveal the higher susceptibility to the progression and rupture of plaques in the inflammatory environment [5]. Several scoring systems were developed to facilitate the estimation of the CV risk in the general population. These scoring systems include particularly the traditional risk factors. The most used and widespread systems are Framingham Risk Score (FRS), Systemic Coronary Risk Evaluation (SCORE), QResearch Risk Score (QRISK2, or rather its updated version QRISK 3), Reynolds Risk Score and many others [161, 162]. FRS was the first developed scoring system and served as a default model for creating newer scoring systems. Nowadays, SCORE is probably the most used and widespread scoring system,

pro-atherogenic, is not clear and has yet to be elucidated [152].

an increased risk of MI, but not of a stroke. The risk of MI has been increased in PM almost four times and in DM three times compared to the general population. Patients were most threatened by these complications during the first years after the onset of IIM [153].

Traditional risk factors in IIM are specifically related to the specific features of the disease, particularly muscle involvement resulting in impaired physical activity and CS therapy. The prevailing effect of CS in IIM, whether anti-inflammatory or pro-atherogenic, is not clear and has yet to be elucidated [152].

#### **3.7 Primary Sjögren's syndrome**

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

3.5 times higher mortality [140]. Due to advances in therapy of scleroderma renal crisis (SRC) and pulmonary arterial hypertension (PAH), new causes of death have got to the front, and the prevalence of ATS in SSc has risen [141]. Cardiac causes account for a quarter of the overall mortality in SSc patients [142]. The prevalence of traditional CV risk does not seem to differ from the general population. SScassociated factors, which participate in endothelial damage, include inflammation and ischemia-reperfusion injury caused by impaired vasodilation [45]. The level of inflammation in SSc is lower than in RA or SLE, which indicates lower rate of acceleration of ATS. Impaired vasodilation characteristic for both SSc and ATS precedes the clinical manifestation of SSc. It is accompanied by the mechanisms typical for both of these pathologies: imbalance between vasodilators (e.g., nitric oxide, NO) and vasoconstrictors (e.g., endothelin), defective angiogenesis caused by the increased expression of VEGF, the presence of AECA and others. The main clinical manifestations of microvascular impairment, Raynaud's phenomenon, PAH

and SRC, probably predict macrovascular impairment in SSc [45].

Reports on the prevalence of ATS and its clinical manifestations in SSc differ in various studies. Among others, the reason is asymptomatic subclinical cardiac involvement. Increased risk of CV events is attributed both to ATS and the pathogenesis of SSc and its consequences (impaired microcirculation, myocardial fibrosis, arrhythmia, etc.), and last but not least, secondary deterioration of cardiac function due to renal vasculopathy, interstitial lung disease (ILD) and PAH [143]. The risk of MI is almost 2.5 times higher compared to the general population, while the impact of SSc itself outweighs the effect of hypertension or diabetes on the risk of MI. Ischemic injury of myocardium can be caused by occlusive vasculopathy and intermittent vasospasm (so-called myocardial Raynaud's phenomenon) [144]. It is not clear whether the prevalence of subclinical ATS in SSc is higher compared to the general population. Nussinovitch and Shoenfeld reported carotid involvement in more than 60% of SSc patients, where the findings were described to be more frequent and more severe than in a control group from the general

Cerebrovascular involvement in SSc patients is 1.3 times more common than in the general population. SSc as an independent risk factor increases the risk of ischemic stroke by up to 43%. There are several pathologic mechanisms in SSc playing a role in the manifestation of a stroke, including vasospasm of cerebral arteries corresponding to the Raynaud's phenomenon, which can manifest as a transient

IIM is a heterogeneous group of diseases, which primary affect the skeletal muscles as the common pathologic mechanism. The most prevalent subtypes are dermatomyositis (DM) and polymyositis (PM) [146, 147]. IIM belongs to orphan rheumatologic diseases and occurs in approximately 0.02% of population [148]. The mortality in IIM is almost four times higher than in the general population, with CV involvement as the leading cause [149]. The main pathology responsible for the cardiac involvement in IIM is myocarditis and accelerated ATS in coronary arteries [150]. Other mechanisms have not been sufficiently studied. Resulting structural alterations in myocardium can lead to disturbed function, arrhythmia

Data on cardiovascular disability in IIM are insufficient. Meta-analysis of studies in IIM reported 2.24 times higher CV risk compared to the general population [152]. With regard to the prevalence of MI in IIM, there are only limited data. A retrospective study by Rai et al. in more than 700 IIM patients described

and other, mostly asymptomatic, rarely fatal manifestations [151].

**38**

population [143].

ischemic attack or a focal neurologic deficit [145].

**3.6 Idiopathic inflammatory myopathies**

Primary Sjögren's syndrome is another relatively rare rheumatic disease with a prevalence of 0.06%. It is characterized by lymphocytic infiltration of exocrine glands (especially lacrimal and salivary) leading to dryness of the mucous membranes (sicca syndrome) and hyperactivity of B lymphocytes. pSS affects preferentially females at the age of 40–60 years [154].

The situation in terms of the CV risk in pSS is similarly unclear as in the above-mentioned rare systemic connective tissue diseases [155]. There is a lack of studies concerning the CV risk in pSS, moreover, the results are conflicting. CVD-associated mortality accounts for 30% of deaths. According to the recent meta-analysis including 14 studies in pSS, the CV risk is significantly increased compared to the general population: the relative risk of coronary artery disease is 1.34, cerebrovascular events 1.46, heart failure 2.54 and thromboembolism 1.78. This meta-analysis has not demonstrated a significantly increased risk of mortality due to CV causes (RR = 1.48) [155].

Similar results have been reported in a population study that also described higher prevalence of arterial hypertension and hypercholesterolemia in pSS patients, and, in addition, suggested pSS as an independent CV risk factor [156]. On the other hand, some studies did not confirm the increased CV risk in pSS [157, 158]. One study has reported subclinical atherosclerotic involvement in pSS patients detected by coronary flow reserve (CFR) and pulse wave velocity (PWV), while the echocardiography showed no pathology [159]. Impaired PWV is thus suggested as a marker of endothelial dysfunction even in patients with normal CFR [160].

Available data rather suggest higher CV risk in pSS patients compared to the general population, and the need of preventive screening and appropriate management, eventually including consultation and monitoring by a cardiologist [155].

#### **4. Examination and estimation of the CV risk**

Chronic inflammatory condition can skew the results of the examination, which have otherwise good reliability in the general population [3]. For example, ultrasound imaging of clinically insignificant atherosclerotic lesions or plaques cannot reveal the higher susceptibility to the progression and rupture of plaques in the inflammatory environment [5]. Several scoring systems were developed to facilitate the estimation of the CV risk in the general population. These scoring systems include particularly the traditional risk factors. The most used and widespread systems are Framingham Risk Score (FRS), Systemic Coronary Risk Evaluation (SCORE), QResearch Risk Score (QRISK2, or rather its updated version QRISK 3), Reynolds Risk Score and many others [161, 162]. FRS was the first developed scoring system and served as a default model for creating newer scoring systems. Nowadays, SCORE is probably the most used and widespread scoring system,

especially in Europe [163]. Above-mentioned classic scoring systems underestimate the CV risk in rheumatic patients and therefore are not suitable for estimating the CV risk in these patients. A certain compromise was made by developing the Reynolds Risk Score by inclusion of CRP value as a marker of inflammation, and QRISK2 by inclusion the presence of RA as an independent risk factor [161]. Based on the recent EULAR recommendations for management of the CV risk in inflammatory arthropathies published in 2016, a modified SCORE system (mSCORE) should be used for evaluation of the CV risk in RA patients, which is calculated by multiplying the standard calculated value by a coefficient of 1.5 in all RA patients [58]. Despite this modification, mSCORE is not completely reliable in estimation of the CV risk, as was shown in studies describing findings of subclinical ATS in rheumatic patients classified in the low-risk category according to the mSCORE, and the evidence of higher tendency to formation of ATS plaques and instability of these plaques in RA. Due to these reasons, EULAR proposed simultaneous regular non-invasive examination by ultrasound of carotids and/or measuring the anklebrachial index (ABI) for detection of subclinical ATS in asymptomatic patients in a low-risk category (SCORE 1–4%) [58, 82].

The CV risk should be assessed at least every 5 years in patients with low disease activity and should be reconsidered after major changes in therapy or progression of the disease [58, 59, 82]. In common practise, this assessment means regular examination of blood pressure and lipidogram during the outpatient control and in case of pathologic findings, early consultation by a preventive cardiologist and an adequate therapeutic intervention [62, 164].

#### **5. Therapy**

Preventive measures are the first-line therapy recommended in the general population to manage the CV risk. In rheumatic patients, these measures may be complicated due to a chronic disease. Therefore, the pharmacological treatment is needed [62, 82].

Metformin is recommended as the first line for the treatment of the MetS. It has a beneficial effect not only on improvement of insulin sensitivity, but also reduces the levels of LDL and TC and has a beneficial effect on the vascular function, as well as statins. Similar beneficial effect on glucose metabolism is related to administration of antimalarial drugs, which are often used in the treatment of SLE, pSS and also RA. HCQ exerts immunomodulatory and anti-inflammatory effect, and, in addition, induces an increase in insulin activity and serum levels of glucagon and improves the glucose tolerance. Moreover, HCQ reduces plasma glucose levels even in the general population and is therefore suitable as a part of MetS therapy [82]. Other drugs for glucose metabolism control include pioglitazone (a nuclear peroxisome proliferator-activated receptor-γ agonist), and liraglutide (glucagon-like peptide-1 analog), which has a beneficial effect in obese patients [13].

When managing and treating dyslipidemia, the recommended target levels of LDL (especially for RA) are lower than for the general population (LDL < 2.6 mmol/L; in individuals at higher risk, even <1.8 mmol/L). At the same time, preventive antiplatelet therapy should be considered [62]. Statins have been extensively discussed, especially in rheumatology. Via competitive inhibition of HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzym A) reductase, they inhibit the intermediate step in the synthesis of cholesterol. Despite the concerns of potential side effects as induction of immune-mediated necrotizing myopathy (IMNM), the use of statins in IIM patients does not seem to be more

**41**

*Atherosclerosis in Rheumatology: Old and New Insights DOI: http://dx.doi.org/10.5772/intechopen.88605*

beneficial effect on Raynaud's phenomenon [169].

and niacin [13].

these hypotheses [13].

**6. Conclusion**

rare rheumatic diseases.

thereby reduces the CV risk [13].

risky than in the general population [165]. Several studies demonstrated a beneficial potential of statins to reduce the CV risk via attenuation of the oxidative stress and improvement of endothelial function. Due to their anti-inflammatory potential, statins are preferentially recommended in the therapy of rheumatic patients according to the EULAR recommendations [62]. For example, atorvastatin, when administrated to RA patients, not only reduces the levels of TC and LDL, but apparently also inhibits the inflammation activity [166]. This favorable effect was confirmed in TRACE-RA study [167]. Rosuvastatin exerts a similar beneficial effect in inflammatory joint diseases [168]. Another therapeutic option for dyslipidemia treatment is fenofibrate, which increases the HDL levels,

Regarding the management of arterial hypertension, targeting the optimal blood pressure is more important than considering the type of drug used in therapy [58]. ACE inhibitors or blockers of AT1 receptor for angiotensin II exert a potential anti-inflammatory effect similar to statins, and therefore are preferentially recommended for treatment of arterial hypertension [62]. There is an exception in SSc patients. ACE inhibitors are recommended in the treatment of manifested SRC, but not as a prevention of SRC. Thus, other antihypertensive drugs should be prescribed (if SRC is not present), especially calcium channel blockers due to their

Among other drugs with beneficial effect, vitamin D should not be forgotten. It was demonstrated that vitamin D acts as an immunomodulator and probably plays a protective role in the development of CV diseases, insulin resistance and obesity, and has anti-inflammatory effect and can potentially prevent from the development of MetS in RA patients. Also, probiotics are worth mentioning. Based on the results of studies showing that adverse changes of gut microbiome can induce autoimmune disorders, administration of probiotics may be profitable, as this could prevent the development of autoimmune disease or mitigate the consequences of already present pathological metabolic changes. However, further studies are needed to confirm

Finally, the other side of this issue must not be forgotten, that is, adequate antiinflammatory therapy of rheumatic diseases using DMARDs (especially MTX and TNF inhibitors in RA). Such therapy leads to mitigation of inflammatory activity and also improvement of quality of life and fitness of patients. Better fitness enables physical activity and thus facilitates the elimination of traditional risk factors and

Rheumatic patients are significantly more at risk of atherosclerosis and its complications than individuals from the general population. Traditional risk factors are in rheumatic patients more frequent. Moreover, these risk factors are often hard to manage by modification of life style. Nowadays, a wide range of therapeutic options is available for elimination of traditional risk factors and reduction of the cardiovascular risk. The appropriate anti-inflammatory therapy represents the golden standard. Despite the growing evidence on the cardiovascular risk in rheumatic patents, the adequate recommendations for management of these patients and early detection of a higher risk are still lacking. The task for the future is to create an examination algorithm to prevent underestimation and negligence of risk in rheumatic patients and also to extend the knowledge on the cardiovascular risk in

*Atherosclerosis, Arteriosclerosis and Arteriolosclerosis*

low-risk category (SCORE 1–4%) [58, 82].

adequate therapeutic intervention [62, 164].

**5. Therapy**

needed [62, 82].