Vaskuläre Kalzifikation – Entstehung und prognostische Bedeutung

Abstract

Vascular calcification is not an inncocent bystander of degenerative cardiovascular disease. It may occur within the intimal layer (atherosclerosis) or medial vascular layer (arteriosclerosis) and poses an additional independent cardiovascular risk irrespective of the anatomical site. Detection of coronary artery calcification allows the reclassification of patients at intermediate risk for future cardiovascular events in either low-risk categories (in case such calcification is absent) or in high risk categories. The pathophysiology of vascular calcification is complex. Noteworthy it is an active process and not just physicochemical precipitation. The occurrence of vascular calcification depends upon a complex interaction and finally a dysbalance between pro-calcifying and anti-calcifying factors. Novel insights into the pathophysiology offer fascinating aspects regarding the role of the adventitial vascular layer and sortelin within the process of vascular calcification. Importantly, microcalcifications exhibit a particular cardiovascular risk since such microcalcifications associate with plaque instability and inflammation. Therapeutic options against vascular calcifications (slowing down its progression or even regression) are currently limited. Interestingly, a well established treatment and preventive tool in cardiovascular disease, the statins, fail to regress vascular calcification. In contrast, vitamin K replenishment might do so via activation of matrix-gla protein. In summary, vascular calcification is a hallmark of late and advanced cardiovascular disease and turns a patient into a candidate for a thorough diagnostic work-up. 

Kernaussagen

• Die Bestimmung von Gefäßkalk kann einfach aus Routineuntersuchungen als Zufallsbefund oder systematisch und gezielt erfolgen.

• Jeder Nachweis von Kalk im Gefäßsystem macht den Patienten zu einem Patienten mit höherem kardiovaskulärem Risiko als bei einem vergleichbaren Patienten ohne Kalknachweis.

• Die Koronarkalkmessung in der Herz-CT erlaubt eine Quantifizierung der Verkalkung und kann helfen, Patienten mit intermediärem Risiko in ihrer Risikoklassifikation herauf- oder herabzustufen.

• Klinisch muss zwischen einer atherosklerotischen Intimaverkalkung und einer arteriosklerotischen Mediaverkalkung unterschieden werden.

• Die Pathophysiologie von Verkalkungsprozessen ist komplex. Phosphat ist ein potenter Risikofaktor für die Induktion von Verkalkung.

• Aktuell ist die serielle Koronarkalkbestimmung nicht als intermediärer Endpunkt für Interventionsstudien zu empfehlen, weil der Zusammenhang zwischen Senkung der Kalklast und Senkung des kardiovaskulären Risikos (noch) nicht erwiesen ist. Statine senken das kardiovaskuläre Risiko überzeugend, obwohl sie bezüglich der Gefäßverkalkung eher neutral sind.

• Literatur

• 1 Schlieper G, Schurgers L, Brandenburg V et al. Vascular calcification in chronic kidney disease: an update. Nephrol Dial Transplant 2016; 31: 31-39
• 2 Koos R, Brandenburg V, Ketteler M et al. Prevalence and pathogenesis of aortic valve calcifications. Herz 2006; 31: 629-634
• 3 Brandenburg VM, Martin H, Sohn CM et al. Calciphylaxis. Dtsch Med Wochenschr 2015; 140: 347-351
• 4 Hecht HS. Coronary artery calcium scanning: past, present, and future. JACC Cardiovasc Imaging 2015; 8: 579-596
• 5 Martin SS, Blaha MJ, Blankstein R et al. Dyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: implications for statin therapy from the multi-ethnic study of atherosclerosis. Circulation 2014; 129: 77-86
• 6 Blaha M, Budoff MJ, Shaw LJ et al. Absence of coronary artery calcification and all-cause mortality. JACC Cardiovasc Imaging 2009; 2: 692-700
• 7 Goff Jr DC, Lloyd-Jones DM, Bennett G et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63: 2935-2959
• 8 Fujimoto N, Iseki K, Tokuyama K et al. Significance of coronary artery calcification score (CACS) for the detection of coronary artery disease (CAD) in chronic dialysis patients. Clin Chim Acta 2006; 367: 98-102
• 9 Hecht HS, Narula J. Coronary artery calcium scanning in asymptomatic patients with diabetes mellitus: a paradigm shift. J Diabetes 2012; 4: 342-350
• 10 Noordzij M, Cranenburg EM, Engelsman LF et al. Progression of aortic calcification is associated with disorders of mineral metabolism and mortality in chronic dialysis patients. Nephrol Dial Transplant 2011; 26: 1662-1669
• 11 Hendriks EJ, de Jong PA, van der Graaf Y et al. Breast arterial calcifications: a systematic review and meta-analysis of their determinants and their association with cardiovascular events. Atherosclerosis 2015; 239: 11-20
• 12 Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol 2004; 15: 2959-2964
• 13 Ritter CS, Slatopolsky E. Phosphate Toxicity in CKD: The Killer among Us. Clin J Am Soc Nephrol 2016; 11: 1088-1100
• 14 Shroff R, Long DA, Shanahan C. Mechanistic insights into vascular calcification in CKD. J Am Soc Nephrol 2013; 24: 179-189
• 15 Isakova T, Ix JH, Sprague SM et al. Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD. J Am Soc Nephrol 2015; 26: 2328-2339
• 16 Ritter CS, Slatopolsky E. Phosphate Toxicity in CKD: The Killer among Us. Clin J Am Soc Nephrol 2016; 11: 1088-1100
• 17 Brandenburg VM, Kleber ME, Vervloet MG et al. Fibroblast growth factor 23 (FGF23) and mortality: the Ludwigshafen Risk and Cardiovascular Health Study. Atherosclerosis 2014; 237: 53-59
• 18 Ritz E, Hahn K, Ketteler M et al. Phosphate additives in food – a health risk. Dtsch Arztebl Int 2012; 109: 49-55
• 19 Floege J. Magnesium in CKD: more than a calcification inhibitor?. J Nephrol 2015; 28: 269-277
• 20 Brandenburg V. Higher cradiovascular risc with hypomagnesemia. Dtsch Med Wochenschr 2016; 141: 379
• 21 Majesky MW, Dong XR, Hoglund V et al. The adventitia: a progenitor cell niche for the vessel wall. Cells Tissues Organs 2012; 195: 73-81
• 22 Sage AP, Tintut Y, Demer LL. Regulatory mechanisms in vascular calcification. Nat Rev Cardiol 2010; 7: 528-536
• 23 Brighton CT, Lorich DG, Kupcha R et al. The pericyte as a possible osteoblast progenitor cell. Clin Orthop Relat Res 1992; 275: 287-299
• 24 Bujan J, Bellon JM, Sabater C et al. Modifications induced by atherogenic diet in the capacity of the arterial wall in rats to respond to surgical insult. Atherosclerosis 1996; 122: 141-152
• 25 Chen Y, Wong MM, Campagnolo P et al. Adventitial stem cells in vein grafts display multilineage potential that contributes to neointimal formation. Arterioscler Thromb Vasc Biol 2013; 33: 1844-1851
• 26 Shanahan CM. Inflammation ushers in calcification: a cycle of damage and protection?. Circulation 2007; 116: 2782-2785
• 27 Pugliese G, Iacobini C, Blasetti FC et al. The dark and bright side of atherosclerotic calcification. Atherosclerosis 2015; 238: 220-230
• 28 Kelly-Arnold A, Maldonado N, Laudier D et al. Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. Proc Natl Acad Sci USA 2013; 110: 10.741-10.746
• 29 Bover J, Evenepoel P, Urena-Torres P et al. Pro: cardiovascular calcifications are clinically relevant. Nephrol Dial Transplant 2015; 30: 345-351
• 30 Sakaguchi M, Hasegawa T, Ehara S et al. New insights into spotty calcification and plaque rupture in acute coronary syndrome: an optical coherence tomography study. Heart Vessels 2016;
• 31 Reith S, Battermann S, Hoffmann R et al. Optical coherence tomography derived differences of plaque characteristics in coronary culprit lesions between type 2 diabetic patients with and without acute coronary syndrome. Catheter Cardiovasc Interv 2014; 84: 700-707
• 32 Criqui MH, Denenberg JO, Ix JH et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA 2014; 311: 271-278
• 33 Hutcheson JD, Goettsch C, Bertazzo S et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat Mater 2016; 15: 335-343
• 34 Goettsch C, Hutcheson JD, Aikawa M et al. Sortilin mediates vascular calcification via its recruitment into extracellular vesicles. J Clin Invest 2016; 126: 1323-1336
• 35 Sheen CR, Kuss P, Narisawa S et al. Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification. J Bone Miner Res 2015; 30: 824-836
• 36 Brandenburg VM, Schurgers LJ, Kaesler N et al. Prevention of vasculopathy by vitamin K supplementation: can we turn fiction into fact?. Atherosclerosis 2015; 240: 10-16
• 37 Luo G, Ducy P, McKee MD et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997; 386: 78-81
• 38 Hirota Y, Nakagawa K, Sawada N et al. Functional characterization of the vitamin K2 biosynthetic enzyme UBIAD1. PLoS One 2015; 10: e0125737
• 39 Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32: 1769-1818
• 40 Arad Y, Spadaro LA, Roth M et al. Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E: the St. Francis Heart Study randomized clinical trial. J Am Coll Cardiol 2005; 46: 166-172
• 41 Houslay ES, Cowell SJ, Prescott RJ et al. Progressive coronary calcification despite intensive lipid-lowering treatment: a randomised controlled trial. Heart 2006; 92: 1207-1212
• 42 Terry JG, Carr JJ, Kouba EO et al. Effect of simvastatin (80 mg) on coronary and abdominal aortic arterial calcium (from the coronary artery calcification treatment with zocor [CATZ] study). Am J Cardiol 2007; 99: 1714-1717
• 43 Stary HC. The development of calcium deposits in atherosclerotic lesions and their persistence after lipid regression. Am J Cardiol 2001; 88: 16E-19E
• 44 Wu B, Elmariah S, Kaplan FS et al. Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease. Arterioscler Thromb Vasc Biol 2005; 25: 592-597
• 45 Burgstahler C, Reimann A, Beck T et al. Influence of a lipid-lowering therapy on calcified and noncalcified coronary plaques monitored by multislice detector computed tomography: results of the New Age II Pilot Study. Invest Radiol 2007; 42: 189-195
• 46 Motro M, Shemesh J. Calcium channel blocker nifedipine slows down progression of coronary calcification in hypertensive patients compared with diuretics. Hypertension 2001; 37: 1410-1413
• 47 Brown MJ, Palmer CR, Castaigne A et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366-372
• 48 Hirota Y, Nakagawa K, Sawada N et al. Functional characterization of the vitamin K2 biosynthetic enzyme UBIAD1. PLoS One 2015; 10: e0125737
• 49 Zoccali C, Bolignano D, D'Arrigo G et al. Validity of Vascular Calcification as a Screening Tool and as a Surrogate End Point in Clinical Research. Hypertension 2015; 66: 3-9