Inflammation and calcification: The chicken or the hen?

In the current issue of the journal, Abdelbaky et al. [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar] present a very interesting study addressing the association of aortic valve inflammation and calcification. To ascertain whether aortic valve inflammation precedes subsequent valvular calcification they utilized sequential PET/CT scans performed for cancer surveillance in patients with stable oncological disorders. Computed tomography provided information regarding the presence and extent of calcification (structural information), while PET provided functional/activity information. 18Fluoro -deoxyglucose (FDG) is used extensively in oncological PET imaging and has been shown to be selectively taken up by inflammatory cells, accumulating in nascent atherosclerotic plaques and the aortic valve [2Rudd J.H. Narula J. Strauss H.W. Virmani R. Machac J. Klimas M. Tahara N. Fuster V. Warburton E.A. Fayad Z.A. Tawakol A.A. Imaging atherosclerotic plaque inflammation by fluorodeoxyglucosewith positron emission tomography: ready for prime time?.J. Am. Coll. Cardiol. 2010; 55: 2527-2535Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 3Marincheva-Savcheva G. Subramanian S. Qadir S. Figueroa A. Truong Q. Vijayakumar J. Brady T.J. Hoffmann U. Tawakol A. Imaging of the aortic valve using fluorodeoxyglucose positron emission tomography increased valvular fluorodeoxyglucose uptake in aortic stenosis.J. Am. Coll. Cardiol. 2011; 57: 2507-2515Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. In the current study Abdelbaky et al. [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar] showed that FDG uptake in the aortic valve was higher among patients who showed subsequent progression of calcification, especially in patients with no detectable calcification at baseline. Several traditional risk factors for atherosclerosis were associated with inflammation and calcification of the aortic valve at the time of the first scan including age, diabetes mellitus, dyslipidemia and hypertension. However, on multivariable analyses only age and a quantitative measure of FDG uptake (maximum standardized uptake value (SUVmax)) were associated with inception or progression of valve calcification [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. In a prior publication the same authors made a very similar observation in aortas, where inflammation preceded subsequent calcification [[4]Abdelbaky A. Corsini E. Figueroa A.L. Fontanez S. Subramanian S. Ferencik M. Brady T.J. Hoffmann U. Tawakol A. Focal arterial inflammation precedes subsequent calcification in the same location: a longitudinal FDG-PET/CT study.Circ. Cardiovasc Imaging. 2013; 6: 747-754Crossref PubMed Scopus (108) Google Scholar].Is inflammation therefore a condition sine-qua-non for future calcification of the aortic valve? Certainly there were patients who demonstrated tracer uptake at baseline who did not calcify during a median follow up of 2 years, hence it does not appear that inflammation is a necessary and sufficient condition for future calcification. Nonetheless, numerous pieces of evidence point to the importance of inflammation in the process of progressive sclerosis of the aortic valve.Atherosclerosis and aortic valve calcification share the same risk factors [[5]Stritzke J. Linsel-Nitschke P. Markus M.R. Mayer B. Lieb W. Luchner A. Döring A. Koenig W. Keil U. Hense H.W. Schunkert H. MONICA/KORA InvestigatorsAssociation between degenerative aortic valve disease and long-term exposure to cardiovascular risk factors: results of the longitudinal population-based KORA/MONICA survey.Eur. Heart J. 2009; 30: 2044-2053Crossref PubMed Scopus (54) Google Scholar] and these may induce inflammation. However, in the current study inflammation was associated with future calcification independent of all risk factors except for age [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]; hence one wonders if risk factors and inflammation are at all correlated in aortic valve disease. Of interest, inflammation showed a close association with future valvular calcification but not pre-existing calcification [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. This could suggest that long standing calcification becomes inert and/or that new stimuli may ignite a strong inflammatory response. Is it possible that calcification itself may promote inflammation, so is inflammation the chicken or the hen? Although limited, there is some experimental and human evidence that this might be the case. Calcification of the aortic valve is associated with disruption of the basal membrane, infiltration of inflammatory cells and lipids deposition [6Mohler 3rd, E.R. Are atherosclerotic processes involved in aortic-valve calcification?.Lancet. 2000 Aug 12; 356: 524-525Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 7Elmariah S. Mohler 3rd, E.R. The pathogenesis and treatment of the valvulopathy of aortic stenosis: beyond the SEAS.Curr. Cardiol. Rep. 2010; 12: 125-132Crossref PubMed Scopus (18) Google Scholar]. Nadra et al. [[8]Nadra I. Mason J.C. Philippidis P. Florey O. Smythe C.D. McCarthy G.M. Landis R.C. Haskard D.O. Proinflammatory activation of macrophages by basic calcium phosphate crystals via protein kinase C and MAP kinase pathways: a vicious cycle of inflammation and arterial calcification?.Circ. Res. 2005; 96: 1248-1256Crossref PubMed Scopus (289) Google Scholar] showed that human macrophages exposed in culture to calcium-phosphate crystals internalize the crystals in vacuoles and release inflammatory cytokines (TNF-α, IL-1β and IL-8) via a protein-kinase-C dependent pathway. TNF-α is capable of inducing osteoblastic differentiation of vascular smooth muscle cells therefore initiating calcification of the interstitium [[9]Tintut Y. Patel J. Parhami F. Demer L.L. Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway.Circulation. 2000; 102: 2636-2642Crossref PubMed Scopus (466) Google Scholar]. Furthermore, recent evidence suggests that macrophages are capable of releasing matrix vesicles that are rich in annexin V and alkaline phosphatase, with high calcifying potential [[10]New S.E. Goettsch C. Aikawa M. Marchini J.F. Shibasaki M. Yabusaki K. Libby P. Shanahan C.M. Croce K. Aikawa E.Macrophage -derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques.Circ. Res. 2013; 113: 72-77Crossref PubMed Scopus (291) Google Scholar]. These results suggest that calcium may promote inflammation which in turn will enhance further calcification. In a randomized trial of patients affected by end-stage renal disease the compound Sevelamer arrested the progression of valvular calcification, while calcium-based phosphate binders allowed further progression [[11]Raggi P. Bommer J. Chertow G. Valvular calcification in hemodialysis patients randomized to calcium-based phosphorus binders or Sevelamer.J. Heart Valve Dis. 2004; 13: 134-141PubMed Google Scholar]. Sevelamer is a non-absorbable polymer used as a gut phosphate binder and has lipid-lowering as well as mild anti-inflammatory activities [[12]Ferramosca E. Burke S. Chasan-Taber S. Ratti C. Chertow G.M. Raggi P. Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients.Am. Heart J. 2005; 149: 820-825Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar]. This trial provided partial support to the hypothesis that calcium and inflammation may be part of a “vicious cycle”.What other risk factors could potentially ignite inflammation and calcification of the aortic valve? As oxidized lipids are found in calcifying aortic valves, it has been suggested that they could promote osteoblastic differentiation of valvular fibroblasts and macrophages via activation of the LDL receptor protein-5 (LRP5)/Wnt and Runx2/Cbfa-1 pathways, eventually inducing calcification [[13]O'Brien K.D. Pathogenesis of calcific aortic valve disease: a disease process comes of age (and a good deal more).Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1721-1728Crossref PubMed Scopus (244) Google Scholar]. Unfortunately, several trials of statin therapy to reduce serum LDL and inflammation failed to slow progression of aortic valve calcification [14Rossebø A.B. Pedersen T.R. Boman K. et al.SEAS InvestigatorsIntensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.N. Engl. J. Med. 2008; 359: 1343-1356Crossref PubMed Scopus (1224) Google Scholar, 15Cowell S.J. Newby D.E. Prescott R.J. Bloomfield P. Reid J. Northridge D.B. Boon N.A. Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) InvestigatorsA randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis.N. Engl. J. Med. 2005; 352: 2389-2399Crossref PubMed Scopus (826) Google Scholar]. These trials may have been initiated too late in the process of calcification to slow it or reverse it, however there is also laboratory evidence that statins may promote valvular calcification rather than inhibit it [[16]Wu B. Elmariah S. Kaplan F.S. et al.Paradoxial effect of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 592-597Crossref PubMed Scopus (80) Google Scholar]. Interestingly, in patients with the genetic disorder familial hypercholesterolemia LDL apheresis slows atherosclerosis progression but aortic valve calcification continues to advance [17Tsuchida M. Kawashiri M.A. Tada H. Takata M. Nohara A. Ino H. Inazu A. Kobayashi J. Koizumi J. Mabuchi H. Yamagishi M. Marked aortic valve stenosis progression after receiving long-term aggressive cholesterol-lowering therapy using low-density lipoprotein apheresis in a patient with familial hypercholesterolemia.Circ. J. 2009; 73: 963-966Crossref PubMed Scopus (6) Google Scholar, 18Makino H. Harada-Shiba M. Long-term effect of low-density lipoprotein apheresis in patients with homozygous familial hypercholesterolemia.Ther. Apher. Dial. 2003 Aug; 7 (Review): 397-401Crossref PubMed Scopus (43) Google Scholar, 19Awan Z. Alrasadi K. Francis G.A. Hegele R.A. McPherson R. Frohlich J. Valenti D. de Varennes B. Marcil M. Gagne C. Genest J. Couture P. Vascular calcifications in homozygote familial hypercholesterolemia.Atheroscler. Thromb. Vasc. Biol. 2008; 28: 777-785Crossref PubMed Scopus (78) Google Scholar]. This suggests that other factors, likely related to LDL-receptor deficiency or abnormal function, play a role which is unlikely to be mediated by inflammation [[20]Fantus D. Awan Z. Seidah N.G. Genest J. Aortic calcification: novel insights from familial hypercholesterolemia and potential role for the low-density lipoprotein receptor.Atherosclerosis. 2013; 226: 9-15Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. It remains to be seen whether the new PCSK-9 inhibitors that have little to no effect on inflammation while reducing LDL levels dramatically and the level of Lp(a) by 20–25% [[21]Santos R.D. Watts G.F. Lancet. 2014 Oct 1; (pii: S0140–6736(14)61702-5)https://doi.org/10.1016/S0140-6736(14)61702-5Abstract Full Text Full Text PDF Scopus (32) Google Scholar], will impact aortic valve calcification in familial hypercholesterolemia.Evidently much remains to be done to attain a better understanding of the mechanisms and potential therapeutic approaches to aortic valve calcification. In the meantime the study by Abdelbaky et al. [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar] adds another thread to the thickly woven mystery of the most common human valvular disease. In the current issue of the journal, Abdelbaky et al. [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar] present a very interesting study addressing the association of aortic valve inflammation and calcification. To ascertain whether aortic valve inflammation precedes subsequent valvular calcification they utilized sequential PET/CT scans performed for cancer surveillance in patients with stable oncological disorders. Computed tomography provided information regarding the presence and extent of calcification (structural information), while PET provided functional/activity information. 18Fluoro -deoxyglucose (FDG) is used extensively in oncological PET imaging and has been shown to be selectively taken up by inflammatory cells, accumulating in nascent atherosclerotic plaques and the aortic valve [2Rudd J.H. Narula J. Strauss H.W. Virmani R. Machac J. Klimas M. Tahara N. Fuster V. Warburton E.A. Fayad Z.A. Tawakol A.A. Imaging atherosclerotic plaque inflammation by fluorodeoxyglucosewith positron emission tomography: ready for prime time?.J. Am. Coll. Cardiol. 2010; 55: 2527-2535Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 3Marincheva-Savcheva G. Subramanian S. Qadir S. Figueroa A. Truong Q. Vijayakumar J. Brady T.J. Hoffmann U. Tawakol A. Imaging of the aortic valve using fluorodeoxyglucose positron emission tomography increased valvular fluorodeoxyglucose uptake in aortic stenosis.J. Am. Coll. Cardiol. 2011; 57: 2507-2515Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. In the current study Abdelbaky et al. [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar] showed that FDG uptake in the aortic valve was higher among patients who showed subsequent progression of calcification, especially in patients with no detectable calcification at baseline. Several traditional risk factors for atherosclerosis were associated with inflammation and calcification of the aortic valve at the time of the first scan including age, diabetes mellitus, dyslipidemia and hypertension. However, on multivariable analyses only age and a quantitative measure of FDG uptake (maximum standardized uptake value (SUVmax)) were associated with inception or progression of valve calcification [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. In a prior publication the same authors made a very similar observation in aortas, where inflammation preceded subsequent calcification [[4]Abdelbaky A. Corsini E. Figueroa A.L. Fontanez S. Subramanian S. Ferencik M. Brady T.J. Hoffmann U. Tawakol A. Focal arterial inflammation precedes subsequent calcification in the same location: a longitudinal FDG-PET/CT study.Circ. Cardiovasc Imaging. 2013; 6: 747-754Crossref PubMed Scopus (108) Google Scholar]. Is inflammation therefore a condition sine-qua-non for future calcification of the aortic valve? Certainly there were patients who demonstrated tracer uptake at baseline who did not calcify during a median follow up of 2 years, hence it does not appear that inflammation is a necessary and sufficient condition for future calcification. Nonetheless, numerous pieces of evidence point to the importance of inflammation in the process of progressive sclerosis of the aortic valve. Atherosclerosis and aortic valve calcification share the same risk factors [[5]Stritzke J. Linsel-Nitschke P. Markus M.R. Mayer B. Lieb W. Luchner A. Döring A. Koenig W. Keil U. Hense H.W. Schunkert H. MONICA/KORA InvestigatorsAssociation between degenerative aortic valve disease and long-term exposure to cardiovascular risk factors: results of the longitudinal population-based KORA/MONICA survey.Eur. Heart J. 2009; 30: 2044-2053Crossref PubMed Scopus (54) Google Scholar] and these may induce inflammation. However, in the current study inflammation was associated with future calcification independent of all risk factors except for age [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]; hence one wonders if risk factors and inflammation are at all correlated in aortic valve disease. Of interest, inflammation showed a close association with future valvular calcification but not pre-existing calcification [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. This could suggest that long standing calcification becomes inert and/or that new stimuli may ignite a strong inflammatory response. Is it possible that calcification itself may promote inflammation, so is inflammation the chicken or the hen? Although limited, there is some experimental and human evidence that this might be the case. Calcification of the aortic valve is associated with disruption of the basal membrane, infiltration of inflammatory cells and lipids deposition [6Mohler 3rd, E.R. Are atherosclerotic processes involved in aortic-valve calcification?.Lancet. 2000 Aug 12; 356: 524-525Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 7Elmariah S. Mohler 3rd, E.R. The pathogenesis and treatment of the valvulopathy of aortic stenosis: beyond the SEAS.Curr. Cardiol. Rep. 2010; 12: 125-132Crossref PubMed Scopus (18) Google Scholar]. Nadra et al. [[8]Nadra I. Mason J.C. Philippidis P. Florey O. Smythe C.D. McCarthy G.M. Landis R.C. Haskard D.O. Proinflammatory activation of macrophages by basic calcium phosphate crystals via protein kinase C and MAP kinase pathways: a vicious cycle of inflammation and arterial calcification?.Circ. Res. 2005; 96: 1248-1256Crossref PubMed Scopus (289) Google Scholar] showed that human macrophages exposed in culture to calcium-phosphate crystals internalize the crystals in vacuoles and release inflammatory cytokines (TNF-α, IL-1β and IL-8) via a protein-kinase-C dependent pathway. TNF-α is capable of inducing osteoblastic differentiation of vascular smooth muscle cells therefore initiating calcification of the interstitium [[9]Tintut Y. Patel J. Parhami F. Demer L.L. Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway.Circulation. 2000; 102: 2636-2642Crossref PubMed Scopus (466) Google Scholar]. Furthermore, recent evidence suggests that macrophages are capable of releasing matrix vesicles that are rich in annexin V and alkaline phosphatase, with high calcifying potential [[10]New S.E. Goettsch C. Aikawa M. Marchini J.F. Shibasaki M. Yabusaki K. Libby P. Shanahan C.M. Croce K. Aikawa E.Macrophage -derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques.Circ. Res. 2013; 113: 72-77Crossref PubMed Scopus (291) Google Scholar]. These results suggest that calcium may promote inflammation which in turn will enhance further calcification. In a randomized trial of patients affected by end-stage renal disease the compound Sevelamer arrested the progression of valvular calcification, while calcium-based phosphate binders allowed further progression [[11]Raggi P. Bommer J. Chertow G. Valvular calcification in hemodialysis patients randomized to calcium-based phosphorus binders or Sevelamer.J. Heart Valve Dis. 2004; 13: 134-141PubMed Google Scholar]. Sevelamer is a non-absorbable polymer used as a gut phosphate binder and has lipid-lowering as well as mild anti-inflammatory activities [[12]Ferramosca E. Burke S. Chasan-Taber S. Ratti C. Chertow G.M. Raggi P. Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients.Am. Heart J. 2005; 149: 820-825Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar]. This trial provided partial support to the hypothesis that calcium and inflammation may be part of a “vicious cycle”. What other risk factors could potentially ignite inflammation and calcification of the aortic valve? As oxidized lipids are found in calcifying aortic valves, it has been suggested that they could promote osteoblastic differentiation of valvular fibroblasts and macrophages via activation of the LDL receptor protein-5 (LRP5)/Wnt and Runx2/Cbfa-1 pathways, eventually inducing calcification [[13]O'Brien K.D. Pathogenesis of calcific aortic valve disease: a disease process comes of age (and a good deal more).Arterioscler. Thromb. Vasc. Biol. 2006; 26: 1721-1728Crossref PubMed Scopus (244) Google Scholar]. Unfortunately, several trials of statin therapy to reduce serum LDL and inflammation failed to slow progression of aortic valve calcification [14Rossebø A.B. Pedersen T.R. Boman K. et al.SEAS InvestigatorsIntensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.N. Engl. J. Med. 2008; 359: 1343-1356Crossref PubMed Scopus (1224) Google Scholar, 15Cowell S.J. Newby D.E. Prescott R.J. Bloomfield P. Reid J. Northridge D.B. Boon N.A. Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) InvestigatorsA randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis.N. Engl. J. Med. 2005; 352: 2389-2399Crossref PubMed Scopus (826) Google Scholar]. These trials may have been initiated too late in the process of calcification to slow it or reverse it, however there is also laboratory evidence that statins may promote valvular calcification rather than inhibit it [[16]Wu B. Elmariah S. Kaplan F.S. et al.Paradoxial effect of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 592-597Crossref PubMed Scopus (80) Google Scholar]. Interestingly, in patients with the genetic disorder familial hypercholesterolemia LDL apheresis slows atherosclerosis progression but aortic valve calcification continues to advance [17Tsuchida M. Kawashiri M.A. Tada H. Takata M. Nohara A. Ino H. Inazu A. Kobayashi J. Koizumi J. Mabuchi H. Yamagishi M. Marked aortic valve stenosis progression after receiving long-term aggressive cholesterol-lowering therapy using low-density lipoprotein apheresis in a patient with familial hypercholesterolemia.Circ. J. 2009; 73: 963-966Crossref PubMed Scopus (6) Google Scholar, 18Makino H. Harada-Shiba M. Long-term effect of low-density lipoprotein apheresis in patients with homozygous familial hypercholesterolemia.Ther. Apher. Dial. 2003 Aug; 7 (Review): 397-401Crossref PubMed Scopus (43) Google Scholar, 19Awan Z. Alrasadi K. Francis G.A. Hegele R.A. McPherson R. Frohlich J. Valenti D. de Varennes B. Marcil M. Gagne C. Genest J. Couture P. Vascular calcifications in homozygote familial hypercholesterolemia.Atheroscler. Thromb. Vasc. Biol. 2008; 28: 777-785Crossref PubMed Scopus (78) Google Scholar]. This suggests that other factors, likely related to LDL-receptor deficiency or abnormal function, play a role which is unlikely to be mediated by inflammation [[20]Fantus D. Awan Z. Seidah N.G. Genest J. Aortic calcification: novel insights from familial hypercholesterolemia and potential role for the low-density lipoprotein receptor.Atherosclerosis. 2013; 226: 9-15Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. It remains to be seen whether the new PCSK-9 inhibitors that have little to no effect on inflammation while reducing LDL levels dramatically and the level of Lp(a) by 20–25% [[21]Santos R.D. Watts G.F. Lancet. 2014 Oct 1; (pii: S0140–6736(14)61702-5)https://doi.org/10.1016/S0140-6736(14)61702-5Abstract Full Text Full Text PDF Scopus (32) Google Scholar], will impact aortic valve calcification in familial hypercholesterolemia. Evidently much remains to be done to attain a better understanding of the mechanisms and potential therapeutic approaches to aortic valve calcification. In the meantime the study by Abdelbaky et al. [[1]Abdelbaky A. Corsini E. Figueroa A.L. Subramanian S. Fontanez S. Hoffmann U. Narula J. Tawakol A. FDG accumulates in macrophages in plaques and aortic valve stenosis.Atheroslcerosis. 2015; 238: 165-172Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar] adds another thread to the thickly woven mystery of the most common human valvular disease. Early aortic valve inflammation precedes calcification: A longitudinal FDG-PET/CT studyAtherosclerosisVol. 238Issue 2PreviewObjectives: Recent data shows a relationship between aortic valve (AV) inflammation and calcification. However, direct evidence linking early valve inflammation (prior to hemodynamic compromise) to subsequent calcium (Ca) deposition is lacking in humans. We sought to test the hypothesis whether local AV inflammation predisposes to subsequent AV Ca deposition. Methods: We identified 111 individuals (age 60[49, 68], 50.5% male) without active cancer or aortic stenosis who underwent 2 PET/CT studies 1–5 years apart for cancer surveillance. Full-Text PDF

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