Progression Of Valvular Calcification Research Articles

Comparison of CT acquired valvular calcification scores in hemodialysis vs peritoneal dialysis patients undergoing open heart surgery

Abstract Background Several factors have been identified as independent risk factors for cardiac valvular calcification (CVC), including but not limited to age, inflammatory conditions, loss of calcification inhibitors, and dysregulated bone mineral metabolism. However, data is scarce regarding which dialysis modality portends more severe CVC. Purpose Our aim was to compare the degree of valvular calcification in hemodialysis (HD) and peritoneal dialysis (PD) patients prior to open heart surgery (OHS) using a computed CT calcium score. Methods Dialysis patients who underwent OHS at our institution from 2009–2019 who had a pre-surgical cardiac CT were grouped according to duration of dialysis modality prior to their surgical date. There were two study cohorts to evaluate outcomes of interest: mitral and aortic calcification. We included the first surgical record per patient for patients undergoing isolated CABG, or CABG+valve surgery (repair or replacement), or valve-only surgery (repair or replacement). To evaluate mitral calcification, we excluded any patients undergoing any mitral valve surgery (repair or replacement). We also excluded patients with a history of mitral valve repair/replacement. To evaluate aortic calcification, we excluded any patients undergoing any aortic valve surgery (repair or replacement). We also excluded patients with a history of aortic valve repair/replacement. Mitral annular and aortic valvular calcification were assessed using the Agatston score. Logistic regression was performed to test for the association of PD and HD cumulative dialysis duration with presence of valvular calcification. Results A total of 296 patients met inclusion criteria for at least one of the strata in our study. Of those, 214 met inclusion for the mitral strata, and 166 met criteria for the aortic strata (Table 1). In the logistic regression model for the mitral strata, age and female sex were associated with higher odds of presence of mitral calcification (Figure 1). Cumulative years on PD and cumulative years on HD were not significantly associated with presence of mitral calcification. In the logistic regression model for the aortic strata, age was associated with higher odds of presence of aortic calcification, while female sex was associated with lower odds (Figure 1). Cumulative years on PD and cumulative years on HD were not significantly associated with presence of aortic calcification. Conclusion Presence of mitral and aortic calcification for patients undergoing OHS was not significantly associated with cumulative length of PD or HD after adjusting for age and gender, suggesting that there may be more factors at play in the progression of valvular calcification in end stage renal disease patients than what was previously thought. Funding Acknowledgement Type of funding sources: None.

Effect of Progression of Valvular Calcification on Left Ventricular Structure and Frequency of Incident Heart Failure (from the Multiethnic Study of Atherosclerosis)

Heart failure (HF) is a leading cause of morbidity. Strategies for preventing HF are paramount. Prevalent extracoronary calcification is associated with HF risk but less is known about progression of mitral annular (MAC) and aortic valve calcification (AVC) and HF risk. Progression of valvular calcification (VC) [interval change of >0 units/yr] was assessed by 2 cardiac computed tomography scans over a median of 2.4 years. We used Cox regression to determine the risk of adjudicated HF and linear mixed effects models to determine 10-year change in left ventricular (LV) parameters measured by cardiac magnetic resonance imaging associated with VC progression. We studied 5,591 MESA participants free of baseline cardiovascular disease. Mean ± SD age was 62 ± 10 years; 53% women; 83% had no VC progression, 15% progressed at 1 site (AVC or MAC) and 3% at both sites. There were 251 incident HF over 15 years. After adjusting for cardiovascular risk factors, the hazard ratios (95% confidence interval) of HF associated with VC progression at 1 and 2 sites were 1.62 (1.21 to 2.17) and 1.88 (1.14 to 3.09), respectively, compared with no progression (p-for-trend <0.001). Hazard ratios were higher for HFpEF (2.52 [1.63 to 3.90] and 2.49 [1.19 to 5.25]) but nonsignificant for HFrEF. Both AVC (1.61 [1.19 to 2.19]) and MAC (1.50 [1.09 to 2.07]) progression were associated with HF. VC was associated with worsening of some LV parameters over 10 years. In conclusion, VC progression was associated with increased risk of HF and change in LV function. Interventions targeted at reducing VC progression may also impact HF risk, particularly HFpEF.

Hydrogen sulfide inhibits aortic valve calcification in heart via regulating RUNX2 by NF-κB, a link between inflammation and mineralization

IntroductionHydrogen sulfide (H2S) was revealed to inhibit aortic valve calcification and inflammation was implicated in the pathogenesis of calcific aortic valve disease (CAVD). ObjectivesWe investigate whether H2S inhibits mineralization via abolishing inflammation. Methods and resultsExpression of pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) were increased in patients with CAVD and in calcified aortic valve of ApoE-/- mice. Administration of H22S releasing donor (4-methoxyphenyl piperidinylphosphinodithioc acid (AP72)) exhibited inhibition on both calcification and inflammation in aortic valve of apolipoprotein E knockout mice (ApoE-/-) mice is reflected by lowering IL-1β and TNF-α levels. Accordingly, AP72 prevented the accumulation of extracellular calcium deposition and decreased nuclear translocation of nuclear factor-κB (NF-κB) in human valvular interstitial cells (VIC). This was also accompanied by reduced cytokine response. Double-silencing of endogenous H2S producing enzymes, Cystathionine gamma-lyase (CSE) and Cystathionine beta-synthase (CBS) in VIC exerted enhanced mineralization and higher levels of IL-1β and TNF-α. Importantly, silencing NF-κB gene or its pharmacological inhibition prevented nuclear translocation of runt-related transcription factor 2 (Runx2) and subsequently the calcification of human VIC. Increased levels of NF-κB and Runx2 and their nuclear accumulation occurred in ApoE-/- mice with a high-fat diet. Administration of AP72 decreased the expression of NF-κB and prevented its nuclear translocation in VIC of ApoE-/- mice on a high-fat diet, and that was accompanied by a lowered pro-inflammatory cytokine level. Similarly, activation of Runx2 did not occur in VIC of ApoE-/- mice treated with H2S donor. Employing Stimulated Emission Depletion (STED) nanoscopy, a strong colocalization of NF-κB and Runx2 was detected during the progression of valvular calcification. ConclusionsHydrogen sulfide inhibits inflammation and calcification of aortic valve. Our study suggests that the regulation of Runx2 by hydrogen sulfide (CSE/CBS) occurs via NF-κB establishing a link between inflammation and mineralization in vascular calcification.

Progression of valvular calcification and risk of incident stroke: The Multi-Ethnic Study of Atherosclerosis (MESA)

Background and aimsPrevalent valvular calcification (VC) is associated with stroke but little is known about associations of VC progression with stroke. MethodsProgression (interval increase >0 Agatston units/year) of aortic valvular calcification (AVC) and mitral annular calcification (MAC) was assessed by two cardiac CTs over a median of 2.4 years. We determined the risk of adjudicated total and ischemic stroke using Cox regression adjusted for cardiovascular disease (CVD) risk factors. ResultsWe studied 5,539 MESA participants free of baseline CVD and atrial fibrillation. Baseline mean ± SD age was 62 ± 10 years; 53% were women; 83% had no progression of VC; 15%, progression at one site (AVC or MAC), and 3%, progression at both sites. Over a median of 12 years, 211 total and 167 ischemic strokes occurred. The number of sites with VC progression (range 0–2) was not associated with total and ischemic stroke (all p > 0.05). We found MAC progression to be associated with increased risk of total stroke [adjusted hazard ratio (95% CI) 1.59 (1.11, 2.28)] and ischemic stroke [1.64 (1.10, 2.45)]. Results remained significant after further adjustment for baseline coronary artery calcification. After excluding participants with interim atrial fibrillation and coronary heart disease, findings were no longer statistically significant in fully-adjusted models. There was no interaction by age, sex, or race/ethnicity. There was no association with AVC progression and stroke. ConclusionsProgression of MAC but not AVC over 2.4 years is associated with increased risk of total and ischemic stroke.

Abstract MP78: Progression of Valvular Calcification and Risk of Incident Stroke: The Multi-ethnic Study of Atherosclerosis (MESA)

Introduction: Stroke is a leading cause of morbidity and mortality in the United States. Identification of individuals at risk for stroke is important for implementation of preventive therapies. Prevalent valvular calcification (VC) has been shown to be associated with stroke but less is known about associations of VC progression with stroke. Methods: Progression (interval increase &gt;0 Agatston units/year) of aortic valvular calcification (AVC) and mitral annular calcification (MAC) was assessed by two cardiac CTs over a median of 2.4 years. We determined the risk of adjudicated total and ischemic stroke using Cox regression adjusted for cardiovascular disease (CVD) risk factors. Results: We studied 5,606 multiethnic participants (39.6% White, 26.9% Black, 21.4% Hispanic, 12.2% Chinese) free of baseline CVD enrolled in MESA. Baseline mean ± SD age was 62 ± 10 years; 53% were women; 12% had prevalent AVC and 9% prevalent MAC at the baseline visit; 83% had no progression of VC, 14%, progression at one site (AVC or MAC), and 3% progression at both sites (AVC and MAC) at follow-up. Over a median of 12 years, 214 total and 170 ischemic strokes occurred. The number of sites with VC progression (range 0-2) was not associated with total and ischemic stroke (all p&gt;0.05). We found MAC progression to be associated with increased risk of total stroke [adjusted hazard ratios (95% CI) 1.59 (1.11 - 2.27)] and ischemic stroke [1.64 (1.10 - 2.43)] in the whole cohort (model 3) and after further adjustment for baseline coronary artery calcification (model 4) ( Table ). Results remained significant for total stroke risk after excluding participants with interim atrial fibrillation or coronary heart disease [1.60 (1.01 - 2.54)]. In women, AVC progression was associated with ischemic stroke [1.87 (1.04 - 3.36)] (p-for-interaction=0.03). Conclusion: Progression of MAC over 2.4 years is associated with increased risk of total and ischemic stroke, and in women, AVC progression with higher ischemic stroke risk.

PROGRESSION OF VALVULAR CALCIFICATION IS ASSOCIATED WITH 10-YEAR CHANGE IN LEFT VENTRICULAR STRUCTURE AND INCIDENT HEART FAILURE: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS

Heart failure (HF) is a leading cause of morbidity. Strategies for preventing HF are paramount. Prevalent valvular calcification (VC) is associated with HF risk but less is known about progression of mitral annular (MAC) and aortic valve calcification (AVC). VC progression (interval change of >0

Comparing the Role of Mechanical Forces in Vascular and Valvular Calcification Progression.

Calcification is a prevalent disease in most fully developed countries and is predominantly observed in heart valves and nearby vasculature. Calcification of either tissue leads to deterioration and, ultimately, failure causing poor quality of life and decreased overall life expectancy in patients. In valves, calcification presents as Calcific Aortic Valve Disease (CAVD), in which the aortic valve becomes stenotic when calcific nodules form within the leaflets. The initiation and progression of these calcific nodules is strongly influenced by the varied mechanical forces on the valve. In turn, the addition of calcific nodules creates localized disturbances in the tissue biomechanics, which affects extracellular matrix (ECM) production and cellular activation. In vasculature, atherosclerosis is the most common occurrence of calcification. Atherosclerosis exhibits as calcific plaque formation that forms in juxtaposition to areas of low blood shear stresses. Research in these two manifestations of calcification remain separated, although many similarities persist. Both diseases show that the endothelial layer and its regulation of nitric oxide is crucial to calcification progression. Further, there are similarities between vascular smooth muscle cells and valvular interstitial cells in terms of their roles in ECM overproduction. This review summarizes valvular and vascular tissue in terms of their basic anatomy, their cellular and ECM components and mechanical forces. Calcification is then examined in both tissues in terms of disease prediction, progression, and treatment. Highlighting the similarities and differences between these areas will help target further research toward disease treatment.

Genetic Polymorphisms, Plasma Levels of Lipoprotein (A) and its Possible Links with Degenerative Aortic Stenosis

Summary Degenerative aortic stenosis is the second most common acquired valvular heart disease in adults (after mitral insufficiency) and the second most common cause for cardiac surgery (after coronary heart disease). The reasons for the occurrence of these diseases (congenital abnormality of the valve: bicuspid aortic valve disease, advanced renal failure, impaired calcium-phosphorus metabolism) have been established only in a small portion of these patients. The absence of a specific reason, causing calcification and narrowing of the aortic valve in recent years has challenged researchers to start investigating genetic factors that may correlate with the development of degenerative aortic stenosis. Regardless of the conducted studies, knowledge and identification of predictive genetic factors in the occurrence and progression of aortic stenosis are still insufficient. It is assumed that a specific genetic variant in the Lipoprotein (a) locus (LPA locus), reflected by the Lipoprotein (a) [Lp(a)] plasma levels, is connected to the pathology of aortic stenosis in multiethnic groups. The study of the genetic nature of aortic stenosis and significance of Lp( a) plasma levels and genetically determined variations of its structure associated with the manifestation and progression of valvular calcification in the future might provide predictive intervention. Similar studies relating to genetic polymorphisms in LPA locus, plasma concentrations of Lp(a) and their correlation with aortic stenosis have not beenconducted in Bulgaria so far.

Abstract 582: Overexpression of Mnsod Reduces Aortic Valve Calcification Through Repression of Pro-osteogenic Signaling

Increased BMP signaling and markers of osteogenic differentiation are strongly associated with regions of valvular calcification in aortic valves from humans with end-stage calcific aortic valve stenosis. While oxidative stress is also markedly elevated in these regions, it is unknown whether increasing antioxidant capacity can reduce pro-osteogenic signaling and valvular calcification. Therefore, we hypothesized that overexpression of manganese superoxide dismutase (MnSOD) can reduce pro-osteogenic signaling in the aortic valves from hypercholesterolemic mice, ultimately resulting in reduced valvular calcification and improved valvular function. We used Ldlr -/- /ApoB 100/100 (LA) mice that were wild-type for MnSOD (LA-MnSOD 0/0 ) or overexpressing MnSOD (LA-MnSOD Tg/0 ) and fed a western diet (TD88137) for six months. We first measured mRNA levels of the BMP ligands BMP2 and BMP4 (qRT-PCR), both of which were unchanged between LA-MnSOD 0/0 and LA-MNSOD Tg/0 mice. While there was a small but significant increase in Runx2 mRNA levels in LA-MnSOD Tg/0 mice compared to wild-type littermates (1.22±0.09, 1.0±0.09, qRT-PCR, p &lt; 0.05.) gene expression levels of late stage osteoblast marker Sp7 were reduced by approximately 50% in LA-MnSOD Tg/0 compared to wild-type littermates (0.53±0.15, 1.0±0.24, qRT-PCR, p &lt; 0.05). Sp7 protein levels (immunohistochemistry) were also significantly reduced in LA-MnSOD Tg/0 compared to wild-type littermates (164.5±12.3 RFU vs 259.6±10.4 RFU, p &lt; 0.05). Critically, aortic valve calcification (Alizarin Red) was also significantly reduced in LA-MnSOD Tg/0 mice compared to their LA-MnSOD 0/0 littermates. Functionally, aortic valve cusp separation distance (high resolution echocardiography) was slightly improved in LA-MnSOD Tg/0 mice compared to LA-MnSOD 0/0 mice (0.98±0.04 mm vs 0.91±0.03 mm, p = n.s.). Collectively, these data suggest that increasing mitochondrial antioxidant capacity can reduce pro-osteogenic signaling and attenuate aortic valve calcification, and may be a potential therapeutic target to slow the progression of valvular calcification and dysfunction in patients with calcific aortic valve stenosis.

Abstract 3030: Differential Regulation of Valvular Interstitial Cell Dysfunction by Extracellular Matrix Components

Calcification is the leading cause of bioprosthetic and native aortic valve failure, but relatively little is known regarding the factors that contribute to the progression of valvular calcification. Because extracellular matrix (ECM) disarray is often observed in explanted diseased valves, we have investigated the role of individual ECM components in the in vitro calcification of valvular interstitial cells (VICs). The transformation of VICs to an osteoblast-like phenotype was quantified in VICs cultured on different types of ECM coatings. The results show that the number and size of calcific nodules formed in VIC cultures, as well as the expression of mineralization markers alkaline phosphatase (ALP) and CBFa1, were highly dependent upon the composition of the culture surface. In fact, VICs cultured on certain ECM components, namely collagen (Coll) and fibronectin (FN), were resistant to calcification, even upon treatment with potent mineralization-inducing growth factors, such as transforming growth factor beta1 (TGFb1). Meanwhile, VIC cultures on fibrin (FB), laminin, and heparin not only had a high number of calcified nodules (p&lt;0.001 vs. Coll, FN), but also elevated levels of ALP and CBFa1 (p&lt;0.02), and the number of nodules on these ‘pro-calcific’ coatings significantly increased upon treatment with exogenous TGFb1 (p&lt;0.05). To explain the ECM-dependence of calcification, the endogenous production of a pro-mineralization factor (TGFb1) was assessed in VICs on anti-calcific (Coll) and pro-calcific (FB) substrates. Quantification of TGFb1 mRNA revealed that VICs on Coll surfaces expressed a significantly lower amount of TGFb1 mRNA than VICs on FB (p&lt;0.01). Furthermore, treatment with a neutralizing antibody to TGFb1 decreased TGFb1 mRNA expression by VICs on Coll in comparison to VICs on FB or polystyrene controls (p&lt;0.02). Thus, we have discovered a strong correlation between VIC calcification and ECM composition. Our findings show that the ECM plays an important role in controlling TGFb1 expression and subsequent calcification of VICs, which may significantly impact the design of biomaterials for valve tissue engineering, understanding of valvular disease, and the development of preventative treatments for valve calcification.