Prognostic significance of aortic valve calcium in relation to coronary artery calcification for long-term, cause-specific mortality: results from the CAC Consortium.
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ABSTRACT: Aims
Aortic valve calcification (AVC) has been shown to be associated with increased cardiovascular disease (CVD) risk; however, whether this is independent of traditional risk factors and coronary artery calcification (CAC) remains unclear.Methods and results
From the multicentre CAC Consortium database, 10 007 patients (mean 55.8±11.7 years, 64% male) with concomitant CAC and AVC scoring were included in the current analysis. AVC score was quantified using the Agatston score method and categorized as 0, 1-99, and ≥100. The endpoints were all-cause, CVD, and coronary heart disease (CHD) deaths. AVC (AVC>0) was observed in 1397 (14%) patients. During a median 7.8 (interquartile range: 4.7-10.6) years of study follow-up, 511 (5.1%) deaths occurred; 179 (35%) were CVD deaths, and 101 (19.8%) were CHD deaths. A significant interaction between CAC and AVC for mortality was observed (P<0.001). The incidence of mortality events increased with higher AVC; however, AVC ≥100 was not independently associated with all-cause, CVD, and CHD deaths after adjusting for CVD risk factors and CAC (P=0.192, 0.063, and 0.206, respectively). When further stratified by CAC<100 or ≥100, AVC ≥100 was an independent predictor of all-cause and CVD deaths only in patients with CAC <100, after adjusting for CVD risk factors and CAC [hazard ratio (HR): 1.93, 95% confidence interval (CI): 1.14-3.27; P=0.013 and HR: 2.71, 95% CI: 1.15-6.34; P=0.022, respectively].Conclusion
Although the overall prognostic significance of AVC was attenuated after accounting for CAC, high AVC was independently associated with all-cause and CVD deaths in patients with low coronary atherosclerosis burden.
SUBMITTER: Han D
PROVIDER: S-EPMC8527330 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:The Coronary Artery Calcium Data and Reporting System (CAC-DRS), which takes into account the Agatston score category (A) and the number of calcified vessels (N) has not yet been validated in terms of its prognostic significance. METHODS:We included 54,678 patients from the CAC Consortium, a large retrospective clinical cohort of asymptomatic individuals free of baseline cardiovascular disease (CVD). CAC-DRS groups were derived from routine, cardiac-gated CAC scans. Cox proportional hazards regression models, adjusted for traditional CVD risk factors, were used to assess the association between CAC-DRS groups and CHD, CVD, and all-cause mortality. CAC-DRS was then compared to CAC score groups and regional CAC distribution using area under the curve (AUC) analysis. RESULTS:The study population had a mean age of 54.2?±?10.7, 34.4% female, and mean ASCVD score 7.3%?±?9.0. Over a mean follow-up of 12?±?4 years, a total of 2,469 deaths (including 398 CHD deaths and 762 CVD deaths) were recorded. There was a graded risk for CHD, CVD and all-cause mortality with increasing CAC-DRS groups ranging from an all-cause mortality rate of 1.2 per 1,000 person-years for A0 to 15.4 per 1,000 person-years for A3/N4. In multivariable-adjusted models, those with CAC-DRS A3/N4 had significantly higher risk for CHD mortality (HR 5.9 (95% CI 3.6-9.9), CVD mortality (HR4.0 (95% CI 2.8-5.7), and all-cause mortality a (HR 2.5 (95% CI 2.1-3.0) compared to CAC-DRS A0. CAC-DRS had higher AUC than CAC score groups (0.762 vs 0.754, P?<?0.001) and CAC distribution (0.762 vs 0.748, P?<?0.001). CONCLUSION:The CAC-DRS system, combining the Agatston score and the number of vessels with CAC provides better stratification of risk for CHD, CVD, and all-cause death than the Agatston score alone. These prognostic data strongly support new SCCT guidelines recommending the use CAC-DRS scoring.
| S-EPMC6765460 | biostudies-literature
Project description:BackgroundIdentifying cancer patients at high risk of CVD is important for targeting CVD prevention strategies and evaluating chemotherapy options in the context of cardiotoxicity. Coronary artery calcium (CAC), a strong marker of coronary atherosclerosis, is used clinically to enhance risk assessment, yet the value of CAC for assessing risk of CVD complications in cancer is poorly understood.ObjectiveIn cases of cancer mortality, to determine the value of CAC for predicting risk of CVD as a supporting cause of death.MethodsThe CAC Consortium is a multi-center cohort of 66,636 asymptomatic adults without CVD who underwent CAC scanning. During a follow-up of 12.5 years, 1129 patients died of cancer and were included in this analysis. The primary outcome was presence of CVD listed as a supporting cause of cancer mortality on official death certificates obtained from the National Death Index. Logistic regression models were used to assess the odds of CVD being listed as a supporting cause of death by CAC.ResultsCVD was listed as a supporting cause of death in 306 (27%) cancer mortality cases. Baseline CAC was significantly higher in individuals with CVD-supported mortality. Odds ratios of having CVD-supported death increased by ASCVD risk score category [1.15 (0.81, 1.65) for 5-20% 10-year risk and 1.97 (1.36, 2.89) for ≥20% risk, in reference to <5% 10-year ASCVD risk] and CAC category [1.07 (0.73, 1.57) for CAC 1-99, 1.29 (0.87, 1.93) for CAC 100-399, and 2.14 (1.48, 3.09) for CAC ≥400 relative to CAC 0]. In the CAC ≥400 group, these associations remained significantly elevated after adjustment for traditional CVD risk factors [1.66 (1.08, 2.55)]. A sensitivity analysis using a more specific ASCVD-supported mortality outcome, defined as coronary heart disease, stroke, and peripheral artery disease, demonstrated that adjusted odds of ASCVD-supported cancer mortality were significantly elevated in the CAC ≥400 group relative to CAC 0 [3.09 (1.39, 7.38)].ConclusionsIn cancer mortality cases, high antecedent CAC predicted risk of having CVD as a supporting cause of death on official death certificates, independently of ASCVD risk score and CVD risk factors. CAC may be useful for identifying cancer patients at high CVD risk who might benefit from more intense preventive cardiovascular therapies.
| S-EPMC8315471 | biostudies-literature
Project description:Background and aimsCoronary artery calcium (CAC) burden displays a stepwise association with atherosclerotic cardiovascular disease (ASCVD) risk. Among primary prevention patients, we sought to determine the CAC scores equivalent to ASCVD mortality rates observed in the FOURIER trial, a modern secondary prevention cohort.Methods and resultsFor the main analysis, we included participants from the CAC Consortium ≥50 years old with a 10-year ASCVD risk ≥7.5% (n = 20,207). Poisson regression was used to define the relationship between CAC and annual ASCVD mortality. Equations generated from the regression models were then used to derive CAC scores associated with equivalent annual ASCVD mortality as observed in FOURIER placebo participants from the overall trial and in key trial subgroups. The CAC Consortium participants had a similar age (65.5 versus 62.5 years) and sex (22% versus 24% female) distribution as FOURIER. The annualized ASCVD mortality rate in FOURIER participants (0.766 per 100 person-years) corresponded to a CAC score of 781 (418-1467). A CAC score of 255 (162-394) corresponded to an ASCVD mortality rate equivalent to the lowest risk FOURIER subgroup (presence of myocardial infarction >2 years prior to trial enrollment). No CAC score produced a risk equivalent to high-risk FOURIER subgroups, particularly those with symptomatic peripheral arterial disease and/or multivessel coronary heart disease.ConclusionsPrimary prevention individuals with increased CAC burden may have annualized ASCVD mortality rates equivalent to persons with stable secondary prevention-level risk. These findings argue for a risk continuum between higher risk primary prevention and stable secondary prevention patients, as their ASCVD risks may overlap.
| S-EPMC9030020 | biostudies-literature
Project description:ObjectivesThis study thoroughly explored the demographic and imaging characteristics, as well as the all-cause and cause-specific mortality risks of patients with a coronary artery calcium (CAC) score ≥1,000 in the largest dataset of this population to date.BackgroundCAC is commonly used to quantify cardiovascular risk. Current guidelines classify a CAC score of >300 or 400 as the highest risk group, yet little is known about the potentially unique imaging characteristics and mortality risk in individuals with a CAC score ≥1,000.MethodsA total of 66,636 asymptomatic adults were included from the CAC consortium, a large retrospective multicenter clinical cohort. Mean patient follow-up was 12.3 ± 3.9 years for patients with cardiovascular disease (CVD), coronary heart disease (CHD), cancer, and all-cause mortality. Multivariate Cox proportional hazards regression models adjusted for age, sex, and conventional risk factors were used to assess the relative mortality hazard of individuals with CAC ≥1,000 compared with, first, a CAC reference of 0, and second, with patients with a CAC score of 400 to 999.ResultsThere were 2,869 patients with CAC ≥1,000 (86.3% male, mean 66.3 ± 9.7 years of age). Most patients with CAC ≥1,000 had 4-vessel CAC (mean: 3.5 ± 0.6 vessels) and had greater total CAC area, higher mean CAC density, and more extracoronary calcium (79% with thoracic artery calcium, 46% with aortic valve calcium, and 21% with mitral valve calcium) than those with CAC scores of 400 to 999. After full adjustment, those with CAC ≥1,000 had a 5.04- (95% confidence interval [CI]: 3.92 to 6.48), 6.79- (95% CI: 4.74 to 9.73), 1.55- (95% CI:1.23 to 1.95), and 2.89-fold (95% CI: 2.53 to 3.31) risk of CVD, CHD, cancer, and all-cause mortality, respectively, compared to those with CAC score of 0. The CAC ≥1,000 group had a 1.71- (95% CI: 1.41 to 2.08), 1.84- (95% CI: 1.43 to 2.36), 1.36- (95% CI:1.07 to 1.73), and 1.51-fold (95% CI: 1.33 to 1.70) increased risk of CVD, CHD, cancer, and all-cause mortality compared to those with CAC scores 400 to 999. Graphic analysis of CAC ≥1,000 patients revealed continued logarithmic increase in risk, with no clear evidence of a risk plateau.ConclusionsPatients with extensive CAC (CAC ≥1,000) represent a unique very high-risk phenotype with mortality outcomes commensurate with high-risk secondary prevention patients. Future guidelines should consider CAC ≥1,000 patients to be a distinct risk group who may benefit from the most aggressive preventive therapy.
| S-EPMC6745300 | biostudies-literature
Project description:Aortic valve calcium (AVC) and coronary artery calcium (CAC) are common complications in end-stage renal disease (ESRD). We investigated the prognostic significance of overlapping presence of AVC and CAC, and whether AVC was associated with all-cause mortality independent of the presence of CAC in ESRD. 259 ESRD patients (median age 55 years, 67% males) undergoing cardiac computed tomography were included. Framingham risk score (FRS), presence of cardiovascular disease (CVD), statin use, nutritional status and other relevant laboratory data were determined at baseline. During follow-up for median 36 months, 44 patients died, and 68 patients underwent renal transplantation. The baseline overlap presence of AVC and CAC was 37%. Multivariate regression analysis showed that FRS (odds ratio (OR) 2.25; 95% confidence interval (95% CI), 1.43-3.55) and CAC score (OR (95% CI), 2.18 (1.34-3.59)) were independent determinants of AVC. In competing-risk regression models adjusted for presence of CAC, inflammation, nutritional status, CVD, FRS and statin use, AVC remained independently associated with all-cause mortality (sub-hazard ratio (95% CI), 2.57 (1.20-5.51)). The overlap of AVC and CAC was 37% in this ESRD cohort. AVC was associated with increased all-cause mortality independent of presence of CAC, traditional risk factors and inflammation.
| S-EPMC7074421 | biostudies-literature
Project description:The involvement of calcium-dependent cytosolic phospholipase A2? (cPLA2?) in aortic valve calcification is not exhaustively elucidated. Here, cPLA2? expression in aortic valve interstitial cell (AVIC) pro-calcific cultures simulating either metastatic or dystrophic calcification was estimated by qPCR, Western blotting, and counting of cPLA2?-immunoreactive cells, with parallel ultrastructural examination of AVIC calcific degeneration. These evaluations also involved pro-calcific AVIC cultures treated with cPLA2? inhibitor dexamethasone. cPLA2? over-expression resulted for both types of pro-calcific AVIC cultures. Compared to controls, enzyme content was found to increase by up to 300% and 186% in metastatic and dystrophic calcification-like cultures, respectively. Increases in mRNA amounts were also observed, although they were not as striking as those in enzyme content. Moreover, cPLA2? increases were time-dependent and strictly associated with mineralization progression. Conversely, drastically lower levels of enzyme content resulted for the pro-calcific AVIC cultures supplemented with dexamethasone. In particular, cPLA2? amounts were found to decrease by almost 88% and 48% in metastatic and dystrophic calcification-like cultures, respectively, with mRNA amounts showing a similar trend. Interestingly, these drastic decreases in cPLA2? amounts were paralleled by drastic decreases in mineralization degrees, as revealed ultrastructurally. In conclusion, cPLA2? may be regarded as a crucial co-factor contributing to AVIC mineralization in vitro, thus being an attractive potential target for designing novel therapeutic strategies aimed to counteract onset or progression of calcific aortic valve diseases.
| S-EPMC7503521 | biostudies-literature
Project description:miR-214 has been recently found to be significantly downregulated in calcified human aortic valves (AVs). ER stress, especially the ATF4-mediated pathway, has also been shown to be significantly upregulated in calcific AV disease. Since elevated cyclic stretch is one of the major mechanical stimuli for AV calcification and ATF4 is a validated target of miR-214, we investigated the effect of cyclic stretch on miR-214 expression as well as those of ATF4 and two downstream genes (CHOP and BCL2L1). Porcine aortic valve (PAV) leaflets were cyclically stretched at 15% for 48 h in regular medium and for 1 week in osteogenic medium to simulate the early remodeling and late calcification stages of stretch-induced AV disease, respectively. For both stages, 10% cyclic stretch served as the physiological counterpart. RT-qPCR revealed that miR-214 expression was significantly downregulated during the late calcification stage, whereas the mRNA expression of ATF4 and BCL2L1 was upregulated and downregulated, respectively, during both early remodeling and late calcification stages. When PAV leaflets were statically transfected with miR-214 mimic in osteogenic medium for 2 weeks, calcification was significantly reduced compared to the control mimic case. This implies that miR-214 may have a protective role in stretch-induced calcific AV disease.
| S-EPMC6416061 | biostudies-literature
Project description:AimsThere is evidence to suggest that the subtype of aortic stenosis (AS), the degree of myocardial fibrosis (MF), and level of aortic valve calcification (AVC) are associated with adverse cardiac outcome in AS. Because little is known about their respective contribution, we sought to investigate their relative importance and interplay as well as their association with adverse cardiac events following transcatheter aortic valve replacement (TAVR).Methods and resultsOne hundred consecutive patients with severe AS and indication for TAVR were prospectively enrolled between January 2017 and October 2018. Patients underwent transthoracic echocardiography, multidetector computed tomography, and left ventricular endomyocardial biopsies at the time of TAVR. The final study cohort consisted of 92 patients with a completed study protocol, 39 (42.4%) of whom showed a normal ejection fraction (EF) high-gradient (NEFHG) AS, 13 (14.1%) a low EF high-gradient (LEFHG) AS, 25 (27.2%) a low EF low-gradient (LEFLG) AS, and 15 (16.3%) a paradoxical low-flow, low-gradient (PLFLG) AS. The high-gradient phenotypes (NEFHG and LEFHG) showed the largest amount of AVC (807 ± 421 and 813 ± 281 mm3 , respectively) as compared with the low-gradient phenotypes (LEFLG and PLFLG; 503 ± 326 and 555 ± 594 mm3 , respectively, P < 0.05). Conversely, MF was most prevalent in low-output phenotypes (LEFLG > LEFHG > PLFLG > NEFHG, P < 0.05). This was paralleled by a greater cardiovascular (CV) mortality within 600 days after TAVR (LEFLG 28% > PLFLG 26.7% > LEFHG 15.4% > NEFHG 2.5%; P = 0.023). In patients with a high MF burden, a higher AVC was associated with a lower mortality following TAVR (P = 0.045, hazard ratio 0.261, 95% confidence interval 0.07-0.97).ConclusionsMF is associated with adverse CV outcome following TAVR, which is most prevalent in low EF situations. In the presence of large MF burden, patients with large AVC have better outcome following TAVR. Conversely, worse outcome in large MF and relatively little AVC may be explained by a relative prominence of an underlying cardiomyopathy. The better survival rates in large AVC patients following TAVR indicate TAVR induced relief of severe AS-associated pressure overload with subsequently improved outcome.
| S-EPMC10375183 | biostudies-literature
Project description:BackgroundCellular communication network factor 3 (CCN3) has been implicated in the regulation of osteoblast differentiation. However, it is not known if CCN3 can regulate valvular calcification. While macrophages have been shown to regulate valvular calcification, the molecular and cellular mechanisms of this process remain poorly understood. In the present study, we investigated the role of macrophage-derived CCN3 in the progression of calcific aortic valve disease.MethodsMyeloid-specific knockout of CCN3 (Mye-CCN3-KO) and control mice were subjected to a single tail intravenous injection of AAV encoding mutant mPCSK9 (rAAV8/D377Y-mPCSK9) to induce hyperlipidemia. AAV-injected mice were then fed a high fat diet for 40 weeks. At the conclusion of high fat diet feeding, tissues were harvested and subjected to histologic and pathologic analyses. In vitro, bone marrow-derived macrophages (BMDM) were obtained from Mye-CCN3-KO and control mice and the expression of bone morphogenic protein signaling related gene were verified via quantitative real-time PCR and Western blotting. The BMDM conditioned medium was cocultured with human valvular intersititial cells which was artificially induced calcification to test the effect of the conditioned medium via Western blotting and Alizarin red staining.ResultsEchocardiography revealed that both male and female Mye-CCN3-KO mice displayed compromised aortic valvular function accompanied by exacerbated valve thickness and cardiac dysfunction. Histologically, Alizarin-Red staining revealed a marked increase in aortic valve calcification in Mye-CCN3-KO mice when compared to the controls. In vitro, CCN3 deficiency augmented BMP2 production and secretion from bone marrow-derived macrophages. In addition, human valvular interstitial cells cultured with conditioned media from CCN3-deficient BMDMs resulted in exaggerated pro-calcifying gene expression and the consequent calcification.ConclusionOur data uncovered a novel role of myeloid CCN3 in the regulation of aortic valve calcification. Modulation of BMP2 production and secretion in macrophages might serve as a key mechanism for macrophage-derived CCN3's anti-calcification function in the development of CAVD. Video Abstract.
| S-EPMC9854076 | biostudies-literature
Project description:Background:Atrioventricular block requiring permanent pacemaker (PPM) implantation is a common complication of transcatheter aortic valve replacement (TAVR). The mechanism of atrioventricular (AV) block during TAVR is not fully understood, but it may be due to the mechanical stress of TAVR deployment, resulting in possible injury to the nearby compact AV node. Aortic valve calcification (AVC) may worsen this condition and has been associated with an increased risk for post-TAVR PPM implantation. We performed a retrospective analysis to determine if AVC is predictive for long-term right ventricular (RV) pacing in post-TAVR pacemaker patients at 30 days. Methods:A total of 262 consecutive patients who underwent TAVR with a balloon-expandable valve were analyzed. AVC data were derived from contrast-enhanced computed tomography and characterized by leaflet sector and region. Results:A total of 25 patients (11.1%) required post-TAVR PPM implantation. Seventeen patients did not require RV pacing at 30 days. Nine of these 17 patients had no RV pacing requirement within 10 days. The presence of intra-procedural heart block (P = 0.004) was the only significant difference between patients who did not require PPM and those who required PPM but they were not RV pacing-dependent at 30 days. Non-coronary cusp (NCC) calcium volume was significantly higher in patients who were pacemaker-dependent at 30 days (P = 0.01) and a calcium volume of > 239.2 mm3 in the NCC was strongly predictive of pacemaker dependence at 30 days (area under the curve (AUC) = 0.813). Pre-existing right bundle branch block (RBBB) (odds ratio (OR) 105.4, P = 0.004), bifascicular block (OR 12.5, P = 0.02), QRS duration (OR 70.43, P = 0.007) and intra-procedural complete heart block (OR 12.83, P = 0.03) were also predictive of pacemaker dependence at 30 days. Conclusions:In patients who required PPM after TAVR, quantification of AVC by non-coronary leaflet calcium volume was found to be a novel predictor for RV pacing dependence at 30 days. The association of NCC calcification and PPM dependence may be related to the proximity of the conduction bundle to the non-coronary leaflet. Further studies are necessary to improve risk prediction for long-term RV pacing requirements following TAVR.
| S-EPMC7239596 | biostudies-literature