Combinations of valvular calcification and serum alkaline phosphatase predict cardiovascular risk among end-stage kidney disease patients.

Background: Valvular calcification (VC) refers to the calcified valvular remodeling associated with kidney dysfunction, especially end-stage kidney disease (ESKD). ESKD patients with VC had significantly higher cardiovascular risk than those without. Factors interacted with VC regarding prognostic prediction in this population were seldom investigated. We aimed to examine the potential synergetic effects of VC and alkaline phosphatase (Alk-P) on ESKD patients' cardiovascular risk and mortality. Methods: ESKD patients undergoing hemodialysis were prospectively enrolled from a medical center in 2018. We identified patients with echocardiography and available serum Alk-P levels. Cox proportional hazard regression was performed to analyze the risk of major adverse cardiovascular events (MACEs), cardiovascular and overall mortality among 4 participant groups (with or without VC versus low or high Alk-P levels). The models were further adjusted for age, sex, and clinical variables. Results: Of the 309 ESKD patients, 38, 46, 112, and 113 had no VC with low Alk-P, no VC with high Alk-P, VC with low Alk-P, and VC with high Alk-P, respectively. After adjusting for age and sex, patients with VC and high Alk-P had a higher risk of developing MACE, cardiovascular and overall mortality (HR, 3.07, 3.67, 3.65; 95% CI 1.38-6.84, 1.1-12.24, 1.29-10.36, respectively). Patients with VC and high Alk-P remained at higher risk of MACE (HR, 2.76; 95% CI 1.17-6.48) than did those without VC and with low Alk-P. Conclusion: Serum Alk-P could be used to identify a subgroup of ESKD patients with elevated cardiovascular risk among those with VC.

Association between serum beclin 1 level and cardiac valvular calcification in hemodialysis patients.

BACKGROUND: Cardiovascular calcification is a pervasive issue throughout chronic kidney disease (CKD) progression. Autophagy, a fundamental cellular process, exerts significant influence on various cardiac pathologies, including arrhythmias, atherosclerosis, heart failure, and notably, valvular, and vascular calcifications. Beclin-1, a crucial eukaryotic protein, plays a major regulatory role in autophagy as part of the phosphatidylinositol-3-kinase (PI3K) complex. Recent evidence suggests a protective role for Beclin-1-mediated autophagy in CKD vascular calcification, raising its potential as a novel therapeutic target in this context. WE AIMED TO: Investigate the association between serum Beclin 1 levels and the presence of cardiovascular valvular calcification in hemodialysis patients. RESULTS: This study evaluated a cohort of 102 hemodialysis patients, evenly divided into two groups based on echocardiographic findings. All participants underwent serum Beclin 1 measurement and transthoracic echocardiography. Patients with acute kidney injury, active malignancy, or diabetes were excluded. Our study revealed significant differences between the two groups in terms of: Serum Beclin 1 levels, all parameters of lipid profile, prevalence of ischemic heart disease, serum albumin levels and Total calcium. Echocardiography in Group 1 showed that most cases (60.78%) exhibited mild aortic valve calcification. Additionally, significant relationships were observed between Beclin 1 and: ischemic heart disease (p=0.011) Aortic valve calcification on echocardiography (p < 0.001) Interestingly, lower Beclin 1 levels were associated with more severe valve calcification. A Beclin 1 cutoff value of ≤ 35.5 ng/ml demonstrated the highest sensitivity (98%) and specificity (92%). CONCLUSION: Our findings suggest that the serum Beclin 1 level could be incorporated into a predictive model for cardiac valvular calcification in hemodialysis patients.

Association of Segment-Specific Pulse Wave Velocity With Vascular Calcification: The ARIC (Atherosclerosis Risk in Communities) Study.

BACKGROUND: Pulse wave velocity (PWV) is a noninvasive measure of arterial stiffness and predictor of cardiovascular disease. However, the association between PWV and vascular calcification across different vascular beds has not been fully investigated. This study aimed to quantify the association between PWV and multiterritory calcification and to explore whether PWV can identify individuals with vascular calcification beyond traditional risk factors. METHODS AND RESULTS: Among 1351 older adults (mean age, 79.2 years [SD, 4.1]) from the ARIC (Atherosclerosis Risk in Communities) study, we measured segment-specific PWVs: heart-carotid, heart-femoral, carotid-femoral, heart-ankle, brachial-ankle, and femoral-ankle. Dependent variables were high calcium score (≥75th percentile of Agatston score) across different vascular beds: coronary arteries, aortic valve ring, aortic valve, mitral valve, ascending aorta, and descending aorta. Quartiles of carotid-femoral, heart-femoral, heart-ankle, and brachial-ankle PWV were significantly associated with coronary artery calcium (eg, adjusted odds ratio [OR] for the highest versus lowest quartile of carotid-femoral PWV, 1.84 [95% CI, 1.24-2.74]). Overall, PWVs were most strongly associated with descending aorta calcification, with significant results for carotid-femoral, heart-femoral, heart-ankle, and brachial-ankle PWV (eg, adjusted OR for the highest versus lowest quartile of carotid-femoral PWV, 3.99 [95% CI, 2.61-6.17]). In contrast, femoral-ankle PWV was inversely associated with descending aorta calcification. Some PWVs improved the discrimination of coronary artery calcium and descending aorta calcification beyond traditional risk factors. CONCLUSIONS: The associations of PWV with vascular calcification varied substantially across segments, with descending aorta calcification most closely linked to PWVs. Our study suggests that some PWVs, especially carotid-femoral PWV, are helpful to identify individuals with coronary artery calcium and descending aorta calcification.

Predictive value of valvular calcification for the recurrence of persistent atrial fibrillation after radiofrequency catheter ablation.

BACKGROUND: Valvular calcification (VC) is an independent risk factor for cardiovascular diseases. The relationship between VC and atrial fibrillation is not clear. HYPOTHESIS: We treated the aortic valve, mitral valve, and tricuspid valve as a whole and considered the possible association between VC and recurrence of persistent atrial fibrillation (PsAF) after radiofrequency catheter ablation (RFCA). METHODS: This study involved 2687 PsAF patients who underwent RFCA. Data were collected to explore the relationship between VC and outcome. VC was defined by echocardiography in aortic valve, mitral valve, or tricuspid valve. After 1 year follow-up, subgroup analysis, mixed model regression analysis, and score system analysis were performed. The external validation of 133 patients demonstrated the accuracy of this clinical prediction model. RESULTS: Overall, 2687 inpatients were assigned to the recurrence group (n = 682) or the no recurrence group (n = 2005) with or without VC. Compared to patients with no recurrence, the incidence of VC was higher in recurrence patients. Recurrence was present in 18.5%, 34.9%, 39.3%, and 52.0% of the four groups, which met VC numbers of 0, 1, 2, and 3, respectively. After adjustment for potential confounding factors, VC was an independent risk factor for AF recurrence in several models. For multivariable logistic regression, a scoring system was established based on the regression coefficient. The receiver operating characteristic area of the scoring system was 0.787 in the external validation cohort. CONCLUSIONS: VC was an independent risk factor for AF recurrence in PsAF after RFCA. The scoring system may be a useful clinical tool to assess AF recurrence.

Interventions to Attenuate Cardiovascular Calcification Progression: A Systematic Review of Randomized Clinical Trials.

BACKGROUND: Cardiovascular calcification, characterized by deposition of calcium phosphate in the arterial wall and heart valves, is associated with cardiovascular morbidity and mortality and is commonly seen in aging, diabetes, and chronic kidney disease. Whether evidence-based interventions could significantly attenuate cardiovascular calcification progression remains uncertain. METHODS AND RESULTS: We conducted a systematic review of randomized controlled trials involving interventions, compared with placebo, another comparator, or standard of care, to attenuate cardiovascular calcification. Included clinical trials involved participants without chronic kidney disease, and the outcome was cardiovascular calcification measured using radiological methods. Quality of evidence was determined by the Cochrane risk of bias and Grading of Recommendations, Assessment, Development, and Evaluations assessment. Forty-nine randomized controlled trials involving 9901 participants (median participants 104, median duration 12 months) were eligible for inclusion. Trials involving aged garlic extract (n=6 studies) consistently showed attenuation of cardiovascular calcification. Trials involving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (n=14), other lipid-lowering agents (n=2), hormone replacement therapies (n=3), vitamin K (n=5), lifestyle measures (n=4), and omega-3 fatty acids (n=2) consistently showed no attenuation of cardiovascular calcification with these therapies. Trials involving antiresorptive (n=2), antihypertensive (n=2), antithrombotic (n=4), and hypoglycemic agents (n=3) showed mixed results. Singleton studies involving salsalate, folate with vitamin B6 and 12, and dalcetrapib showed no attenuation of cardiovascular calcification. Overall, Cochrane risk of bias was moderate, and the Grading of Recommendations, Assessment, Development, and Evaluations assessment for a majority of analyses was moderate certainty of evidence. CONCLUSIONS: Currently, there are insufficient or conflicting data for interventions evaluated in clinical trials for mitigation of cardiovascular calcification. Therapy involving aged garlic extract appears most promising, but evaluable studies were small and of short duration.

Inactive Matrix Gla Protein in Relation to Renal and Cardiac Functions and Cardiac Valvular Calcification Among Type 2 Diabetes Patients.

Background: Matrix Gla protein (MGP) is a robust innate suppressor of the detrimental process of vascular calcification in the human body. Objectives: The interrelationship between circulating MGP levels and renal and cardiac dysfunction, besides echocardiographic calcification score (ECS) was investigated in a sample of type 2 diabetes (T2D) patients. Methods: The study included 130 subjects. They were 95 patients with T2D and 35 age- and sex-matched healthy controls. Patients were further subdivided into 52 T2D patients without DKD (eGFR ⩾ 60 ml/minute/1.73 m²) and 43 T2D persons with DKD (eGFR > 60 ml/minute/1.73 m²). Serum MGP levels, determined by ELISA, renal function tests, lipid profile, and echocardiography were studied in all participants. Results: Significantly elevated circulating inactive MGP level was noted in individuals having T2D compared to controls. It correlated negatively with eGFR and left ventricular (LV) diastolic and systolic functions and positively with indices of LV hypertrophy. ECS was significantly increased in both T2D groups compared to controls and in DKD group compared to the diabetic group without DKD. A significant positive correlation was observed between inactive MGP and ECS. Conclusion: Serum inactive MGP may contribute to the development of DKD and to the associated process of cardiac valvular calcification. It may be a beneficial diagnostic marker for early prediction of cardiac calcification and preclinical LV systolic and diastolic dysfunction in T2D patients, especially in those complicated with DKD.

Extensive cardiovascular involvement in a young boy with Gaucher's disease: a case report.

Background: Lysosomal storage diseases (LSDs) are rare, progressive, multi-organ disorders caused by inherited enzyme deficiencies. Gaucher's disease (GD) is the most prevalent form of LSDs. Case summary: A 19-year-old Caucasian male presented with exertional dyspnoea. Physical examination revealed a Grade III/VI systolic diamond murmur at the heart base and a Grade IV/VI systolic murmur at the apex. Electrocardiogram showed signs of left ventricular hypertrophy (LVH). Trans-thoracic echocardiography (TTE) and trans-oesophageal echocardiography (TEE) demonstrated moderate LVH, severe aortic valve stenosis, severe supra-valvular aortic stenosis, and moderate mitral stenosis with severe degenerative mitral valve regurgitation. Bone marrow biopsy and aspiration confirmed the presence of characteristic Gaucher's cells. The patient underwent the Bentall procedure and mitral valve replacement and was discharged in good condition. Discussion: Gaucher's disease exhibits three clinical phenotypes, and cardiovascular involvement is commonly seen in GD Type III. Valvular calcification and ascending aorta involvement are frequent cardiovascular manifestations. Although severe valvular heart involvement is rare in GD, cardiac valve surgery has shown favourable outcomes in previous studies and our case.

Single-cell transcriptomics reveals cellular heterogeneity and macrophage-to-mesenchymal transition in bicuspid calcific aortic valve disease.

BACKGROUND: Bicuspid aortic valve (BAV) is the most prevalent congenital valvular heart defect, and around 50% of severe isolated calcific aortic valve disease (CAVD) cases are associated with BAV. Although previous studies have demonstrated the cellular heterogeneity of aortic valves, the cellular composition of specific BAV at the single-cell level remains unclear. METHODS: Four BAV specimens from aortic valve stenosis patients were collected to conduct single-cell RNA sequencing (scRNA-seq). In vitro experiments were performed to further validate some phenotypes. RESULTS: The heterogeneity of stromal cells and immune cells were revealed based on comprehensive analysis. We identified twelve subclusters of VICs, four subclusters of ECs, six subclusters of lymphocytes, six subclusters of monocytic cells and one cluster of mast cells. Based on the detailed cell atlas, we constructed a cellular interaction network. Several novel cell types were identified, and we provided evidence for established mechanisms on valvular calcification. Furthermore, when exploring the monocytic lineage, a special population, macrophage derived stromal cells (MDSC), was revealed to be originated from MRC1+ (CD206) macrophages (Macrophage-to-Mesenchymal transition, MMT). FOXC1 and PI3K-AKT pathway were identified as potential regulators of MMT through scRNA analysis and in vitro experiments. CONCLUSIONS: With an unbiased scRNA-seq approach, we identified a full spectrum of cell populations and a cellular interaction network in stenotic BAVs, which may provide insights for further research on CAVD. Notably, the exploration on mechanism of MMT might provide potential therapeutic targets for bicuspid CAVD.

Abnormal mechanical stress on bicuspid aortic valve induces valvular calcification and inhibits Notch1/NICD/Runx2 signal.

Background: Bicuspid aortic valve (BAV) is a congenital cardiac deformity, increasing the risk of developing calcific aortic valve disease (CAVD). The disturbance of hemodynamics can induce valvular calcification, but the mechanism has not been fully identified. Methods: We constructed a finite element model (FEM) of the aortic valve based on the computed tomography angiography (CTA) data from BAV patients and tricuspid aortic valve (TAV) individuals. We analyzed the hemodynamic properties based on our model and investigated the characteristics of mechanical stimuli on BAV. Further, we detected the expression of Notch, NICD and Runx2 in valve samples and identified the association between mechanical stress and the Notch1 signaling pathway. Results: Finite element analysis showed that at diastole phase, the equivalent stress on the root of BAV was significantly higher than that on the TAV leaflet. Correspondingly, the expression of Notch1 and NICH decreased and the expression of Runx2 elevated significantly on large BAV leaflet belly, which is associated with equivalent stress on leaflet. Our findings indicated that the root of BAV suffered higher mechanical stress due to the abnormal hemodynamic environment, and the disturbance of the Notch1/NICD/Runx2 signaling pathway caused by mechanical stimuli contributed to valvular calcification.

Clinical Implication of Consistently Strict Phosphate Control for Coronary and Valvular Calcification in Incident Patients Undergoing Hemodialysis.

AIMS: Serum phosphate control is crucial for the progression of vascular and valvular calcifications. Strict phosphate control is recently suggested; however, there is a lack of convincing evidence. Therefore, we explored the effects of strict phosphate control on vascular and valvular calcifications in incident patients undergoing hemodialysis. METHODS: A total of 64 patients undergoing hemodialysis from our previous randomized controlled trial were included in this study. Coronary artery calcification score (CACS) and cardiac valvular calcification score (CVCS) were evaluated using computed tomography and ultrasound cardiography at baseline and 18 months after the initiation of hemodialysis. The absolute changes in CACS (ΔCACS) and CVCS (ΔCVCS) and the percent change in CACS (%ΔCACS) and CVCS (%ΔCVCS) were calculated. Serum phosphate level was measured at 6, 12, and 18 months after the initiation of hemodialysis. Moreover, phosphate control status was evaluated using the area under the curve (AUC) by the amount of time spent with a serum phosphate level of ≥ 4.5 mg/dL and the extent to which this threshold exceeded over the observation period. RESULTS: ΔCACS, %ΔCACS, ΔCVCS, and %ΔCVCS were significantly lower in the low AUC group than in the high AUC group. ΔCACS and %ΔCACS were also significantly lower. ΔCVCS and %ΔCVCS tended to be lower in patients whose serum phosphate level never exceeded 4.5 mg/dL than in those whose serum phosphate level continuously exceeded 4.5 mg/dL. AUC significantly correlated with ΔCACS and ΔCVCS. CONCLUSION: Consistently strict phosphate control may slow the progression of coronary and valvular calcifications in incident patients undergoing hemodialysis.

Prognosis of Heart Valve Calcification on Cardiovascular Events in Hemodialysis Patients without Central Venous Catheters.

INTRODUCTION: Heart valvular calcification (HVC) is an important predictor of cardiovascular events (CEs) and all-cause mortality in dialysis patients. Patients in the early stage of dialysis or those with central venous catheters (CVC) are also at high risk of cardiovascular and all-cause mortality. It could be a confounding factor for the prognosis of HVC on CE. METHODS: From March 2017 to April 2022, the prognosis of HVC on CE and all-cause mortality was studied retrospectively in 158 hemodialysis (HD) patients who used arteriovenous fistulas or arteriovenous grafts as vascular access and entered HD for more than 12 months. RESULTS: Out of 158 patients, 70 (44.3%) were diagnosed with HVC via echocardiography. A total of 180 CEs occurred during follow-up. Among them, acute heart failure accounted for 62.66%, and its prevalence was significantly higher in the HVC group than that in the non-HVC group (p < 0.0001). The cumulative incidence of CE-free survival in the HVC group was significantly lower than that in the non-HVC group (p = 0.030). Only 11 patients died, and there was no significant difference in all-cause mortality between the two groups (p = 0.560). Multivariate COX regression analyses showed that HD vintage, mitral valve calcification, and aortic valve regurgitation (AR)/aortic valve stenosis (AS) but not aortic valve calcification were risk factors for CE (p < 0.05). CONCLUSION: After excluding the factors of the early stage of HD and CVC, HVC remained a predictor of adverse CE in HD patients.

Predictive role of cardiac valvular calcification in all-cause mortality of Chinese initial haemodialysis patients: a follow-up study of 4 years.

BACKGROUND: Cardiac valvular calcification (CVC) is prevalent in haemodialysis (HD) patients. Its association with mortality in Chinese incident haemodialysis (IHD) patients remains unknown. METHODS: A total of 224 IHD patients who had just begun HD therapy at Zhongshan Hospital, Fudan University, were enrolled and divided into two groups according to the detection of cardiac valvular calcification (CVC) by echocardiography. The patients were followed for a median of 4 years for all-cause mortality and cardiovascular mortality. RESULTS: During follow-up, 56 (25.0%) patients died, including 29 (51.8%) of cardiovascular disease. The adjusted HR related to all-cause mortality was 2.14 (95% CI, 1.05-4.39) for patients with cardiac valvular calcification. However, CVC was not an independent risk factor for cardiovascular mortality in patients who had just begun HD therapy. CONCLUSION: CVC at baseline is an independent risk factor for all-cause mortality in HD patients and makes an independent contribution to the prediction of all-cause mortality. These findings support the use of echocardiography at the beginning of HD.

Myeloid CCN3 protects against aortic valve calcification.

BACKGROUND: Cellular 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. METHODS: Myeloid-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. RESULTS: Echocardiography 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. CONCLUSION: Our 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.

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

Study objective: Data is scarce regarding which dialysis modality portends more severe cardiac valvular calcification (CVC). Our aim was to compare the degree of CVC in hemodialysis (HD) and peritoneal dialysis (PD) patient cohorts prior to open heart surgery (OHS) using a CT calcium score. Design setting and participants: Dialysis patients who underwent OHS at our institution from 2009 to 2019 and who had pre-surgical cardiac CT were included in our study. We obtained duration of dialysis modality prior to their surgical date. There were two study cohorts to evaluate outcomes of interest: mitral and aortic calcification. CVC was assessed using the Agatston score. Logistic regression was performed to test for the association of PD and HD cumulative dialysis duration with presence of CVC. Results: A total of 214 and 166 patients met inclusion for the mitral and aortic strata, respectively. Age, female sex, and BMI were associated with higher odds of presence of mitral calcification. Age and BMI were associated with higher odds of presence of aortic calcification, while female sex was associated with lower odds in the aortic strata. Cumulative years on PD and cumulative years on HD were not significantly associated with presence of CVC in either cohort. 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, gender, and BMI suggesting that there may be more factors at play in the progression of CVC in end stage renal disease patients than what was previously established.

Overview on hydrogen sulfide-mediated suppression of vascular calcification and hemoglobin/heme-mediated vascular damage in atherosclerosis.

Vulnerable atherosclerotic plaques with hemorrhage considerably contribute to cardiovascular morbidity and mortality. Calcification is the main characteristic of advanced atherosclerotic lesions and calcified aortic valve disease (CAVD). Lyses of red blood cells and hemoglobin (Hb) release occur in human hemorrhagic complicated lesions. During the interaction of cell-free Hb with plaque constituents, Hb is oxidized to ferric and ferryl states accompanied by oxidative changes of the globin moieties and heme release. Accumulation of both ferryl-Hb and metHb has been observed in atherosclerotic plaques. The oxidation hotspots in the globin chain are the cysteine and tyrosine amino acids associated with the generation of Hb dimers, tetramers and polymers. Moreover, fragmentation of Hb occurs leading to the formation of globin-derived peptides. A series of these pro-atherogenic cellular responses can be suppressed by hydrogen sulfide (H2S). Since H2S has been explored to exhibit a wide range of physiologic functions to maintain vascular homeostasis, it is not surprising that H2S may play beneficial effects in the progression of atherosclerosis. In the present review, we summarize the findings about the effects of H2S on atherosclerosis and CAVD with a special emphasis on the oxidation of Hb/heme in atherosclerotic plaque development and vascular calcification.

Diffused calcification in a patient with long-term warfarin therapy: a case report.

Background: Lifelong warfarin is mandatory in patients with mechanic valvular replacement. The main adverse effect of warfarin is haemorrhage; however, there are several rare adverse events associated with long-term warfarin treatment, such as calcification, cholesterol microembolization, and nephropathy. Here we report a case of chronic warfarin use that gradually manifested with diffused calcification. Case summary: A 78-year-old woman received a prosthetic mechanical mitral valve replacement when she was 46 years old due to rheumatic mitral stenosis. She has been taking warfarin ever since. Ten years prior to admission, the chest radiography revealed a mild diffused calcification tracheobronchial and subsequent chest imaging indicated a progressive calcification of the tracheobronchial tree. In addition, a series of echocardiography examinations indicated progressive calcific aortic stenosis and diffused calcification in abdominal aorta. Furthermore, the patient gradually presented with advanced heart failure. Finally, she received transcatheter aortic valve replacement and the symptoms of the heart failure significantly improved. Discussion: Currently, patients with valvular atrial fibrillation or mechanical valve replacement have no other choice for anticoagulation medication except warfarin. However, long-term use of warfarin was associated with some rare complications such as diffused calcification. Therefore, close monitoring of such side effects in patients with long-term use of warfarin is warranted.

Small particles with large impact: Insights into the unresolved roles of innate immunity in extracellular vesicle-mediated cardiovascular calcification.

Extracellular vesicles (EVs) are critical in the initiation and progression of cardiovascular calcification, and immune cell infiltration and inflammation have a central role in this process. EVs egress from various cardiovascular cell types, which when acquiring specific properties, become calcifying. These calcifying EVs form nidi for microcalcification, which can progress to the macrocalcification lesions that are visualized clinically. We make the distinction between inflammatory-driven and mineral dysregulation-driven calcification, which both share EVs as a central initiator. In inflammation-mediated calcification, inflammation precedes microcalcification and results from EV release from macrophages. Local cellular crosstalk mediated by EVs as well as circulating EVs and other inflammatory nanoparticles, such as calciprotein particles and lipoproteins, are also critical in the progression of cardiovascular calcification. It is imperative that future work links the already established and to be discovered roles of inflammation and innate immunity in cardiovascular calcification to these key signaling and functional roles of these nanoparticles. It remains an understudied area with high potential to unravel mechanistic roles and has important implications in drug target research.

Cardiac valve calcification prevalence and association with neutrophil-to-lymphocyte ratio in newly diagnosed patients with non-dialysis chronic kidney disease stage 3-5.

OBJECTIVE: Cardiac valvular calcification (CVC) is the main cause of cardiovascular disease and all-cause death in patients with chronic kidney disease (CKD). However, the relationship between Neutrophil lymphocyte ratio (NLR) and CVC in patients with CKD is not clear. In this study, we aimed to investigate the prevalence of CVC in newly diagnosed patients with non-dialysis CKD stage 3-5 and evaluate the correlation between NLR and CVC. METHODS: A total of 483 newly diagnosed patients with non-dialysis CKD stage 3-5 were included. According to the presence of CVC, these patients were retrospectively divided into two groups: CVC group and non-CVC group. RESULTS: CVC was found in 80 patients (16.56 %), 53 (10.97 %) of whom had only aortic valve calcification (AVC), 18 (3.73 %) had mitral valve calcification (MVC), and 9 (1.86 %) had both AVC and MVC. The level of NLR in the CVC group was significantly higher than that in the non-CVC group (p=0.002). Multivariate logistic regression analysis showed that NLR was an independent risk factor for CVC (95% CI 1.017~1.225, p=0.020). ROC curve analysis showed that the area under the curve of NLR for predicting CVC was 0.610 (95% CI 0.543-0.676, p=0.002). The best cut-off point of NLR was 3.340, with a sensitivity of 49.4 % and a specificity of 70.0 %. CONCLUSION: CVC is not uncommon in newly diagnosed patients with non-dialysis CKD stage 3-5, and NLR is an independent risk factor for CVC (Tab. 4, Fig. 1, Ref. 34).

Cardiac Calcifications: Phenotypes, Mechanisms, Clinical and Prognostic Implications.

There is a growing interest in arterial and heart valve calcifications, as these contribute to cardiovascular outcome, and are leading predictors of cardiovascular and kidney diseases. Cardiovascular calcifications are often considered as one disease, but, in effect, they represent multifaced disorders, occurring in different milieus and biological phenotypes, following different pathways. Herein, we explore each different molecular process, its relative link with the specific clinical condition, and the current therapeutic approaches to counteract calcifications. Thus, first, we explore the peculiarities between vascular and valvular calcium deposition, as this occurs in different tissues, responds differently to shear stress, has specific etiology and time courses to calcification. Then, we differentiate the mechanisms and pathways leading to hyperphosphatemic calcification, typical of the media layer of the vessel and mainly related to chronic kidney diseases, to those of inflammation, typical of the intima vascular calcification, which predominantly occur in atherosclerotic vascular diseases. Finally, we examine calcifications secondary to rheumatic valve disease or other bacterial lesions and those occurring in autoimmune diseases. The underlying clinical conditions of each of the biological calcification phenotypes and the specific opportunities of therapeutic intervention are also considered and discussed.

Influence of rivaroxaban compared to vitamin K antagonist treatment upon development of cardiovascular calcification in patients with atrial fibrillation and/or pulmonary embolism.

BACKGROUND: Vitamin K antagonists (VKA) such as warfarin or phenprocoumon have been the mainstay of therapy for long-term oral anticoagulant therapy (OAT) in patients with atrial fibrillation or with pulmonary embolism. Due to interferences with matrix Gla-protein, an important vitamin K-dependent local calcification inhibitor in cardiovascular structures, VKA antagonists stimulate cardiovascular calcification (CVC). In contrast, rivaroxaban, a nonvitamin K-dependent oral anticoagulant (NOAC), should be neutral in terms of CVC. We seek to investigate these potential differences in CVC development between VKA versus NOACs in a randomized controlled trial (RCT). METHODS: The influence of rivaroxaban compared to vitamin K antagonist treatment upon development of cardiovascular calcification in patients with atrial fibrillation and/or pulmonary embolism trial (NCT02066662) is a multicenter, prospective RCT with a two-arm, open-label study design. The primary endpoint is the progression of coronary and aortic valve calcification (quantified as calcification volume score) as assessed by cardiac computed tomography (CT) at 24 months in patients either treated by rivaroxaban or VKA. A total of 192 patients were randomized in a 1:1 fashion. The main inclusion criteria were the presence of atrial fibrillation and/or pulmonary embolism with the indication for OAT and pre-existent coronary calcification. The development of CVC will be assessed by follow-up CT at 12 and 24 months. RESULTS: In total 192 patients (median age 70, 72% male) were enrolled over a period of 5 years and followed up for 2 years.