Association of Matrix Metalloproteinase-2 (MMP-2) and MMP-9 Promoter Variants, Their Serum Levels, and Activities with Aortic Valve Calcification (AVC) in a Population from Western Iran.

Background: Matrix metalloproteinase (MMP) enzyme gene polymorphisms MMP-2-1575G/A and MMP-9-1562C/T promoter polymorphism, their serum levels, and activity are associated with aortic valve calcification (AVC). Materials and Methods: The synergistic link between the risk of AVC and the alleles T and A of MMP-9 and MMP-2 was investigated, respectively. Ninety-two cases with AVC and 92 healthy individuals from the west of Iran were included, and MMP- 2-1575G/A and MMP-9-1562C/T promoter polymorphisms were detected using PCR-RFLP. The serum levels and activity of MMP-2 and -9 were assessed using ELISA and gelatin zymography methods, respectively. In addition, serum biochemical markers, including FBS, urea and creatinine, cholesterol, triglyceride, HDL, LDL, calcium, phosphorus, and blood pressure: systolic blood pressure and diastolic blood pressure were measured. Results: Heart valve calcification disease was associated with a comparatively higher frequency of the A allele of the MMP2-1575 variation (p = 0.002). In addition, the frequency of T allele of the MMP9-1562 variant was higher than the control group (p = 0.007). Conclusion: MMP-2 and MMP-9 serum levels and activities were observed to be considerably higher in the experimental group than in the control group (p < 0.001). Patients are more susceptible to cardiovascular disease than the control group due to elevated serum levels and activity of MMP-2 and MMP-9.

The association of peritoneal dialysis and hemodialysis on mitral and aortic valve calcification associated mortality: a meta-analysis.

Cardiac valve calcification (CVC), characterized by the accumulation of calcium in the heart valves, is highly prevalent among patients undergoing dialysis. This meta-analysis aimed to provide an updated summary of recent studies on the prognostic value of CVC in patients undergoing dialysis. We conducted a search of PubMed, Embase, and Web of Science to identify observational studies investigating cardiovascular or all-cause mortality associated with CVC in dialysis patients until March 2023. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were calculated for the meta-analysis, and the strength and significance of the associations between CVC and mortality outcomes in dialysis patients were assessed. From 6218 initially identified studies, we included 10 critical studies with a total of 3376 dialysis patients in a further meta-analysis. Pooled analyses demonstrated a significant association between CVC and an elevated risk of all-cause and cardiovascular mortality in dialysis patients. In our study, we discovered HRs of 1.592 (95% CI 1.410-1.797) for all-cause mortality and 2.444 (95% CI 1.632-3.659) for cardiovascular mortality. Furthermore, subgroup analysis revealed elevated all-cause mortality among patients with mitral valve calcification (HR 1.572; 95% CI 1.200-2.060) compared to those with aortic valve calcification (HR 1.456; 95% CI 1.105-1.917). Similarly, patients undergoing peritoneal dialysis faced a greater risk for all-cause mortality (HR 2.094; 95% CI 1.374-3.191) than those on hemodialysis (HR 1.553; 95% CI 1.369-1.763). This highlights the possibility of CVC being an independent risk factor for dialysis patients, particularly in relation to mitral valve calcification or peritoneal dialysis.

Nuclear Abnormalities in LMNA p.(Glu2Lys) Variant Segregating with LMNA-Associated Cardiocutaneous Progeria Syndrome.

The LMNA gene encodes lamin A and lamin C, which play important roles in nuclear organization. Pathogenic variants in LMNA cause laminopathies, a group of disorders with diverse phenotypes. There are two main groups of disease-causing variants: missense variants affecting dimerization and intermolecular interactions, and heterozygous substitutions activating cryptic splice sites. These variants lead to different disorders, such as dilated cardiomyopathy and Hutchinson-Gilford progeria (HGP). Among these, the phenotypic terms for LMNA-associated cardiocutaneous progeria syndrome (LCPS), which does not alter lamin A processing and has an older age of onset, have been described. Here, we present the workup of an LMNA variant of uncertain significance, NM_170707.2 c. 4G>A, p.(Glu2Lys), in a 36-year-old female with severe calcific aortic stenosis, a calcified mitral valve, premature aging, and a family history of similar symptoms. Due to the uncertainty of in silico predictions for this variant, an assessment of nuclear morphology was performed using the immunocytochemistry of stable cell lines to indicate whether the p.(Glu2Lys) had a similar pathogenic mechanism as a previously described pathogenic variant associated with LCPS, p.Asp300Gly. Indirect immunofluorescence analysis of nuclei from stable cell lines showed abnormal morphology, including lobulation and occasional ringed nuclei. Relative to the controls, p.Glu2Lys and p.Asp300Gly nuclei had significantly (p < 0.001) smaller average nuclear areas than controls (mean = 0.10 units, SD = 0.06 for p.Glu2Lys; and mean = 0.09 units, SD = 0.05 for p.Asp300Gly versus mean = 0.12, SD = 0.05 for WT). After functional studies and segregation studies, this variant was upgraded to likely pathogenic. In summary, our findings suggest that p.Glu2Lys impacts nuclear morphology in a manner comparable to what was observed in p.Asp300Gly cells, indicating that the variant is the likely cause of the LCPS segregating within this family.

Caseous Calcification of the Mitral Valve.

Teaching Point: Caseous calcification of the mitral annulus is a benign mass-like lesion which can mimic cardiac tumor or abscess; therefore, multimodal imaging should be considered, avoiding unnecessary interventions.

High lipoprotein(a) levels and mitral valve disease: A systematic review.

AIMS: The role of lipoprotein(a) [Lp(a)] as a possibly causal risk factor for atherosclerotic artery disease and aortic valve stenosis has been well established. However, the information available on the association between Lp(a) levels and mitral valve disease is limited and controversial. The main objective of the present study was to assess the association between Lp(a) levels and mitral valve disease. DATA SYNTHESIS: This systematic review was performed according to PRISMA guidelines (PROSPERO CRD42022379044). A literature search was performed to detect studies that evaluated the association between Lp(a) levels or single-nucleotide polymorphisms (SNPs) related to high levels of Lp(a) and mitral valve disease, including mitral valve calcification and valve dysfunction. Eight studies including 1,011,520 individuals were considered eligible for this research. The studies that evaluated the association between Lp(a) levels and prevalent mitral valve calcification found predominantly positive results. Similar findings were reported in two studies that evaluated the SNPs related to high levels of Lp(a). Only two studies evaluated the association of Lp(a) and mitral valve dysfunction, showing contradictory results. CONCLUSIONS: This research showed disparate results regarding the association between Lp(a) levels and mitral valve disease. The association between Lp(a) levels and mitral valve calcification seems more robust and is in line with the findings already demonstrated in aortic valve disease. New studies should be developed to clarify this topic.

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.

Case Report: Aicardi-Goutières Syndrome Type 6 and Dyschromatosis Symmetrica Hereditaria With Congenital Heart Disease and Mitral Valve Calcification - Phenotypic Variants Caused by Adenosine Deaminase Acting on the RNA 1 Gene Homozygous Mutations.

Dyschromatosis symmetrica hereditaria (DSH), characterized by a mixture of hyper- and hypopigmented macules on the skin, is a rare pigmentary dermatosis of autosomal dominant inheritance. The pathogenic gene is adenosine deaminase acting on the RNA 1 gene (ADAR1), mutations in this gene also lead to Aicardi-Goutières syndrome type 6 (AGS 6), a rare hereditary encephalopathy with isolated spastic paraplegia. The pathomechanism of the ADAR1 gene mutations inducing DSH has not been clarified yet. We report the first case of DSH combined with AGS caused by the homozygous mutation of the ADAR1 gene in China (c.1622T > A) and reviewed the relevant literature. AGS 6 could occur in both men and women, and start in infancy. The main characteristics are growth retardation, skin depigmentation, intracranial calcification, and cerebral white matter lesions. In the current paper, the proband also had patent ductus arteriosus (PDA), ventricular septal defect (VSD), and mitral valve calcification, which are new symptoms that have not been reported in other cases. Additionally, we also aim to discuss the possible molecular mechanisms underlying the clinical heterogeneity caused by ADAR1 gene mutations.

The relationship between plasma vitamin D level and heart valves calcification in acute coronary syndrome and non acute coronary syndrome patients.

BACKGROUND: There is conflicting data regarding the association between low levels of plasma vitamin D and ischemic heart disease. We aimed to investigate the relationship between plasma vitamin D levels and heart valve calcification in hospitalized patients with ischemic heart disease versus non-ischemic heart disease controls. METHODS: A prospective case-control study comprising two age and gender-matched groups. The study group included consecutive patients hospitalized due to acute coronary syndrome; the control group included consecutive non-ischemic heart disease patients hospitalized for noncardiac causes. Blood samples for 25-hydroxyvitamin D level were drawn. An echocardiogram was performed during the first 3 days of hospitalization and reviewed for presence and degree of valvular calcification. RESULTS: Forty patients with acute coronary syndrome and 40 controls (age 58 ± 11 years, 64% male in both groups) were included. Mean plasma 25-hydroxyvitamin D vitamin level in the entire cohort was 24.5 ± 8 ng/ml. Valve calcification rates were similar in acute coronary syndrome versus non-acute coronary syndrome group (28 vs. 21 had valvular calcification; 18 vs. 12 had aortic valve calcification; 21 vs. 14 had mitral valve calcification, respectively; P = NS for all). We found no significant relationship between vitamin D level and valvular calcification, aortic valve calcification, or mitral valve calcification rate or degree in the entire cohort and in each group alone (P = NS for all). There was a negative correlation between 25-hydroxyvitamin D levels and age in the acute coronary syndrome group (r = -0.399, P = 0.012). CONCLUSIONS: We did not find a significant relationship between plasma vitamin D levels and the rate or degree of calcification of either aortic/mitral/both valves in hospitalized patients with or without ischemic heart disease.

Differential expression patterns of Toll Like Receptors and Interleukin-37 between calcific aortic and mitral valve cusps in humans.

BACKGROUND: Significant differences are mentioned in the progress of calcification between aortic and mitral valve. Evidence of inflammation in calcific aortic and mitral valve disease suggests that pathways of Toll Like Receptors (TLR) and Interleukin (IL)-37 expression may contribute to this process. We sought to investigate the role of TLR-mediated inflammatory response and IL-37 pathway expression on aortic and mitral valve calcification. MATERIAL AND METHODS: One-hundred twenty stenotic valve cusps/leaflets (60 aortic, 60 mitral) were excised during surgery and were collected for histological, immunohistochemistry and morphometric analysis at our department. After total RNA isolation from a second part of valve cusps/leaflets, cDNA synthesis and quantitative reverse transcription polymerase chain reaction (qRT-PCR) protocols were performed and relative mRNA levels of target genes were assessed. RESULTS: By histological analysis, the anti-inflammatory IL-37 levels were increased in mitral valve leaflets (MVL) compared to aortic valve cusps (AVCu) while all other biomarkers, including TLR, presented a reverse pattern with decreased levels as compared to AVCu. In terms of calcification biomarkers, only osteopontin differed between AVCu and MVL. mRNA analysis confirmed increased expression of IL-37 and decreased levels of TLR in MVL compared to AVCu. CONCLUSIONS: Stenotic cusps of aortic valves express lower IL-37 and increased TLRs levels than stenotic mitral valve leaflets, suggesting a differential pro-calcification and pro-inflammatory profile between the two valves. This may explain the higher incidence of calcification of AVCu than MVL and offer therapeutic considerations.

Cardiac valve calcification and use of anticoagulants: Preliminary observation of a potentially modifiable risk factor.

AIMS: Direct oral anticoagulant (DOAC) has been recently introduced in the clinical practice. Rather than interfering with vitamin K-dependent posttranscriptional modification of various proteins, DOACs selectively inhibit factors involved in the coagulation cascade. In particular, in contrast with Warfarin, Rivaroxabn does not interfere with activation of matrix Gla Protein (MGP), a potent vascular calcification Inhibitor. We herein sought to investigate the impact of Rivaroxaban and Warfarin on cardiac valve calcifications in a cohort of moderate-to advanced CKD patients. METHODS AND RESULTS: This is a multicenter, observational, retrospective, longitudinal study. Consecutive CKD stage 3b - 4 (according to KDIGO guidelines) patients from 8 cardiologic outpatient clinics were enrolled between May 2015 and October 2017. All patients received anticoagulation (100 Warfarin vs 247 Rivaroxaban) as part of their non-valvular atrial fibrillation management. Cardiac valve calcification was evaluated via standard trans-thoracic echocardiogram. 347 patients (mean age: 66 years; mean eGFR: 37 ml/min/1.73 m2) were studied. Over a mean follow-up period of 16 months, Rivaroxaban compared to Warfarin reduced both mitral and aortic valve calcifications (p < 0.001) independently of the degree of calcifications at baseline and potential confounders. Notably, Rivaroxaban use was also associated with a significant reduction in C reactive protein (CRP) (p < 0.001) during follow-up. CONCLUSION: This study generates the hypothesis that the use of Rivaroxaban associates with a reduction of cardiac valve calcification deposition and progression as compared to Warfarin, in a cohort of CKD stage 3b-4 patients. Future endeavors are needed to confirm and to establish the mechanisms responsible for these findings.

Caseous calcification of posterior mitral annulus: a forgotten benign condition mimicking atrial mass.

Caseous calcification of posterior mitral annulus is considered a variant of mitral annular calcification and accounts for less than 1% cases of mitral valve calcification (MAC). Usually benign and asymptomatic and has typical features on imaging studies but may contribute to unnecessary investigations and interventions in some patients, transthoracic echocardiography (TTE) is most useful tool in the diagnosis of this condition, whether it is associated with increased risk of atherosclerosis is unknown. We are presenting a case of caseous calcification of posterior mitral annulus that is discovered during elective coronary angiography in a patient with extensive history of coronary heart disease who had abnormal stress test.

Relationship of Aortic Wall Distensibility to Mitral and Aortic Valve Calcification: The Multi-Ethnic Study of Atherosclerosis.

Data are limited on whether valvular calcification is associated with aortic wall stiffness. We tested whether aortic valve calcification (AVC) and/or mitral valve calcification (MVC) is inversely associated with aortic distensibility (AD). Cross-sectional study conducted in a subset of the Multi-Ethnic Study of Atherosclerosis (MESA) included 3676 MESA participants aged 44 to 84 years with AD measured with magnetic resonance imaging and with AVC and MVC measured with noncontrast cardiac computed tomography scans. Both AVC and MVC were divided into 3 categories: zero, < median values (low), and ≥ median values (high) for patients with nonzero values. Overall, 88% (n = 3256) and 92% (n = 3365) of participants had zero AVC and MVC, while 6% (n = 211) and 4% (n = 156) had low, and 6% (n = 209) and 4% (n = 155) had high values of AVC and MVC, respectively. The AVC was independently associated with AD after adjusting for age, gender, and ethnicity ( P = .035). No association was noted between AVC groups and AD after adjustment for all covariates or MVC groups and AD in any model.

Fibroblast growth factor 23 and parathyroid hormone predict extent of aortic valve calcifications in patients with mild to moderate chronic kidney disease.

BACKGROUND: Cardiac valve calcifications are present in dialysis patients and regarded as dependent on a deranged mineral metabolism. Few data are available for patients with chronic kidney disease (CKD) not on dialysis. This study evaluates the potential association between the extent of cardiac valve calcification and levels of intact parathyroid hormone (i-PTH), phosphorus, calcium, 25-OH vitamin D, fibroblast growth factor 23 (FGF-23), Klotho and C-reactive protein (CRP) simultaneously measured in patients with mild to moderate CKD. METHODS: Consecutive non-hospitalized patients referring to five nephrology units were evaluated. Inclusion criteria were age >18 years, CKD Stages 3-4, and the presence of aortic and/or mitral valve calcification assessed by echocardiography as routinely clinical evaluation. Patients underwent clinical examination and routine biochemistry. Baseline i-PTH, phosphorus, calcium, 25-OH vitamin D, FGF-23, Klotho and CRP were simultaneously ascertained. RESULTS: Extent of aortic valve calcification (n = 100 patients) was moderate in 68 patients and mild in the remaining patients. Mitral valve calcification (n = 96 patients) score was 1, 2 and 3 in 61, 34 and 1 patients, respectively. In univariate analysis, no association was found between extent of mitral valve calcification and markers of mineral metabolism and CRP; aortic valve extent of calcification was positively associated with i-PTH (r(2) = 0.212; P = 0.03) and FGF-23 (r(2) = 0.272; P = 0.01), and negatively with Klotho (r(2) = -0.208; P = 0.04). In multivariable analysis, extent of aortic valve calcification was associated with FGF-23 (P = 0.01) and PTH (P = 0.01) levels. CONCLUSIONS: Extent of aortic valve calcification is associated to FGF-23 and PTH in naïve CKD patients with mild to moderate CKD. Further studies should examine whether FGF-23 assay should be included in routine clinical evaluation of CKD as part of cardiovascular risk stratification.

Mitral Valve Annuloplasty Ring Dehiscence Diagnosed Intraoperative With Real-Time 3D Transesophageal Echocardiogram.

Mitral annular calcification (MAC) is often a result of the accumulation of lipids around the annulus, which can lead to degeneration and calcification of the valve. Multiple risk factors have been associated with the progression of MAC and life-threatening complications such as the early mitral valve annuloplasty dehiscence. Our case describes the different risk factors for annuloplasty dehiscence in a patient with severe MAC, as well as the importance of its early recognition intraoperatively with 3D transesophageal echocardiography.