Effect of aortic valve phenotype and sex on aorta dilation in patients with aortic stenosis.

BACKGROUND: Bicuspid aortic valve (BAV) is often associated with a concomitant aortopathy. However, few studies have evaluated the effect of the aortic valve (AV) phenotype on the rate of dilation of the aorta. This study aimed to compare the progression rate of aorta dimensions according to AV phenotype (BAV vs tricuspid AV (TAV)), fusion type and sex in patients with aortic stenosis (AS). METHODS: 310 patients with AS (224 TAV and 86 BAV) recruited in the Metabolic Determinants of the Progression of Aortic Stenosis study (PROGRESSA, NCT01679431) were included in this analysis. Doppler echocardiography was performed annually to assess AS severity and measure ascending aorta (AA) dimensions. Baseline and last follow-up visit measurements were used to assess the annualised change. RESULTS: Median AA annualised change was larger in BAV versus TAV (0.33±0.65 mm/year vs 0.21±0.56 mm/year, p=0.04). In the whole cohort, BAV phenotype and higher low-density lipoprotein (LDL) levels were significantly associated with fast progression of AA dilation in univariate analysis (OR 1.80, 95% CI 1.08 to 2.98, p=0.02; 1.37, 95% CI 1.04 to 1.80, p=0.03, respectively). AA dilation rate did not vary according to the BAV subtype (p=0.142). Predictors of AA progression rate were different between valve phenotypes, with higher apolipoprotein B/apolipoprotein A-I ratio, higher baseline peak aortic jet velocity (Vpeak) and smaller baseline AA diameter in the TAV cohort (all p<0.05) versus absence of hypertension, higher LDL levels and smaller baseline AA diameter in the BAV cohort (all p<0.02). In men, higher baseline Vpeak and smaller baseline AA (p<0.001) were independently associated with increased annualised AA dilation, while in women, higher LDL levels (p=0.026) were independently associated with faster AA dilation. CONCLUSION: This study suggests that BAV is associated with faster dilation of the AA. Predictors of AA dilation are different between valve phenotype and sex, with higher LDL levels being associated with faster AA dilation in BAV.

Association Between Body Mass Index and Risk of Aortic Stenosis in Women in the Swedish Medical Birth Registry.

BACKGROUND: Overweight and obesity are increasing globally with aging, as are life expectancy and aging-associated disorders, including calcific aortic stenosis (AS). Studies investigating the correlation between high body mass index (BMI) and AS are contradictory and inconclusive. This study examines a potential association between BMI and AS in women. METHODS AND RESULTS: By linking the Swedish Medical Birth Register and the Swedish National Patient Register, we included women aged 18 to 55 years with a first childbirth from 1981 to 2020. Diagnosis of AS and comorbidities were defined according to the International Classification of Diseases (ICD) codes. The women were divided into groups on the basis of BMI. Cox proportional hazards regression models were used to investigate the difference in the risk of being diagnosed with AS, with reference BMI 20 to <22.5 kg/m2. Among the 1 722 625 included women, the mean age was 28 years, and mean BMI was 24 kg/m2, with 21% being overweight (BMI 25 to <30 kg/m2) and 8.5% obese (BMI ≥30 kg/m2). During median follow-up of 19.5 years, 2488 women (0.14%) were diagnosed with AS. The age-adjusted risk of being diagnosed with AS increased with higher BMI to 2.82 (95% CI, 2.44-3.25) times higher in women with BMI 30 to <35 kg/m2, and to 3.72 (95% CI, 2.95-4.70) times higher in those with BMI ≥35 kg/m2. Similar results were found after excluding AS of rheumatic pathogenesis. CONCLUSIONS: An increase in BMI from its upper normal range was consistently and independently associated with the risk of developing AS in women.

Correlation between staging classification of aortic stenosis based on the extent of cardiac damage and platelet indices.

BACKGROUND: Platelets play a key role in the natural history of aortic stenosis (AS) and after transcatheter aortic valve implantation (TAVI). An echo-based staging system stratifies patients with severe AS into 5 groups according to the associated cardiac damage phenotype. We aimed to correlate these AS stages with platelet indices in post-TAVI patients. METHODS: Patients with severe AS who underwent TAVI and were admitted to intensive cardiac care unit (ICCU) were prospectively identified and divided into 5 groups according to extra-valvular cardiac damage [no extravalvular cardiac damage (Stage 0), left ventricular damage (Stage 1), left atrial or mitral valve damage (Stage 2), pulmonary vasculature or tricuspid valve damage (Stage 3), or right ventricular damage (Stage 4)]. Baseline characteristics and complete blood count including mean platelet volume (MPV) and immature platelet fraction (IPF) were collected within 2 h after the procedure and analyzed in relation to aortic stenosis staging. RESULTS: A total of 220 patients were included. The mean age was 81 years old and 112 (50.9%) were female. Two (1%) patients were classified in stage 0; 34 (15%) in stage 1; 48 (22%) in stage 2; 49 (22%) in stage 3 and 87 (40%) in stage 4. Higher mean MPV values were correlated with higher AS staging (10.8 fL, 11 fL, 11.3 fL and 10.8 fL in stages 1, 2, 3 and 4, respectively, P = 0.02) as well as lower hemoglobin values (12 mg/dl, 11.6 mg/dl, 11 mg/dl and 11.3 mg/dl in stages 1, 2, 3 and 4, respectively P = 0.04). Mean IPF values were 5.3%, 5.58%, 5.57% and 4.83% in stage 1, 2, 3 and 4, respectively (P = 0.4). In a multivariate logistic regression model only MPV (OR = 2.6, P = 0.03) and body mass index (BMI) (OR = 1.17, P = 0.004) were correlated with higher staging (0-3) of AS. CONCLUSIONS: Although IPF and MPV levels increased in stages 0-3, there was a decrease in indices in stage 4, (probably due to bone marrow dysfunction) in this end-stage population. Higher levels of MPV and lower levels of hemoglobin were independently correlated with higher stages (0-3) of AS.

Multiomics identification of ALDH9A1 as a crucial immunoregulatory molecule involved in calcific aortic valve disease.

Mitochondrial dysfunction and immune cell infiltration play crucial yet incompletely understood roles in the pathogenesis of calcific aortic valve disease (CAVD). This study aimed to identify immune-related mitochondrial genes critical to the pathological process of CAVD using multiomics approaches. The CIBERSORT algorithm was employed to evaluate immune cell infiltration characteristics in CAVD patients. An integrative analysis combining weighted gene coexpression network analysis (WGCNA), machine learning, and summary data-based Mendelian randomization (SMR) was performed to identify key mitochondrial genes implicated in CAVD. Spearman's rank correlation analysis was also performed to assess the relationships between key mitochondrial genes and infiltrating immune cells. Compared with those in normal aortic valve tissue, an increased proportion of M0 macrophages and resting memory CD4 T cells, along with a decreased proportion of plasma cells and activated dendritic cells, were observed in CAVD patients. Additionally, eight key mitochondrial genes associated with CAVD, including PDK4, LDHB, SLC25A36, ALDH9A1, ECHDC2, AUH, ALDH2, and BNIP3, were identified through the integration of WGCNA and machine learning methods. Subsequent SMR analysis, incorporating multiomics data, such as expression quantitative trait loci (eQTLs) and methylation quantitative trait loci (mQTLs), revealed a significant causal relationship between ALDH9A1 expression and a reduced risk of CAVD. Moreover, ALDH9A1 expression was inversely correlated with M0 macrophages and positively correlated with M2 macrophages. These findings suggest that increased ALDH9A1 expression is significantly associated with a reduced risk of CAVD and that it may exert its protective effects by modulating mitochondrial function and immune cell infiltration. Specifically, ALDH9A1 may contribute to the shift from M0 macrophages to anti-inflammatory M2 macrophages, potentially mitigating the pathological progression of CAVD. In conclusion, ALDH9A1 represents a promising molecular target for the diagnosis and treatment of CAVD. However, further validation through in vivo and n vitro studies is necessary to confirm its role in CAVD pathogenesis and therapeutic potential.

Circulating Matrix Metalloproteinases for Prediction of Aortic Dilatation in Children with Bicuspid Aortic Valve: A Single-Center, Observational Study.

Circulating biomarkers have been proposed for early identification of aortic dilatation progression associated with bicuspid aortic valve (BAV), but matrix metalloproteinases (MMPs) are distinguished as signatures of increased extracellular matrix degradation, a landmark of aneurysm formation. The current study aims to identify the role of MMP-1, MMP-2, MMP-9, and the MMP inhibitor, TIMP-1, in identifying aortic dilation in children with BAV. We conducted a study on 73 children divided into two study groups, depending on the presence of aortic dilatation (group 1-43 BAV controls and group 2-30 children with BAV and aortic dilatation). Each patient underwent a cardiac ultrasound and, in each case, serum MMP-1, MMP-2, MMP-9, and TIMP-1 were quantified using xMAP technology. Comparison of the MMPs between the two study groups revealed significantly higher values only in the case of TIMP-1, among BAV controls. Moreover, the same TIMP-1 inversely correlated with aortic annulus absolute size and z score, as well as with ascending aorta z score. No particular correlation between the aortic phenotype and the presence of aortic dilatation was found. Future longitudinal research starting at pediatric ages could show the significance of MMPs screening in BAV individuals as predictors of aortic aneurysm formation.

Genetics of Calcific Aortic Stenosis: A Systematic Review.

Background: Calcific aortic stenosis is the most prevalent valvular abnormality in the Western world. Factors commonly associated with calcific aortic stenosis include advanced age, male sex, hypertension, diabetes and impaired renal function. This review synthesises the existing literature on genetic associations with calcific aortic stenosis. Methods: A systematic search was conducted in the PubMed, Ovid and Cochrane libraries from inception to 21 July 2024 to identify human studies investigating the genetic factors involved in calcific aortic stenosis. From an initial pool of 1392 articles, 78 were selected for full-text review and 31 were included in the final qualitative synthesis. The risk of bias in these studies was assessed using the Newcastle Ottawa Scale. Results: Multiple genes have been associated with calcific aortic stenosis. These genes are involved in different biological pathways, including the lipid metabolism pathway (PLA, LDL, APO, PCSK9, Lp-PLA2, PONS1), the inflammatory pathway (IL-6, IL-10), the calcification pathway (PALMD, TEX41) and the endocrine pathway (PTH, VIT D, RUNX2, CACNA1C, ALPL). Additional genes such as NOTCH1, NAV1 and FADS1/2 influence different pathways. Mechanistically, these genes may promote a pro-inflammatory and pro-calcific environment in the aortic valve itself, leading to increased osteoblastic activity and subsequent calcific degeneration of the valve. Conclusions: Numerous genetic associations contribute to calcific aortic stenosis. Recognition of these associations can enhance risk stratification for individuals and their first-degree relatives, facilitate family screening, and importantly, pave the way for targeted therapeutic interventions focusing on the identified genetic factors. Understanding these genetic factors can also lead to gene therapy to prevent calcific aortic stenosis in the future.

The known and unknown of post-pump chorea: a case report on robust steroid responsiveness implicating occult neuroinflammation.

Post-pump chorea (PPC) is characterized by the development of choreiform movements following cardiopulmonary bypass (CPB) surgery. PPC occurs almost exclusively in children, and its pathophysiology remains unclear. Here we present an adult case of PPC after bovine aortic valve replacement (AVR) which exhibited dramatic and reproducible response to steroid, suggesting the presence of occult neuroinflammation. This observation suggests a novel underlying mechanism in certain subgroups of PPC, which is likely a heterogeneous condition to start with. Further research into the pathomechanisms of PPC could offer insights into managing this otherwise symptomatic control-only condition.

Left Ventricular Outflow Tract Morphology as a Predictor of Conductance Disturbances Following Transcatheter Aortic Valve Replacement.

BACKGROUND: Conduction disturbances represent one of the most common complications following transcatheter aortic valve replacement (TAVR). We sought to investigate the role of left ventricular outflow tract (LVOT) morphology in the development of conduction disturbances following TAVR. METHODS AND RESULTS: Consecutive patients who underwent TAVR in our center were included. The ratio between the LVOT area and the aortic annulus area was calculated. Patients were then divided into 2 groups on the basis of this ratio: group 1, which included patients with an LVOT area/aortic annulus area ratio <0.9; and group 2, which included patients with an LVOT area/aortic annulus area ratio ≥0.9. The primary end point was to assess the relationship between LVOT shape and the rate of permanent pacemaker implantation following TAVR. A multivariable analysis was performed to identify predictors of permanent pacemaker implantation following TAVR. From January 2018 to December 2020, 276 patients were included. Ninety-one patients with tapered LVOT morphology were assigned to group 1 and the rest (n=185 patients), tubular LVOT or flared LVOT shape, to group 2. The mean age was 81.5±5.7 years and 57% were women. After adjusting by confounding factors, tapered morphology of the LVOT and prior right bundle-branch block were found to be independent predictors of permanent pacemaker implantation (hazard ratio [HR], 2.6 [95% CI, 1.2-5.7]; P=0.014; and HR: 4.3 [95% CI 2.4-7.6], P<0.001); at a median follow-up time of 15.5 (interquartile range, 15) months. CONCLUSIONS: A tapered-LVOT morphology was associated with increased risk for permanent pacemaker implantation. LVOT morphology may be an additional factor to consider when choosing prosthesis size.

Case report: membranoproliferative glomerulonephritis associated with Q fever causing chronic endocarditis.

BACKGROUND: Membranoproliferative glomerulonephritis is a rare entity which can be a result from autoimmune diseases, caused by various medications and infections. CASE PRESENTATION: We herein present the case of a 62-year-old male patient who presented with fatigue and was found to have severe anemia, impaired renal function, and nephrotic syndrome. A renal biopsy revealed membranoproliferative glomerulonephritis (MPGN) of the immune complex type with activation of the classical complement pathway. Further investigations led to the diagnosis of a chronic Coxiella burnetii-infection (Q fever), likely acquired during cycling trips in a region known for intensive sheep farming. Additionally, the patient was found to have a post endocarditic destructive bicuspid aortic valve caused by this pathogen. Treatment with hydroxychloroquine and doxycycline was administered for a duration of 24 months. The aortic valve was replaced successfully and the patient recovered completely. CONCLUSIONS: Early detection and targeted treatment of this life-threatening disease is crucial for complete recovery of the patient.

Role of CD34 in calcification of human aortic valve interstitial cells from patients with aortic valve stenosis.

Various osteogenic factors are involved in ectopic human aortic valve calcification; however, the key cell species involved in calcification remains unclear. In a previous study, we reported that mesenchymal stem (CD73, 90, 105) and endothelial (VEGFR2) cell markers are positive in almost all human aortic valve interstitial cells (HAVICs) obtained from a patient with calcified aortic valve stenosis (CAVS). Further, CD34-negative HAVICs are highly sensitive to calcification stimulations. Here, we aimed to pathophysiologically clarify the role of CD34 in HAVICs obtained from individual patients with severe CAVS. A DNA microarray between CD34-positive and CD34-negative HAVICs, separated by fluorescence-activated cell sorting, indicated that tenascin X (TNX) mRNA expression significantly decreased in CD34-negative cells. Furthermore, the inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1ß significantly downregulated CD34 expression in HAVICs. TGF-ß, a key cytokine of endothelial-mesenchymal transition, did not affect HAVIC calcification. CD34 overexpression strongly inhibited TNF-α- and IL-1ß-induced calcification and maintained TNX mRNA expression. These results suggest one possibility that CD34 is an inhibitory regulator of valve calcification. Furthermore, TNF-α- and IL-1ß-induced CD34 downregulation in HAVICs contributes to HAVIC calcification by downregulating TNX protein expression.

[Amaurosis fugax in Marfan syndrome with myxomatous degeneration].

A 28-year-old male presented with a sudden, transient visual impairment in the right eye. Brain MRI revealed no obvious ischemic lesions, and he was diagnosed with amaurosis fugax. Physical examination revealed characteristic features of Marfan syndrome, along with a family history of tall stature and valvular heart disease. Further investigation revealed: 1) an ascending aortic aneurysm, 2) a bicuspid aortic valve with fenestration and regurgitation, and 3) a mitral valve prolapse with regurgitation. Genetic testing identified a heterozygous variant c.6905G>A of FBN1, confirming the diagnosis of Marfan syndrome. Bentall operation and mitral valve replacement were performed, resulting in a favorable outcome. Pathological examination showed extensive myxomatous degeneration with thickening of the aortic and mitral valves, suggesting a potential source of embolism.

Arteriosclerotic Calcification and Atrial Fibrillation in the General Population: The Rotterdam Study.

Limited population-based data on the gender differences and association between arteriosclerotic calcification at different sites and atrial fibrillation (AF) exist. We aimed to investigate the (gender-specific) associations between arteriosclerotic calcification at different sites with the risk of AF in the general population. Arteriosclerotic calcification was quantified using computed tomography examinations between 2003 and 2006 in 2,259 participants free of AF from the population-based Rotterdam Study. Cox proportional hazards models, adjusted for cardiovascular risk factors, were used to assess the associations of volumes of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial and intracranial carotid arteries, vertebrobasilar arteries, and the aortic valve with incident AF. During a median follow-up of 8.6 years, 182 incident AF cases occurred. A larger CAC was associated with incident AF (hazard ratio [HR], 95% confidence interval [CI] 1.25 1.09 to 1.44, p = 0.0019). The gender-stratified analyses showed that larger CAC in men (HR 1.43, 95% CI 1.10 to 1.86, p = 0.0068) and larger AAC in women were associated with incident AF (HR1.44, 95% CI 1.04 to 2.01, p = 0.0299). In conclusion, CAC in the general population, especially in men, and AAC in women were significantly associated with new-onset AF. Our findings imply that interventions to lower arteriosclerotic calcification, particularly, CAC, carry potential for the prevention of AF in the general population, especially in men.

Deficient GATA6-CXCR7 signaling leads to bicuspid aortic valve.

The cardiac outflow tract (OFT) transiently links the ventricles to the aortic sac and forms the arterial valves. Abnormalities in these valves, such as bicuspid aortic valve (BAV), are common congenital anomalies. GATA6-inactivating variants cause cardiac OFT defects and BAV, but their mechanisms are unclear. We generated Gata6STOP/+ mice using CRISPR-Cas9, which show highly penetrant BAV (70%) and membranous ventricular septal defects (43%). These mice exhibited decreased proliferation and increased ISL1-positive progenitor cells in the OFT, indicating abnormal cardiovascular differentiation. Gata6 deletion with the Mef2cCre driver line recapitulated Gata6STOP/+ phenotypes, indicating a cell-autonomous role for Gata6 in the second heart field. Gata6STOP/+ mice showed reduced OFT length and caliber, associated with deficient cardiac neural crest cell contribution, which may cause valvulo-septal defects. RNA-sequencing analysis showed depletion in pathways related to cell proliferation and migration, highlighting Cxcr7 (also known as Ackr3) as a candidate gene. Reduced mesenchymal cell migration and invasion were observed in Gata6STOP/+ OFT tissue. CXCR7 agonists reduced mesenchymal cell migration and increased invasion in wild-type but not in Gata6STOP/+ explants, indicating the GATA6-dependent role of CXCR7 in OFT development and its potential link to BAV.

Rare genomic copy number variants implicate new candidate genes for bicuspid aortic valve.

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in a BAV cohort with late onset sporadic disease (n = 5040). We identified 3 large and rare (< 1,1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 9% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

Effect of Evogliptin on the Progression of Aortic Valvular Calcification.

BACKGROUND: Medical therapy for aortic stenosis (AS) remains an elusive goal. OBJECTIVES: This study sought to establish whether evogliptin, a dipeptidyl peptidase-4 inhibitor, could reduce AS progression. METHODS: A total of 228 patients (age 67 ± 11 years; 33% women) with AS were randomly assigned to receive placebo (n = 75), evogliptin 5 mg (n = 77), or evogliptin 10 mg (n = 76). The primary endpoint was the 96-week change in aortic valve calcium volume (AVCV) on computed tomography. Secondary endpoints included the 48-week change in active calcification volume measured using 18F-sodium fluoride positron emission tomography (18F-NaF PET). RESULTS: There were no significant differences in the 96-week changes in AVCV between evogliptin 5 mg and placebo (-5.27; 95% CI: -55.36 to 44.82; P = 0.84) or evogliptin 10 mg and placebo (-18.83; 95% CI: -32.43 to 70.10; P = 0.47). In the placebo group, the increase in AVCV between 48 weeks and 96 weeks was higher than that between baseline and 48 weeks (136 mm3; 95% CI: 108-163 vs 102 mm3; 95% CI: 75-129; P = 0.0485). This increasing trend in the second half of the study was suppressed in both evogliptin groups. The 48-week change in active calcification volume on 18F-NaF PET was significantly lower in both the evogliptin 5 mg (-1,325.6; 95% CI: -2,285.9 to -365.4; P = 0.008) and 10-mg groups (-1,582.2; 95% CI: -2,610.8 to -553.5; P = 0.0038) compared with the placebo group. CONCLUSIONS: This exploratory study did not demonstrate the protective effect of evogliptin on AV calcification. Favorable 18F-NaF PET results and possible suppression of aortic valve calcification with longer medication use in the evogliptin groups suggest the need for larger confirmatory trials. (A Multicenter, Double-blind, Placebo-controlled, Stratified-randomized, Parallel, Therapeutic Exploratory Clinical Study to Evaluate the Efficacy and Safety of DA-1229 in Patients With Calcific Aortic Valve Disease; NCT04055883).

Whole-exome sequencing uncovers the genetic complexity of bicuspid aortic valve in families with early-onset complications.

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate genes that are associated with autosomal-dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants drive early-onset presentations of BAV disease.

Differentiating Left Ventricular Remodeling in Aortic Stenosis From Systemic Hypertension.

BACKGROUND: Left ventricular (LV) hypertrophy occurs in both aortic stenosis (AS) and systemic hypertension (HTN) in response to wall stress. However, differentiation of hypertrophy due to these 2 etiologies is lacking. The aim was to study the 3-dimensional geometric remodeling pattern in severe AS pre- and postsurgical aortic valve replacement and to compare with HTN and healthy controls. METHODS: Ninety-one subjects (36 severe AS, 19 HTN, and 36 healthy controls) underwent cine cardiac magnetic resonance. Cardiac magnetic resonance was repeated 8 months post-aortic valve replacement (n=18). Principal component analysis was performed on the 3-dimensional meshes reconstructed from 109 cardiac magnetic resonance scans of 91 subjects at end-diastole. Principal component analysis modes were compared across experimental groups together with conventional metrics of shape, strain, and scar. RESULTS: A unique AS signature was identified by wall thickness linked to a LV left-right axis shift and a decrease in short-axis eccentricity. HTN was uniquely linked to increased septal thickness. Combining these 3 features had good discriminative ability between AS and HTN (area under the curve, 0.792). The LV left-right axis shift was not reversible post-aortic valve replacement, did not associate with strain, age, or sex, and was predictive of postoperative LV mass regression (R2=0.339, P=0.014). CONCLUSIONS: Unique remodeling signatures might differentiate the etiology of LV hypertrophy. Preliminary findings suggest that LV axis shift is characteristic in AS, is not reversible post-aortic valve replacement, predicts mass regression, and may be interpreted to be an adaptive mechanism.

Current Management and Therapy of Severe Aortic Stenosis and Future Perspective.

Intervention for severe aortic stenosis (AS) has dramatically progressed since the introduction of transcatheter aortic valve replacement (TAVR). Decades ago, controversies existed regarding comparing clinical outcomes between TAVR and surgical aortic valve replacement (SAVR) in various risk profiles. Recently, we discussed the durability of transcatheter heart valves and their lifetime management after aortic valve replacement (AVR). Regarding the management of AS, we discuss the appropriate timing of intervention for severe aortic stenosis, especially in asymptomatic patients. In spite of dramatic progression of intervention for AS, there are no established medications available to prevent or slow the progression of AS at present. Basic research and genome studies have suggested several targets associated with the progression of aortic valve calcification. Randomized controlled trials evaluating the efficacy of medications to prevent AS progression are ongoing, which might lead to new strategies for AS management. In this review, we summarize the current management of AS and the drugs expected to prevent the progression of AS.