Transcatheter or Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis and Small Aortic Annulus: A Randomized Clinical Trial.

BACKGROUND: The optimal treatment in patients with severe aortic stenosis and small aortic annulus (SAA) remains to be determined. This study aimed to compare the hemodynamic and clinical outcomes between transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR) in patients with a SAA. METHODS: This prospective multicenter international randomized trial was performed in 15 university hospitals. Participants were 151 patients with severe aortic stenosis and SAA (mean diameter <23 mm) randomized (1:1) to TAVR (n=77) versus SAVR (n=74). The primary outcome was impaired valve hemodynamics (ie, severe prosthesis patient mismatch or moderate-severe aortic regurgitation) at 60 days as evaluated by Doppler echocardiography and analyzed in a central echocardiography core laboratory. Clinical events were secondary outcomes. RESULTS: The mean age of the participants was 75.5±5.1 years, with 140 (93%) women, a median Society of Thoracic Surgeons predicted risk of mortality of 2.50% (interquartile range, 1.67%-3.28%), and a median annulus diameter of 21.1 mm (interquartile range, 20.4-22.0 mm). There were no differences between groups in the rate of severe prosthesis patient mismatch (TAVR, 4 [5.6%]; SAVR, 7 [10.3%]; P=0.30) and moderate-severe aortic regurgitation (none in both groups). No differences were found between groups in mortality rate (TAVR, 1 [1.3%]; SAVR, 1 [1.4%]; P=1.00) and stroke (TAVR, 0; SAVR, 2 [2.7%]; P=0.24) at 30 days. After a median follow-up of 2 (interquartile range, 1-4) years, there were no differences between groups in mortality rate (TAVR, 7 [9.1%]; SAVR, 6 [8.1%]; P=0.89), stroke (TAVR, 3 [3.9%]; SAVR, 3 [4.1%]; P=0.95), and cardiac hospitalization (TAVR, 15 [19.5%]; SAVR, 15 [20.3%]; P=0.80). CONCLUSIONS: In patients with severe aortic stenosis and SAA (women in the majority), there was no evidence of superiority of contemporary TAVR versus SAVR in valve hemodynamic results. After a median follow-up of 2 years, there were no differences in clinical outcomes between groups. These findings suggest that the 2 therapies represent a valid alternative for treating patients with severe aortic stenosis and SAA, and treatment selection should likely be individualized according to baseline characteristics, additional anatomical risk factors, and patient preference. However, the results of this study should be interpreted with caution because of the limited sample size leading to an underpowered study, and need to be confirmed in future larger studies. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03383445.

Functional continuum: independent predictor of one-year mortality and key decision-making element in older adults with severe aortic stenosis amenable to aortic valve replacement.

OBJECTIVES: The impact of functional capacity over the entire functional continuum in older adults undergoing aortic valve replacement (AVR) has not been studied to date. This study aims to analyze 1.- the distribution of a cohort of older adults presenting severe aortic stenosis (AS) amenable to AVR in the different categories of the Functional Continuum Scale (FCS); 2.- its association with decision-making regarding valve disease; and 3.- its impact upon the one-year mortality rate of surgical (SAVR), transcatheter (TAVR) aortic valve replacement, or the decision to provide conservative management (OMT). METHODS: This prospective study included patients from the FRESAS (FRailty-Evaluation-in-Severe-Aortic-Stenosis) registry evaluated by the reference Heart-Team of a region in northern Spain. All the patients underwent comprehensive geriatric assessment. RESULTS: The study comprised 257 patients aged 84.0 ± 3.9 years. MANAGEMENT: SAVR: 25.3%, TAVR: 58.0% and OMT: 16.7%. Increased patient functional capacity was associated with an increased tendency to perform more invasive valve disease treatment. The overall one-year survival rate was 81.3%. One-year all-cause mortality: FCS-1 to FCS-2 "robust" 11.5%, FCS-3 to FCS-4 "prefrail" 14.7%, FCS-5 "frail" 19.2% and FCS-6 to FCS-8 "dependent" 45.0%; p < 0.001. Adjusted mortality analysis: FCS with HR = 1.206 [95%CI, 0.999-1.451 (p = 0.051)]; EuroSCORE-II with HR = 1.071 [95%CI, 1.006-1.161 (p = 0.033)]; and OMT with HR = 2.840 [95%CI, 1.409-5.772 (p = 0.004)] were retained in the final multivariable logistic regression model. CONCLUSIONS: In older AS patients amenable to AVR, the FCS is a useful predictive tool that may aid clinical decision-making.

Evaluation of cardiovascular events in patients with hepatocellular carcinoma treated with sorafenib in the clinical practice. The CARDIO-SOR study.

BACKGROUND AND AIMS: The effectiveness of systemic treatment in advanced hepatocellular carcinoma (HCC) depends on the selection of patients, management of cirrhosis complications and expertise to treat adverse events. The aims of the study are to assess the frequency and management of cardiovascular events in HCC patients treated with sorafenib (SOR) and to create a scale to predict the onset of major adverse cardiovascular events (MACE). METHOD: Observational retrospective study with consecutive HCC patients treated with SOR between 2007 and 2019 in a western centre. In order to classify cardiovascular risk pre-SOR, we designed the CARDIOSOR scale with age, hypertension, diabetes, dyslipidaemia and peripheral vascular disease. Other adverse events, dosing and outcome data were collected during a homogeneous protocolled follow-up. RESULTS: Two hundred ninety-nine patients were included (219 BCLC-C). The median overall survival was 11.1 months (IQR 5.6-20.5), and duration of treatment was 7.4 months (IQR 3.3-14.7). Seventeen patients (6%) stopped SOR due to cardiovascular event. Thirty-three patients suffered MACE (7 heart failure, 11 acute coronary syndrome, 12 cerebrovascular accident and 8 peripheral vascular ischemia); 99 had a minor cardiovascular event, mainly hypertension (n = 81). Age was the only independent factor associated to MACE (HR 1.07; 95% CI 1.03-1.12; P = .002). The CARDIOSOR scale allows to identify the group of patients with higher risk of MACE (sHR 3.4; 95% CI 1.4-6.7; P = .04). CONCLUSION: The incidence of cardiovascular events in HCC patients treated with SOR is higher than expected. Multidisciplinary approach and clinical tools like CARDIOSOR scale could be helpful to manage these patients.

The APOB polymorphism rs1801701 A/G (p.R3638Q) is an independent risk factor for early-onset coronary artery disease: Data from a Spanish cohort.

BACKGROUND AND AIMS: Apoliprotein B (ApoB) has been associated with hypercholesterolemia and ischemic coronary disease. This study was aimed to determine the effect of two APOB gene variants in the risk of developing early-onset coronary artery disease (EO-CAD) in a Spanish population. The association of these polymorphisms with hypercholesterolemia was also analysed. METHODS AND RESULTS: The study involved a total of 889 healthy population controls (397 male) and 790 EO-CAD cases (636 male; EO-CAD was defined as male <60 years and women <65 years). All the patients had at least one vessel with angiography documented atherosclerotic lesion. Patients and controls were genotyped for the APOB variants rs1801701 A/G (p.R3638Q) and rs1367117 C/T (p.T98I). Allele and genotype frequencies were compared between the groups (patients vs. controls, hyper-vs. normo-cholesterolemia) by logistic regression. The rs1801701 was significantly associated with EO-CAD in male (OR = 1.44, 95%CI = 1.05-1.99) and female (OR = 2.22, 95%CI = 1.58-3.14). This SNP was significantly associated with hypercholesterolemia in female, with a trend in male. The association with EO-CAD was independent of hypercholesterolemia (multiple logistic regression). CONCLUSION: A common APOB polymorphism (rs1801701) was an independent risk factor for EO-CAD in our population. The risk-effect was more significant in female than in male.

A comprehensive formula for computing corrected QT intervals in patients with wide QRS.

BACKGROUND: There is increasing interest in developing appropriate methods for correction of the QT intervals in patients with prolonged depolarization of the ventricles. From an experimental model of controlled heart rate and QRS widening, we aimed to develop a new formula with better performance. METHODS: After exclusions, incremental pacing was performed (AAI mode; 50-120 bpm) in 17 patients admitted for self-expanding aortic valve implantation in two different phases: before and immediately after the release of the prosthesis. Mixed linear models were built to predict variation in QRS and JT intervals, and subsequently calculate the corrected QT (QTQRS-C). Internal and external validation on a new cohort of 48 patients was performed. RESULTS: Significant QRS widening (32.5 ms; CI95%:31.5-33.6) and QT prolongation (35.4 ms; CI95%:33.4-37.4) was observed after the release of the prosthesis. The best fit formula was computed as QTQRS-C = QTmeasured - (1.058*QRSmeasured - 108.397) - (0.0496*JTmeasured - 11.038). Internal validation provided a good correlation between measured and predicted QT (Pearson's coefficient:0.76; CI95%:0.70-0.80). In an external cohort (n = 48), the QRS widening was 28.4 ms(CI95%:21.8-35.1) and the JT widening was 16.58 ms(CI95%:8.73-24.4). Compared to other formulas, our proposed formula tends to display better performance as a result of a combination of appropriate correlation (Pearson's:0.75), being the closer to identity line (slope 0.83) and minimizing the relative standard error of the estimates (RSE 0.11). CONCLUSIONS: We developed a formula with better performance for QT correction in patients with wide QRS.

IL17RA in early-onset coronary artery disease: Total leukocyte transcript analysis and promoter polymorphism (rs4819554) association.

BACKGROUND AND AIMS: The interleukin-17 (IL-17) pathway would play an important role in the pathogenesis of atherosclerosis and coronary-artery disease (CAD). The IL-17 inflammatory mediators are expressed by Th17 cells, a group of CD4 + leukocytes that infiltrate the vascular milieu and are pivotal in the origin, progression, stability and rupture of the atherosclerotic lesion. Cigarette smoke compounds stimulated the expression of IL-17 and IL-17-receptors. In atherogenic mice models the deficiency of IL-17RA resulted in a reduction of the atherosclerotic lesion size and leukocyte infiltrate. We hypothesised that common the IL-17RA transcript might be differential expressed in the leukocytes from CAD patients and healthy individuals. METHODS: The relative amount of the IL-17RA to ACTB transcript was determined in total leukocytes of 55 patients and 50 controls, all smokers. We genotyped the IL-17RA rs48195554 promoter polymorphisms in 390 healthy controls and 450 early-onset CAD patients. RESULTS: Patients showed significantly higher mean IL-17RA normalised transcript value than controls (p < 0.001). For the IL-17RA rs48195554 promoter polymorphisms, IL-17RA G-carriers showed higher transcript values. However, allele and genotype frequencies did not differ between patients and controls and we thus excluded a significant association with CAD. CONCLUSIONS: The higher levels of the IL-17RA transcript among CAD-patients was in agreement with a role for the IL-17 pathway in the pathogenesis of coronary atherosclerosis.

Intraprocedural high-degree atrioventricular block or complete heart block in transcatheter aortic valve replacement recipients with no prior intraventricular conduction disturbances.

BACKGROUND: Conduction disturbances are the most frequent complication of transcatheter aortic valve replacement (TAVR). However, no data exists regarding the outcomes of intraprocedural high-degree atrioventricular block (HAVB) or complete heart block (CHB) in patients without previous conduction disturbances. OBJECTIVES: The aim of this study was to evaluate the outcomes of intraprocedural-HAVB/CHB in patients without previous intraventricular conduction disturbances. METHODS: The occurrence of intraprocedural-HAVB/CHB was assessed in 676 consecutive patients undergoing TAVR, and two groups were established according to its duration: persistent-HAVB/CHB (PHAVB/CHB) and transient-HAVB/CHB (THAVB/CHB), not present at the end of the procedure. RESULTS: Intraprocedural-HAVB/CHB occurred in 50 patients (7.4%), being persistent in 32 (64.0%), and transient in 18 (36.0%). The use of Medtronic Corevalve Revalving System (MCRS) and a greater oversizing of the valve increased the risk of intraprocedural-HAVB/CHB (p < 0.001). Permanent pacemaker implantation (PPI) was more frequent in the PHAVB/CHB than in the THAVB/CHB group (96.9% vs. 33.3%; p < 0.001). At 1-month follow-up, the PHAVB/CHB group showed a 98% ventricular pacing rate (VPR) compared to 16% in the THAVB/CHB group (p < 0.001), and similar VPR were observed at 1-year follow-up (98% vs. 37%, p < 0.001). Left ventricular ejection fraction (LVEF) decreased at 1-year follow-up in patients with PHAVB/CHB (-3.9 ± 1.8%, p = 0.003). CONCLUSIONS: In TAVR recipients with no prior intraventricular conduction disturbances, intraprocedural-HAVB/CHB occurred in 7.4% of cases. HAVB/CHB was persistent in most cases and determined a high rate of PPI post-TAVR. Very high VPR at 1- and 12-month follow-up were observed, which in turn was associated with a negative effect on LVEF. These results support early PPI and close follow-up in patients developing intraprocedural-PHAVB/CHB.

Incidence and outcome of peri-procedural transcatheter heart valve embolization and migration: the TRAVEL registry (TranscatheteR HeArt Valve EmboLization and Migration).

AIMS: Peri-procedural transcatheter valve embolization and migration (TVEM) is a rare but potentially devastating complication of transcatheter aortic valve implantation (TAVI). We sought to assess the incidence, causes, and outcome of TVEM in a large multicentre cohort. METHODS AND RESULTS: We recorded cases of peri-procedural TVEM in patients undergoing TAVI between January 2010 and December 2017 from 26 international sites. Peri-procedural TVEM occurred in 273/29 636 (0.92%) TAVI cases (age 80.8 ± 7.3 years; 53.8% female), of which 217 were to the ascending aorta and 56 to the left ventricle. The use of self-expanding or first-generation prostheses and presence of a bicuspid aortic valve were independent predictors of TVEM. Bail-out measures included repositioning attempts using snares or miscellaneous tools (41.0%), multiple valve implantations (83.2%), and conversion to surgery (19.0%). Using 1:4-propensity matching, we identified a cohort of 235 patients with TVEM (TVEMPS) and 932 patients without TVEM (non-TVEMPS). In the matched cohort, all-cause mortality was higher in TVEMPS than in non-TVEMPS at 30 days (18.6% vs. 4.9%; P < 0.001) and after 1 year (30.5% vs. 16.6%; P < 0.001). Major stroke was more frequent in TVEMPS at 30 days (10.6% vs. 2.8%; P < 0.001), but not at 1 year (4.6% vs. 1.9%; P = 0.17). The need for emergent cardiopulmonary support, major stroke at 30 days, and acute kidney injury Stages 2 and 3 increased the risk of 1-year mortality, whereas a better renal function at baseline was protective. CONCLUSION: Transcatheter valve embolization and migration occurred in approximately 1% and was associated with increased morbidity and mortality.

Incidence and outcomes of emergent cardiac surgery during transfemoral transcatheter aortic valve implantation (TAVI): insights from the European Registry on Emergent Cardiac Surgery during TAVI (EuRECS-TAVI).

Aims: Life-threatening complications occur during transcatheter aortic valve implantation (TAVI) which can require emergent cardiac surgery (ECS). Risks and outcomes of patients needing ECS during or immediately after TAVI are still unclear. Methods and results: Incidence, risk factors, management, and outcomes of patients requiring ECS during transfemoral (TF)-TAVI were analysed from a contemporary real-world multicentre registry. Between 2013 and 2016, 27 760 patients underwent TF-TAVI in 79 centres. Of these, 212 (0.76%) patients required ECS (age 82.4 ± 6.3 years, 67.5% females, logistic EuroSCORE: 17.1%, STS-score 5.8%). The risk of ECS declined from 2013 (1.07%) to 2014 (0.70%) but remained stable since. Annual TF-TAVI numbers have more than doubled from 2013 to 2016. Leading causes for ECS were left ventricular perforation by the guidewire (28.3%) and annular rupture (21.2%). Immediate procedural mortality (<72 h) of TF-TAVI patients requiring ECS was 34.6%. Overall in-hospital mortality was 46.0%, and highest in case of annular rupture (62%). Independent predictors of in-hospital mortality following ECS were age > 85 years [odds ratio (OR) 1.87, 95% confidence interval (95% CI) (1.02-3.45), P = 0.044], annular rupture [OR 1.96, 95% CI (0.94-4.10), P = 0.060], and immediate ECS [OR 3.12, 95% CI (1.07-9.11), P = 0.037]. One year of survival of the 114 patients surviving the in-hospital period was only 40.4%. Conclusion: Between 2014 and 2016, the need for ECS remained stable around 0.7%. Left ventricular guidewire perforation and annular rupture were the most frequent causes, accounting for almost half of ECS cases. Half of the patients could be salvaged by ECS-nevertheless, 1 year of all-cause mortality was high even in those ECS patients surviving the in-hospital period.

Variants in cardiac GATA genes associated with bicuspid aortic valve.

BACKGROUND: Bicuspid aortic valve (BAV) is a heterogeneous and still not fully understood condition, with diverse genetic aetiology and associated phenotypes ranging from aortic stenosis or regurgitation to aneurysm and dissection. Several genes have been associated with the presence of BAV, notably some members of the GATA family of transcription factors that play important roles in cardiac embryogenesis. METHODS: A case-control study with 122 unrelated and ethnically matched patients with bicuspid and 154 with tricuspid aortic valve was performed. All exons of GATA4, GATA5, and GATA6 genes were sequenced searching for variants. Frequencies were compared and functional effects of rare variants were analysed by informatic prediction tools. RESULTS: Four rare and potentially pathogenic variants were identified in only five sporadic cases: a missense p.Arg202Gln (rs782614097) in GATA5 and three synonymous variants, p.Cys274= (rs55980825) and p.His302= (rs201516339) in GATA4, and p.Asn458= (rs143026087) in GATA6. Minor alleles of p.His302=, p.Arg202Gln and rs3764962 are enriched in BAV patients compared to ExAC database (P = 0.01, 0.03, and 0.01 respectively). In addition, a common polymorphism in GATA5 (p.Asp203=, rs41305803) is associated with BAV showing a protective effect in carriers of the minor allele (OR [95%CI] = 0.45[0.25-0.81]; P = 0.004). CONCLUSION: This study associates additional genetic variants in GATA4 and GATA5 with BAV, supporting the implication of these genes in the development of this valvulopathy. The discovery of all the genetic factors involved will contribute to a better understanding of the process and, therefore, to detect a genetic predisposition and even to the identification of therapeutic targets.

Role of syncope in predicting adverse outcomes in patients with suspected Brugada syndrome undergoing standardized flecainide testing.

Aims: Sensitivity to flecainide testing results in suboptimal findings in patients with Brugada syndrome (BrS), leading to safety concerns. Because cardiac syncope effectively predicts outcomes in BrS, we aimed to explore its predictive value in a large cohort of negative and positive responders (NR and PR) to standard flecainide testing. Methods and results: We analysed the data of 251 consecutive patients, 177 NR vs. 74 PR, to flecainide testing, performed according to standard recommendations. Cardiac syncope was defined as syncope presenting without prodromal symptoms and in the absence of any specific situation. Comparing PR with NR, there were no differences regarding age (39 ± 15 vs. 44 ± 13 years; P = 0.052), male gender (70.1% vs. 66.2%; P = 0.553), and family history of sudden cardiac death in relatives younger than 45 years (27% vs. 27%; P = 1). Cardiac syncope was more frequent in PR (12.2% vs. 4%; P = 0.022), and previous sudden cardiac arrest (SCA) was documented only in PR (5.4% vs. 0%; P = 0.007). During the follow-up period (6.2 ± 3.3 years), one NR, who had previously experienced cardiac syncope, developed SCA 3 months after flecainide testing. Following resuscitation, a type I electrocardiogram was spontaneously recorded. The follow-up event rate was higher in patients with cardiac syncope, both in PR and in NR (P < 0.001 both). In a multivariate analysis, cardiac syncope was the unique variable that predicted adverse outcomes (hazard ratio 14.9, 95% confidence interval 1.84-121.25; P = 0.011). Conclusions: In patients with false-negative responses to the provocative testing with flecainide, cardiac syncope predicts SCA, allowing a more extensive and individualized evaluation.

Delta of the local ventriculo-atrial intervals at the septal location to differentiate tachycardia using septal accessory pathways from atypical atrioventricular nodal re-entry.

Aims: Tachycardia mediated by septal accessory pathways (AP) and atypical atrioventricular nodal re-entry (AVNRT) require careful electrophysiologic evaluation for differential diagnosis. We aim to describe the differential behaviour of local ventriculo-atrial (VA) intervals which predicts the tachycardia mechanism. Methods and results: The local VA intervals at the para-Hisian septum were measured under three different situations: (i) tachycardia; (ii) sustained entrainment from the right ventricular apex (RVA); and (iii) continuous pacing from the RVA during sinus rhythm. Differences were computed as follows: Δ-VAentr = VA during entrainment - VA during tachycardia; and Δ-VApac = VA while pacing during sinus rhythm - VA during tachycardia. In contrast to AVNRT, we hypothesized that an invariable retrograde conduction through the septal AP will keep the result of the subtractions close to 0 ms in cases of ortodromic atrioventricular re-entrant tachycardia (AVRT). We analysed 55 atypical AVNRT (45% posterior type) and 82 AVRT (10 anteroseptal, 18 para-Hisian, 12 mid-septal, and 42 posteroseptal). Δ-VAentr was longer for AVNRT (98.5 ± 40.3 ms) compared with septal AP (-5.7 ± 19.3 ms; P < 0.001). A value of 50 ms showed 98.7% sensitivity and 92% specificity (AUC 0.99; 95% CI 0.98-1). According to physiological criteria, a negative Δ-VAentr remains unobserved in the case of AVNRT (positive predictive value 100% for septal AP). Δ-VApac was also longer for AVNRT (66.5 ± 14.6 ms) compared with septal AP (-9.7 ± 3.3 ms; P < 0.001). A value of 50 ms showed 100% sensitivity and 74% specificity (AUC 0.86; 95% CI 0.76-0.93). Conclusions: Delta of the local VA intervals enables distinction between atypical AVNRT and AVRT mediated by septal AP.

Characterization of a stepwise approach in cavotricuspid isthmus ablation for typical atrial flutter: A randomized study comparing three catheters.

INTRODUCTION: Our aim was to characterize a stepwise approach in cavotricuspid isthmus ablation for typical atrial flutter in a prospective, noncrossover randomized study. METHODS: One hundred and fifty patients referred for cavotricuspid isthmus (CTI)-dependent atrial flutter ablation were randomized to undergo an ablation with an 8-mm-tip catheter (group 1), a 3.5-mm open irrigation-tip catheter (group 2), and a 3.5-mm open irrigation porous-tip catheter (group 3). A stepwise approach was performed, changing the ablation site from medial to septal aspects of the CTI, in case it was not effective without crossover between catheters. RESULTS: CTI block was achieved in all the patients using only one catheter. There was a 68% efficacy in group 1, 40% in group 2, and 28% in group 3 to achieve CTI block within 10 minutes (P  =  0.001) and 96%, 70%, and 70% in groups 1, 2, and 3, respectively, within 20 minutes (P  =  0.002) of radiofrequency ablation. The 8-mm catheter was also faster in fluoroscopy time and CTI block time. There were no differences in efficiency in the both irrigated catheters. There were no significant differences in complications among three catheters. CONCLUSIONS: With this stepwise approach, it is possible to achieve CTI block in all cases, using a single catheter without crossover, with good times of procedure and with a low complication rate. The 8-mm solid catheter is faster than the other irrigated-tip catheters. The 3.5-mm open irrigation porous-tip catheter is as effective and safe as the conventional irrigated-tip catheter.

Beta-Blockers and Calcium Channel Blockers: First Line Agents.

Beta-blockers and calcium channel blockers (CCB) are milestones in the treatment of stable coronary ischaemic disease. Their main effects are particularly suited for the management of effort-induced angina because of the reduction of oxygen demand they achieve. The clinical benefits of these drugs are highly reproducible and have been shown to improve overall clinical outcomes. Despite the availability of other, and newer antianginal drugs, treatment guidelines continue to recommend the use of beta-blockers and calcium channel blockers as first line therapies.

A Semiconductor Chip-Based Next Generation Sequencing Procedure for the Main Pulmonary Hypertension Genes.

The aim of this study was to characterize the mutational spectrum of pulmonary hypertension (PH) patients through a next generation sequencing platform. In a total of 22 patients, the BMPR2, SMAD9, CAV1, KCNK3, and EIF2AK4 genes were sequenced with semiconductor chips and the ion torrent personal genome machine. We found six putative mutations in SMAD (p.R263Q), BMPR2 (p.S301P, p.T493I), CAV1 (p.V155I), and EIF2AK4 (p.L489P, p.P1115L) in five patients. One patient was compound heterozygous for BMPR2 + SMAD mutations, and one patient was homozygous for EIF2AK4 p.P1115L. The reported procedure would facilitate the rapid mutational screening of large cohorts of PH patients.

Mutation analysis of the main hypertrophic cardiomyopathy genes using multiplex amplification and semiconductor next-generation sequencing.

BACKGROUND: Mutations in at least 30 genes have been linked to hypertrophic cardiomyopathy (HCM). Due to the large size of the main HCM genes, Sanger sequencing is labor intensive and expensive. The purpose was to develop a next-generation sequencing (NGS) procedure for the main HCM genes. METHODS AND RESULTS: Multiplex amplification of the coding exons of MYH7,MYBPC3,TNNT2,TNNI3,ACTC1,TNNC1,MYL2,MYL3, and TPM1 was designated, followed by NGS with the Ion Torrent PGM (Life Technologies). A total of 8 pools containing DNA from HCM patients were sequenced in a 2-step approach. First, a total of 60 patients (validation cohort) underwent both PGM and Sanger sequencing for the 9 genes. No false-negative variants were found on NGS (100% sensitivity), and a specificity of 97% and 80% was achieved for single-nucleotide and insertion/deletion variants, respectively. Second, the PGM was used to search for mutations in a total of 76 cases not previously studied (discovery cohort). A total of 19 putative mutations were identified in the discovery pools, which were confirmed and assigned to specific patients on Sanger sequencing. CONCLUSIONS: An NGS procedure has been developed for the main sarcomeric genes that would facilitate the screening of large cohorts of patients. In addition, this procedure would facilitate the uncovering of rare gene variants on a population scale.

Moderate patient-prosthesis mismatch predicts cardiac events and advanced functional class in young and middle-aged patients undergoing surgery due to severe aortic stenosis.

BACKGROUND AND AIM: The clinical impact of patient-prosthesis mismatch (PPM) on outcomes in young and middle-aged patients undergoing surgery for aortic valve replacement (AVR) remains unknown. Our objective was to examine the mid-term impact of PPM on overall mortality, quality of life, and cardiac events in this population. METHODS: All patients younger than 70 years of age undergoing isolated AVR from October 2005 to October 2011 were analyzed. PPM was defined as the indexed effective orifice area ≤ 0.85 cm(2) /m(2) . We studied the impact of PPM on mid-term overall mortality, cardiac events, and New York Heart Association functional class using an analysis stratified for propensity score. Cardiac events were defined as cardiac death, sudden death, hospital readmission due to angina, syncope or heart failure or reoperation on aortic prosthesis. RESULTS: Two hundred and ninety-three patients were included in the study, of whom 81 (27.61%) had some degree of PPM. PPM had no impact on mid-term overall mortality (HR=1.45; 95% CI=0.65-3.22; p=0.36), although it had a negative impact on cardiac events (HR=11.52; 95% CI=5.25-25.24; p<0.001) and functional class (RR=7.55; 95% CI=2.59-22.03; p<0.001). CONCLUSIONS: Moderate PPM appears to be a strong and independent predictor of cardiac events and advanced functional class in young and middle-aged patients undergoing AVR for severe stenosis. However, it is possible that it has no impact on overall mortality.

Hemodynamic performance of self-expandable transcatheter aortic valve replacement systems during valve deployment.

OBJECTIVES: Little is known about valve hemodynamic performance during the Evolut and Neo deployment course. We aimed to evaluate transvalvular mean and peak-to-peak gradients over several intraprocedural timepoints during TAVR with Evolut PRO+ (Medtronic) and Neo (Boston Scientific) systems. METHODS: This was single-center pilot sub-study from the SavvyWire EFficacy and SafEty in Transcatheter Aortic Valve Implantation Procedures (SAFE-TAVI) trial. Participants received either the Evolut PRO+ or Neo for native valve severe aortic stenosis and the SavvyWire (OpSens Medical) was used for device delivery, pacing, and continuous left ventricular and aortic pressure measurements. For the Evolut, evaluation was done for baseline, two-thirds of valve deployment (still recapturable), 90% of valve deployment (no longer recapturable), and post-deployment hemodynamics. For the Neo, analysis was done at baseline, after the first step (top-crown deployment), and at final status. RESULTS: Nineteen patients were included (Evolut = 15; Neo = 4). There were no statistically significant changes in peak-to-peak gradients (44 mm Hg [IQR:33-69] vs 43 mm Hg [IQR:26-62], P = .41) between baseline and two-thirds of valve deployment in the Evolut patients. There was a significant decrease in mean (40 mm Hg [IQR:32-54] vs 14 mm Hg [IQR:10-18], P less than .001) and peak-to-peak (43 mmHg [IQRS:26-62] vs 9 mm Hg [IQR:8-13], P less than .001) transvalvular gradients between two-thirds and 90% of valve deployment for Evolut. Neo patients exhibited a decrease in transvalvular gradients after top-crown deployment (42.5 mm Hg baseline vs 13 mm Hg). CONCLUSIONS: Transvalvular gradients did not vary between the point of "no-recapture" compared to baseline values in patients receiving the Evolut, whereas a significant reduction in transvalvular gradients was observed when the valve was deployed at 90% and fully deployed. The Neo valve was slightly obstructive after the first step of deployment.

Late bleeding events in TAVI patients receiving vitamin K antagonists or direct oral anticoagulants.

INTRODUCTION AND OBJECTIVES: The optimal chronic antithrombotic regimen for patients with atrial fibrillation undergoing transcatheter aortic valve implantation (TAVI) remains uncertain. Our aim was to compare the incidence of late bleeding events between patients on direct oral anticoagulants (DOACs) and those on vitamin-K antagonists (VKA). METHODS: This single-center observational study included TAVI patients requiring oral anticoagulation at discharge between 2015 and 2021. The primary endpoint was any clinically significant bleeding event. Secondary endpoints were stroke, heart failure, and all-cause mortality. RESULTS: A total of 702 TAVI procedures were performed, with 297 patients requiring oral anticoagulation at discharge. Among them, 206 (69.4%) received VKA and 91 (30.6%) received DOAC. Baseline clinical, procedural and in-hospital characteristics did not significantly differ between groups, except for better renal function among DOAC patients. The median length of follow-up was 2.8 years. The risk of bleeding events was higher in patients receiving DOACs than in those receiving VKA (HR, 2.27; 95%CI, 1.21-4.26; incidence of 9.7 and 4.2 events per 100 patient-years of follow-up for DOAC and VKA patients, respectively). There were no statistically significant differences in the rates of stroke (HR, 1.28; 95%CI, 0.4-4.3), heart failure hospitalization (HR, 0.92; 95%CI, 0.46-1.86), or all-cause mortality (HR, 1.02; 95%CI, 0.68-1.55). CONCLUSIONS: In older patients undergoing TAVI and receiving anticoagulant therapy for atrial fibrillation, the use of DOAC was associated with a higher risk of late bleeding events than VKA.