Impact of Surgical and Transcatheter Aortic Valve Replacement in Low-Gradient Aortic Stenosis: A Meta-Analysis

ObjectivesThe aim of this study was to assess the impact of aortic valve replacement (AVR) on survival in patients with each subclass of low-gradient (LG) aortic stenosis (AS) and to compare outcomes following surgical AVR (SAVR) and transcatheter AVR (TAVR).BackgroundLG severe AS encompasses a wide variety of pathophysiology, including classical low-flow, LG (LF-LG), paradoxical LF-LG, and normal-flow, LG (NF-LG) AS, and uncertainty exists regarding the impact of AVR on each subclass of LG AS.MethodsPubMed and Embase were queried through October 2020 to identify studies comparing survival with different management strategies (SAVR, TAVR, and conservative) in patients with LG AS. Pairwise meta-analysis comparing AVR versus conservative management and network meta-analysis comparing SAVR versus TAVR versus conservative management were performed.ResultsThirty-two studies with a total of 6,515 patients and a median follow-up time of 24.2 months (interquartile range: 36.5 months) were included. AVR was associated with a significant decrease in all-cause mortality in classical LF-LG (hazard ratio [HR]: 0.42; 95% confidence interval [CI]: 0.36 to 0.48), paradoxical LF-LG (HR: 0.41; 95% CI: 0.29 to 0.57), and NF-LG (HR: 0.41; 95% CI: 0.27 to 0.62) AS compared with conservative management. SAVR and TAVR were each associated with a decrease in all-cause mortality in classical LF-LG (HR: 0.46 [95% CI: 0.38 to 0.55] and 0.49 [95% CI: 0.37 to 0.64], respectively), paradoxical LF-LG (HR: 0.42 [95% CI: 0.28 to 0.65] and 0.42 [95% CI: 0.25 to 0.72], respectively), and NF-LG (HR: 0.40 [95% CI: 0.21 to 0.77] and 0.46 [95% CI: 0.26 to 0.84], respectively) AS compared with conservative management. No significant difference was observed between SAVR and TAVR.ConclusionsIn all subclasses of LG AS, AVR was associated with a significant decrease in all-cause mortality regardless of surgical or transcatheter approach.     

Pericardial Fat and the Risk of Heart Failure

BackgroundObesity is a well-established risk factor for heart failure (HF). However, implications of pericardial fat on incident HF is unclear.ObjectivesThis study sought to examine the association between pericardial fat volume (PFV) and newly diagnosed HF.MethodsThis study ascertained PFV using cardiac computed tomography in 6,785 participants (3,584 women and 3,201 men) without pre-existing cardiovascular disease from the MESA (Multi-Ethnic Study of Atherosclerosis). Cox proportional hazards regression was used to evaluate PFV as continuous and dichotomous variable, maximizing the J-statistic: (Sensitivity + Specificity – 1).ResultsIn 90,686 person-years (median: 15.7 years; interquartile range: 11.7 to 16.5 years), 385 participants (5.7%; 164 women and 221 men) developed newly diagnosed HF. PFV was lower in women than in men (69 ± 33 cm³ vs. 92 ± 47 cm³; p < 0.001). In multivariable analyses, every 1-SD (42 cm³) increase in PFV was associated with a higher risk of HF in women (hazard ratio [HR]: 1.44; 95% confidence interval [CI]: 1.21 to 1.71; p < 0.001) than in men (HR: 1.13; 95% CI: 1.01 to 1.27; p = 0.03) (interaction p = 0.01). High PFV (≥70 cm³ in women; ≥120 cm³ in men) conferred a 2-fold greater risk of HF in women (HR: 2.06; 95% CI: 1.48 to 2.87; p < 0.001) and a 53% higher risk in men (HR: 1.53; 95% CI: 1.13 to 2.07; p = 0.006). In sex-stratified analyses, greater risk of HF remained robust with additional adjustment for anthropometric indicators of obesity (p ≤ 0.008), abdominal subcutaneous or visceral fat (p ≤ 0.03) or biomarkers of inflammation and hemodynamic stress (p < 0.001) and was similar among Whites, Blacks, Hispanics, and Chinese (interaction p = 0.24). Elevated PFV predominantly augmented the risk of HF with preserved ejection fraction (p < 0.001) rather than reduced ejection fraction (p = 0.31).ConclusionsIn this large, community-based, ethnically diverse, prospective cohort study, pericardial fat was associated with an increased risk of HF, particularly HF with preserved ejection fraction, in women and men.     

Impact of Moderate Aortic Stenosis on Long-Term Clinical Outcomes: A Systematic Review and Meta-Analysis

BackgroundThe clinical course of patients with moderate aortic stenosis (AS) remains incompletely defined.ObjectivesThis study sought to analyze the clinical course of moderate AS and compare it with other stages of the disease.MethodsMultiple electronic databases were searched to identify studies on adult moderate AS. Random-effects models were used to derive pooled estimates. The primary endpoint was all-cause death. The secondary endpoints were cardiac death, heart failure, sudden death, and aortic valve replacement.ResultsAmong a total of 25 studies (12,143 moderate AS patients, 3.7 years of follow-up), pooled rates per 100 person-years were 9.0 (95% CI: 6.9 to 11.7) for all-cause death, 4.9 (95% CI: 3.1 to 7.5) for cardiac death, 3.9 (95% CI: 1.9 to 8.2) for heart failure, 1.1 (95% CI: 0.8 to 1.5) for sudden death, and 7.2 (95% CI: 4.3 to 12.2) for aortic valve replacement. Meta-regression analyses detected that diabetes (P = 0.019), coronary artery disease (P = 0.017), presence of symptoms (P < 0.001), and left ventricle (LV) dysfunction (P = 0.009) were associated with a significant impact on the overall estimate of all-cause death. All-cause mortality was higher in patients with reduced LV ejection fraction (<50%) than with normal LV ejection fraction: 16.5 (95% CI: 5.2 to 52.3) and 4.2 (95% CI: 1.4 to 12.8) per 100 person-years, respectively. Compared with moderate AS, the incidence rate difference of all-cause mortality was -3.9 (95% CI: -6.7 to -1.1) for no or mild AS and +2.2 (95% CI: +0.8 to +3.5) for severe AS patients.ConclusionsModerate AS appears to be associated with a mortality risk higher than no or mild AS but lower than severe AS, which increases in specific population subsets. The impact of early intervention in moderate AS patients having high-risk features deserves further investigation.     

Transvalvular Flow,Sex, and Survival After Valve Replacement Surgery in Patients With Severe Aortic Stenosis

BackgroundThe respective impacts of transvalvular flow, gradient, sex, and their interactions on mortality in patients with severe aortic stenosis undergoing surgical aortic valve replacement (AVR) are unknown.ObjectivesThis study sought to compare the impact of pre-operative flow-gradient patterns on mortality after AVR and to examine whether there are sex differences.MethodsThis study analyzed clinical, echocardiographic, and outcome data prospectively collected in 1,490 patients (544 women [37%]), with severe aortic stenosis and preserved left ventricular ejection fraction who underwent AVR.ResultsIn this cohort, 601 patients (40%) had normal flow (NF) with high gradient (HG), 405 (27%) NF with low gradient (LG), 246 (17%) paradoxical low flow (LF)/HG, and 238 (16%) LF/LG. During a median follow-up of 2.42 years (interquartile range: 1.04 to 4.29 years), 167 patients died. Patients with LF/HG exhibited the highest mortality after AVR (hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.33 to 3.03; p < 0.01), which remained significant after multivariate adjustment (HR: 1.96; 95% CI: 1.29 to 2.98; p < 0.01). Both LF/LG and NF/LG patients had comparable outcome to NF/HG (p ≥ 0.47). Optimal thresholds of stroke volume index were obtained for men (40 ml/m²) and women (32 ml/m²). Using these sex-specific cutpoints, paradoxical LF was independently associated with increased mortality in both women (adjusted HR: 2.05; 95% CI: 1.21 to 3.47; p < 0.01) and men (adjusted HR: 1.54; 95% CI: 1.02 to 2.32; p = 0.042), whereas guidelines’ threshold (35 ml/m²) does not.ConclusionsParadoxical LF/HG was associated with higher mortality following AVR, suggesting that a reduced flow is a marker of disease severity even in patients with HG aortic stenosis. Early surgical AVR (i.e., before gradient attains 40 mm Hg) might be preferable in these patients. Furthermore, the use of sex-specific thresholds (<40 ml/m² for men and <32 ml/m² for women) to define low-flow outperforms the guidelines’ threshold of 35 ml/m² in risk stratification after AVR.     

Cardiac Damage and Quality of Life After Aortic Valve Replacement in the PARTNER Trials

BackgroundThe extent of extravalvular cardiac damage is associated with increased risk of adverse events among patients with severe aortic stenosis undergoing aortic valve replacement (AVR).ObjectivesThe goal was to describe the association of cardiac damage on health status before and after AVR.MethodsPatients from the PARTNER (Placement of Aortic Transcatheter Valves) 2 and 3 trials were pooled and classified by echocardiographic cardiac damage stage at baseline and 1 year as previously described (stage 0-4). We examined the association between baseline cardiac damage and 1-year health status (assessed by the Kansas City Cardiomyopathy Questionnaire Overall Score [KCCQ-OS]).ResultsAmong 1,974 patients (794 surgical AVR, 1,180 transcatheter AVR), the extent of cardiac damage at baseline was associated with lower KCCQ scores both at baseline and at 1 year after AVR (P < 0.0001) and with increased rates of a poor outcome (death, KCCQ-OS <60, or a decrease in KCCQ-OS of ≥10 points) at 1 year (stages 0-4: 10.6% vs 19.6% vs 29.0% vs 44.7% vs 39.8%; P < 0.0001). In a multivariable model, each 1-stage increase in baseline cardiac damage was associated with a 24% increase in the odds of a poor outcome (95% CI: 9%-41%; P = 0.001). Change in stage of cardiac damage at 1 year after AVR was associated with the extent of improvement in KCCQ-OS over the same period (mean change in 1-year KCCQ-OS: improvement of ≥1 stage +26.8 [95% CI: 24.2-29.4] vs no change +21.4 [95% CI: 20.0-22.7] vs deterioration of ≥1 stage +17.5 [95% CI: 15.4-19.5]; P < 0.0001).ConclusionsThe extent of cardiac damage before AVR has an important impact on health status outcomes, both cross-sectionally and after AVR. (PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - XT Intermediate and High Risk (PII A), NCT01314313; The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves - PII B [PARTNERII B], NCT02184442; PARTNER 3 Trial: Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis [P3], NCT02675114)     

Long-Term Prognostic Value of Stress CMR in Patients With Heart Failure and Preserved Ejection Fraction

ObjectivesThe objectives of this study were to investigate the long-term prognostic value of inducible myocardial ischemia assessed by vasodilator stress cardiovascular magnetic resonance (CMR) in patients with HFpEF.BackgroundSome studies suggest that ischemia could play a key role in HF in patients with preserved ejection fraction (HFpEF).MethodsBetween 2008 and 2019, consecutive patients prospectively referred for stress CMR with HFpEF as defined by current guidelines, without known coronary artery disease (CAD), were followed for the occurrence of major adverse cardiovascular events (MACE), as defined by cardiovascular mortality or nonfatal myocardial infarction (MI). Secondary composite outcomes included cardiovascular mortality or hospitalization for acute HF. Cox regression analysis was performed to determine the prognostic value of inducible ischemia or late gadolinium enhancement (LGE) by CMR.ResultsAmong the 1,203 patients with HFpEF (73 ± 13 years of age; 29% males) who underwent stress CMR and completed follow-up (6.9 years interquartile range [IQR]: 6.7 to 7.7 years]), 108 experienced a MACE (9%). Kaplan-Meier analysis showed inducible ischemia and LGE were significantly associated with MACE (HR: 6.63; 95% confidence interval [CI]: 4.54 to 9.69; and HR: 2.56; 95% CI: 1.60 to 4.09, respectively; both p < 0.001) and secondary outcomes (HR: 8.40; 95% CI: 6.31 to 11.20; p < 0.001; and HR: 1.87; 95% CI: 1.27 to 2.76, respectively; p = 0.002). In multivariate analysis, inducible ischemia and LGE were independent predictors of MACE (HR: 6.10; 95% CI: 4.14 to 9.00; p < 0.001 and HR: 1.62; 95% CI: 1.06 to 2.49; p = 0.039; respectively).ConclusionsStress CMR-inducible myocardial ischemia and LGE have accurate discriminative long-term prognostic value in HFpEF patients without known CAD to predict the occurrence of MACE.     

Systolic Blood Pressure and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction

BackgroundNational guidelines recommend that systolic blood pressure (SBP) in patients with heart failure with reduced ejection fraction (HFrEF) and hypertension be maintained below 130 mm Hg.ObjectivesThis study sought to determine associations of SBP <130 mm Hg with outcomes in patients with HFrEF.MethodsOf the 25,345 patients in the Medicare-linked OPTIMIZE-HF registry, 10,535 had an ejection fraction (EF) ≤40%. Of these, 5,615 had stable SBP (≤20 mm Hg admission to discharge variation), and 3,805 (68%) had a discharge SBP <130 mm Hg. Propensity scores for SBP <130 mm Hg, estimated for each of the 5,615 patients, were used to assemble a matched cohort of 1,189 pairs of patients with SBP <130 versus ≥130 mm Hg, balanced on 58 baseline characteristics (mean age 76 years; mean EF 28%, 45% women, 13% African American). This process was repeated in 3,946 patients, after excluding 1,669 patients (30% of 5,615) with a discharge SBP <110 mm Hg and assembled a second matched balanced cohort of 1,099 pairs of patients with SBP 110 to 129 mm Hg versus ≥130 mm Hg.ResultsThirty-day all-cause mortality occurred in 7% and 4% of matched patients with SBP <130 mm Hg versus ≥130 mm Hg, respectively (hazard ratio [HR]: 1.76; 95% confidence interval [CI]: 1.24 to 2.48; p = 0.001). HRs (95% CIs) for all-cause mortality, all-cause readmission, and HF readmission at 1 year, associated with SBP <130 mm Hg, were 1.32 (1.15 to 1.53; p < 0.001), 1.11 (1.01 to 1.23; p = 0.030), and 1.24 (1.09 to 1.42; p = 0.001), respectively. HRs (95% CIs) for 30-day and 1-year all-cause mortality associated with SBP 110 to 129 mm Hg (vs. ≥130 mm Hg) were 1.50 (1.03 to 2.19; p = 0.035), and 1.19 (1.02 to 1.39; p = 0.029), respectively.ConclusionsAmong hospitalized older patients with HFrEF, SBP <130 mm Hg is associated with poor outcomes. This association persisted when the analyses were repeated after excluding patients with SBP <110 mm Hg. There is an urgent need for randomized controlled trials to evaluate optimal SBP reduction goals in patients with HFrEF.     

Predictors and Clinical Impact of Prosthesis-Patient Mismatch After Self-Expandable TAVR in Small Annuli

ObjectivesThe aim of this study was to define predictors of prosthesis-patient mismatch (PPM) and its impact on mortality after transcatheter aortic valve replacement (TAVR) with self-expandable valves (SEVs) in patients with small annuli.BackgroundTAVR seems to reduce the risk for PPM compared with surgical aortic valve replacement, especially in patients with small aortic annuli. Nevertheless, predictors and impact of PPM in this population have not been clarified yet.MethodsPredictors of PPM and all-cause mortality were investigated using multivariable logistic regression analysis from the cohort of the TAVI-SMALL (International Multicenter Registry to Evaluate the Performance of Self-Expandable Valves in Small Aortic Annuli) registry, which included patients with severe aortic stenosis and small annuli (annular perimeter <72 mm or area <400 mm² on computed tomography) treated with transcatheter SEVs: 445 patients with (n = 129) and without (n = 316) PPM were enrolled.ResultsIntra-annular valves conferred increased risk for PPM (odds ratio [OR]: 2.36; 95% confidence interval [CI]: 1.16 to 4.81), while post-dilation (OR: 0.46; 95% CI: 0.25–0.84) and valve oversizing (OR: 0.53; 95% CI: 0.28–1.00) seemed to protect against PPM occurrence. At a median follow-up of 354 days, patients with severe PPM, but not those with moderate PPM, had a higher all-cause mortality rate compared with those without PPM (log-rank p = 0.008). Multivariable Cox regression confirmed severe PPM as an independent predictor of all-cause mortality (hazard ratio: 4.27; 95% CI: 1.34 to 13.6).ConclusionsAmong patients with aortic stenosis and small aortic annuli undergoing transcatheter SEV implantation, use of intra-annular valves yielded higher risk for PPM; conversely, post-dilation and valve oversizing protected against PPM occurrence. Severe PPM was independently associated with all-cause mortality.     

Impact of Prosthesis-Patient Mismatch After Transcatheter Aortic Valve Replacement: Meta-Analysis of Kaplan-Meier–Derived Individual Patient Data

BackgroundIt remains controversial whether prosthesis-patient mismatch (PPM) (in general considered moderate if indexed effective orifice area is 0.65-0.85 cm²/m² and severe when <0.65 cm²/m²) affects the outcomes after transcatheter aortic valve replacement (TAVR).ObjectivesThe purpose of this study is to evaluate the time-varying effects and association of PPM with the risk of overall mortality.MethodsStudy-level meta-analysis of reconstructed time-to-event data from Kaplan-Meier curves of studies published by December 30, 2021.ResultsIn total, 23 studies met our eligibility criteria and included a total of 81,969 patients included in the Kaplan-Meier curves (19,612 with PPM and 62,357 without PPM). Patients with moderate/severe PPM had a significantly higher risk of mortality compared with those without PPM (HR: 1.09 [95% CI: 1.04-1.14]; P < 0.001). In the first 30 months after the procedure, mortality rates were significantly higher in the moderate/severe PPM group (HR: 1.1 [95% CI: 1.05-1.16]; P < 0.001). In contrast, the landmark analysis beyond 30 months yielded a reversal of the HR (0.83 [95% CI: 0.68-1.01]; P = 0.064), but without statistical significance. In the sensitivity analysis, although the authors observed that severe PPM showed higher risk of mortality in comparison with no PPM (HR: 1.25 [95% CI: 1.16-1.36]; P < 0.001), they did not observe a statistically significant difference for mortality between moderate PPM and no PPM (HR: 1.03 [95% CI: 0.96-1.10]; P = 0.398).ConclusionsSevere PPM, but not moderate PPM, was associated with higher risk of mortality following TAVR. These results provide support to implementation of preventive strategies to avoid severe PPM following TAVR.     

Transcatheter Self-Expandable Valve Implantation for Aortic Stenosis in Small Aortic Annuli: The TAVI-SMALL Registry

ObjectivesThe aim of this study was to evaluate and compare the outcomes of transcatheter self-expandable prostheses in patients with small annuli.BackgroundTranscatheter aortic heart valves appear to have better performance than surgical valves in terms of prosthesis-patient mismatch, especially in patients with aortic stenosis with small aortic annuli.MethodsTAVI-SMALL (International Multicenter Registry to Evaluate the Performance of Self-Expandable Valves in Small Aortic Annuli) is a retrospective registry of patients with severe aortic stenosis and small annuli (annular perimeter <72 mm or area <400 mm² on computed tomography) treated with transcatheter self-expandable valves (n = 859; Evolut R, n = 397; Evolut PRO, n = 84; ACURATE, n = 201; Portico, n = 177). Primary endpoints were post-procedural mean aortic gradient, indexed effective orifice area, and rate of severe prosthesis-patient mismatch.ResultsPre-discharge gradients were consistently low in every group, with a slight benefit with the Evolut R (8.1 mm Hg; 95% confidence interval [CI]: 7.7 to 8.5 mm Hg) and Evolut PRO (6.9 mm Hg; 95% CI: 6.3 to 7.6 mm Hg) compared with the ACURATE (9.6 mm Hg; 95% CI: 8.9 to 10.2 mm Hg) and Portico (8.9 mm Hg; 95% CI: 8.2 to 9.6 mm Hg) groups (p < 0.001). Mean indexed effective orifice area was 1.04 cm²/m² (95% CI: 1.01 to 1.08 cm²/m²) with a trend toward lower values with the Portico. No significant differences were reported in terms of severe prosthesis-patient mismatch (overall rate 9.4%; p = 0.134), permanent pacemaker implantation (15.6%), and periprocedural and 1-year adverse events. Pre-discharge more than mild paravalvular leaks were significantly more common with the Portico (19.2%) and less common with the Evolut PRO (3.6%) compared with the Evolut R (11.8%) and ACURATE (9%) groups.ConclusionsTranscatheter self-expandable valves showed optimal clinical and echocardiographic results in patients with small aortic annuli, although supra-annular functioning transcatheter heart valves seemed to slightly outperform intra-annular functioning ones. The role of transcatheter aortic valve replacement with self-expandable valves for the treatment of aortic stenosis in patients with small annuli needs to be confirmed in larger trials.     

Clonal Hematopoiesis and Risk of Progression of Heart Failure With Reduced Left Ventricular Ejection Fraction

BackgroundClonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown.ObjectivesThe purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology.MethodsThe study cohort comprised 62 patients with HF and LVEF <45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization.ResultsCHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology.ConclusionsSomatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology.     

Impact of Pre-Existing and New-Onset Atrial Fibrillation on Outcomes After Transcatheter Aortic Valve Replacement

ObjectivesThis study sought to evaluate impact of new-onset and pre-existing atrial fibrillation (AF) on transcatheter aortic valve replacement (TAVR) long-term outcomes compared with patients without AF.BackgroundPre-existing and new-onset AF in patients undergoing TAVR are associated with poor outcomes.MethodsThe study identified 72,660 patients ≥65 years of age who underwent nonapical TAVR between 2014 and 2016 using Medicare inpatient claims. History of AF was defined by diagnoses on claims during the 3 years preceding the TAVR, and new-onset AF was defined as occurrence of AF during the TAVR admission or within 30 days after TAVR in a patient without prior history of AF. Outcomes included all-cause mortality, and readmission for bleeding, stroke, and heart failure (HF).ResultsOverall, 40.7% had pre-existing AF (n = 29,563) and 6.8% experienced new-onset AF (n = 2,948) after TAVR. Mean age was 81.3, 82.4, and 83.8 years in patients with no AF, pre-existing, and new-onset AF, respectively. Pre-existing AF patients had the highest burden of comorbidities. After follow-up of 73,732 person-years, mortality was higher with new-onset AF compared with pre-existing and no AF (29.7, 22.6, and 12.8 per 100 person-years, respectively; p < 0.001). After adjusting for patient characteristics and hospital TAVR volume, new-onset AF remained associated with higher mortality compared with no AF (adjusted hazard ratio: 2.068, 95% confidence interval [CI]: 1.92 to 2.20; p < 0.01) and pre-existing AF (adjusted hazard ratio: 1.35; 95% CI: 1.26 to 1.45; p < 0.01). In competing risk analysis, new-onset AF was associated with higher risk of bleeding (subdistribution hazard ratio [sHR]: 1.66; 95% CI: 1.48 to 1.86; p < 0.01), stroke (sHR: 1.92; 95% CI: 1.63 to 2.26; p < 0.01), and HF (sHR: 1.98; 95% CI: 1.81 to 2.16; p < 0.01) compared with pre-existing AF.ConclusionsIn patients undergoing TAVR, new-onset AF is associated with increased risk of mortality and bleeding, stroke, and HF hospitalizations compared with pre-existing AF or no AF.     

Mitral Regurgitation in Low-Flow,Low-Gradient Aortic Stenosis Patients Undergoing TAVR: Insights From the TOPAS-TAVI Registry

ObjectivesThis study sought to determine the incidence, clinical impact, and changes over time of mitral regurgitation (MR) in patients with low-flow, low-gradient aortic stenosis (LFLG-AS) undergoing transcatheter aortic valve replacement (TAVR).BackgroundFew data exist on the clinical impact and changes in severity over time of MR in patients with LFLG-AS undergoing TAVR.MethodsA total of 308 TAVR candidates with LFLG-AS were included. Patients were categorized according to MR severity at baseline, and presence of MR improvement at 12-month follow-up. Clinical outcomes were assessed at 1 and 12 months (+ echocardiography), and yearly thereafter.ResultsBaseline mild and moderate-to-severe MR were present in 118 (38.3%) and 115 (37.3%) patients, respectively. MR was of functional and mixed etiology in 77.2% and 22.7% of patients, respectively. A total of 131 patients (42.5%) died after a median follow-up of 2 (1 to 3) years. Baseline moderate-or-greater MR had no impact on mortality (hazard ratio [HR]: 1.34; 95% confidence interval [CI]: 0.72 to 2.48) or heart failure hospitalization (HR: 1.02; 95% CI: 0.49 to 2.10). At 1-year follow-up, MR improved in 44.3% of patients and remained unchanged/worsened in 55.7%. The lack of MR improvement was associated with a higher risk of all-cause and cardiac mortality (HR: 2.02; 95% CI: 1.29 to 3.17; HR: 3.03; 95% CI: 1.27 to 7.23, respectively), rehospitalization for cardiac causes (HR: 1.50; 95% CI: 1.04 to 2.15), and an increased overall-mortality/heart failure rehospitalization (HR: 1.94; 95% CI: 1.25 to 3.02). A higher baseline left ventricular end-diastolic diameter and a higher increase in left ventricular ejection fraction were found to be independent predictors of MR improvement at 1-year follow-up (odds ratio: 0.69; 95% CI: 0.51 to 0.94; and odds ratio: 0.81; 95% CI: 0.67 to 0.96, respectively).ConclusionsMost TAVR candidates with LFLG-AS had some degree of MR, of functional origin in most cases. MR improved in about one-half of patients, with larger left ventricular size and a higher increase in left ventricular ejection fraction post-TAVR determining MR improvement over time. The lack of MR improvement at 1 year was associated with poorer outcomes.     

Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Complex Coronary Artery Disease

ObjectivesThe aim of this study was to compare, in a cohort of patients with complex coronary artery disease (CAD) and severe aortic stenosis (AS), the clinical outcomes associated with transfemoral transcatheter aortic valve replacement (TAVR) (plus percutaneous coronary intervention [PCI]) versus surgical aortic valve replacement (SAVR) (plus coronary artery bypass grafting [CABG]).BackgroundPatients with complex CAD were excluded from the main randomized trials comparing TAVR with SAVR, and no data exist comparing TAVR + PCI vs SAVR + CABG in such patients.MethodsA multicenter study was conducted including consecutive patients with severe AS and complex CAD (SYNTAX [Synergy Between PCI with Taxus and Cardiac Surgery] score >22 or unprotected left main disease). A 1:1 propensity-matched analysis was performed to account for unbalanced covariates. The rates of major adverse cardiac and cerebrovascular events (MACCE), including all-cause mortality, nonprocedural myocardial infarction, need for new coronary revascularization, and stroke, were evaluated.ResultsA total of 800 patients (598 undergoing SAVR + CABG and 202 undergoing transfemoral TAVR + PCI) were included, and after propensity matching, a total of 156 pairs of patients were generated. After a median follow-up period of 3 years (interquartile range: 1-6 years), there were no significant differences between groups for MACCE (HR for transfemoral TAVR vs SAVR: 1.33; 95% CI: 0.89-1.98), all-cause mortality (HR: 1.25; 95% CI: 0.81-1.94), myocardial infarction (HR: 1.16; 95% CI: 0.41-3.27), and stroke (HR: 0.42; 95% CI: 0.13-1.32), but there was a higher rate of new coronary revascularization in the TAVR + PCI group (HR: 5.38; 95% CI: 1.73-16.7).ConclusionsIn patients with severe AS and complex CAD, TAVR + PCI and SAVR + CABG were associated with similar rates of MACCE after a median follow-up period of 3 years, but TAVR + PCI recipients exhibited a higher risk for repeat coronary revascularization. Future trials are warranted.     

Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure

BackgroundMesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF).ObjectivesThis study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF.MethodsThis randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies. The primary endpoint was time-to-recurrent events caused by decompensated HFrEF or successfully resuscitated symptomatic ventricular arrhythmias. Hierarchical secondary endpoints included components of the primary endpoint, time-to-first terminal cardiac events, and all-cause death. Separate and composite major adverse cardiovascular events analyses were performed for myocardial infarction or stroke or cardiovascular death. Baseline and 12-month echocardiography was performed. Baseline plasma high-sensitivity C-reactive protein levels were evaluated for disease severity.ResultsThe primary endpoint was similar between treatment groups (HR: 1.17; 95% CI: 0.81-1.69; P = 0.41) as were terminal cardiac events and secondary endpoints. Compared with control subjects, MPCs increased left ventricular ejection fraction from baseline to 12 months, especially in patients with inflammation. MPCs decreased the risk of myocardial infarction or stroke by 58% (HR: 0.42; 95% CI: 0.23-0.76) and the risk of 3-point major adverse cardiovascular events by 28% (HR: 0.72; 95% CI: 0.51-1.03) in the analysis population (n = 537), and by 75% (HR: 0.25; 95% CI: 0.09-0.66) and 38% (HR: 0.62; 95% CI: 0.39-1.00), respectively, in patients with inflammation (baseline high-sensitivity C-reactive protein ≥2 mg/L).ConclusionsThe primary and secondary endpoints of the trial were negative. Positive signals in prespecified, and post hoc exploratory analyses suggest MPCs may improve outcomes, especially in patients with inflammation.     

Transcatheter Replacement of Transcatheter Versus Surgically Implanted Aortic Valve Bioprostheses

BackgroundSurgical aortic valve replacement and transcatheter aortic valve replacement (TAVR) are now both used to treat aortic stenosis in patients in whom life expectancy may exceed valve durability. The choice of initial bioprosthesis should therefore consider the relative safety and efficacy of potential subsequent interventions.ObjectivesThe aim of this study was to compare TAVR in failed transcatheter aortic valves (TAVs) versus surgical aortic valves (SAVs).MethodsData were collected on 434 TAV-in-TAV and 624 TAV-in-SAV consecutive procedures performed at centers participating in the Redo-TAVR international registry. Propensity score matching was applied, and 330 matched (165:165) patients were analyzed. Principal endpoints were procedural success, procedural safety, and mortality at 30 days and 1 year.ResultsFor TAV-in-TAV versus TAV-in-SAV, procedural success was observed in 120 (72.7%) versus 103 (62.4%) patients (p = 0.045), driven by a numerically lower frequency of residual high valve gradient (p = 0.095), ectopic valve deployment (p = 0.081), coronary obstruction (p = 0.091), and conversion to open heart surgery (p = 0.082). Procedural safety was achieved in 116 (70.3%) versus 119 (72.1%) patients (p = 0.715). Mortality at 30 days was 5 (3%) after TAV-in-TAV and 7 (4.4%) after TAV-in-SAV (p = 0.570). At 1 year, mortality was 12 (11.9%) and 10 (10.2%), respectively (p = 0.633). Aortic valve area was larger (1.55 ± 0.5 cm² vs. 1.37 ± 0.5 cm²; p = 0.040), and the mean residual gradient was lower (12.6 ± 5.2 mm Hg vs. 14.9 ± 5.2 mm Hg; p = 0.011) after TAV-in-TAV. The rate of moderate or greater residual aortic regurgitation was similar, but mild aortic regurgitation was more frequent after TAV-in-TAV (p = 0.003).ConclusionsIn propensity score–matched cohorts of TAV-in-TAV versus TAV-in-SAV patients, TAV-in-TAV was associated with higher procedural success and similar procedural safety or mortality.     

Valve-in-Valve Transcatheter Aortic Valve Replacement Versus Redo Surgical Aortic Valve Replacement: An Updated Meta-Analysis

ObjectivesThe aim of this study was to evaluate early results of valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) versus redo surgical aortic valve replacement (SAVR) for structural valve degeneration (SVD).BackgroundViV TAVR has been increasingly used for SVD, but it remains unknown whether it produces better or at least comparable results as redo SAVR.MethodsObservational studies comparing ViV TAVR and redo SAVR were identified in a systematic search of published research. Random-effects meta-analysis was performed, comparing clinical outcomes between the 2 groups.ResultsTwelve publications including a total of 16,207 patients (ViV TAVR, n = 8,048; redo SAVR, n = 8,159) were included from studies published from 2015 to 2020. In the pooled analysis, ViV TAVR was associated with lower rates of 30-day mortality overall (odds ratio [OR]: 0.52; 95% confidence interval [CI]: 0.39 to 0.68; p < 0.001) and for matched populations (OR: 0.419; 95% CI: 0.278 to 0.632; p = 0.003), major bleeding (OR 0.48; 95% CI: 0.28 to 0.80; p = 0.013), as well as with shorter hospital stay (OR: ?3.30; 95% CI: ?4.52 to ?2.08; p < 0.001). In contrast, ViV TAVR was associated with higher rates of severe patient-prosthesis mismatch (OR: 4.63; 95% CI: 3.05 to 7.03; p < 0.001). The search revealed an important lack of comparative studies with long-term results.ConclusionsViV TAVR is a valuable option in the treatment of patients with SVD because of its lower incidence of post-operative complications and better early survival compared with redo SAVR. However, ViV TAVR is associated with higher rates of myocardial infarction and severe patient-prosthesis mismatch.     

Prognostic Value of Computed Tomography–Derived Extracellular Volume in TAVR Patients With Low-Flow Low-Gradient Aortic Stenosis

ObjectivesThe association between extracellular volume (ECV) measured by computed tomography angiography (CTA) and clinical outcomes was evaluated in low-flow low-gradient (LFLG) aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR).BackgroundPatients with LFLG AS comprise a high-risk group with respect to clinical outcomes. Although ECV, a marker of myocardial fibrosis, is traditionally measured with cardiac magnetic resonance, it can also be measured using cardiac CTA. The authors hypothesized that in LFLG AS, increased ECV may be associated with adverse clinical outcomes.MethodsIn 150 LFLG patients with AS who underwent TAVR, ECV was quantified using pre-TAVR CTA. Echocardiographic and clinical information including all-cause death and heart failure rehospitalization (HFH) was obtained from electronic medical records. A Cox proportional hazards model was used to evaluate the association between ECV and death+HFH.ResultsDuring a median follow-up of 13.9 months (range 0.07 to 28.9 months), there were 31 death+HFH events (21%). Patients who experienced death+HFH had a greater median Society of Thoracic Surgery score (9.9 vs. 4.7; p < 0.01), lower left ventricular ejection fraction (42.3 ± 20.2% vs. 52.7 ± 17.2%; p < 0.01), lower mean transvalvular gradient (24.9 ± 8.9 mm Hg vs. 28.1 ± 7.3 mm Hg; p = 0.04) and increased mean ECV (35.5 ± 9.6% vs. 29.9 ± 8.2%; p < 0.01) compared with patients who did not experience death+HFH. In a multivariable Cox proportional hazards model, increase in ECV was associated with increase in death+HFH, (hazard ratio per 1% increase: 1.04, 95% confidence interval: 1.01 to 1.09; p < 0.01).ConclusionsIn patients with LFLG AS, CTA measured increase in ECV is associated with increased risk of adverse clinical outcomes post-TAVR and may thus serve as a useful noninvasive marker for prognostication.     

Subphenotyping of Patients With Aortic Stenosis by Unsupervised Agglomerative Clustering of Echocardiographic and Hemodynamic Data

ObjectivesThe aim of this retrospective analysis was to categorize patients with severe aortic stenosis (AS) according to clinical presentation by applying unsupervised machine learning.BackgroundPatients with severe AS present with heterogeneous clinical phenotypes, depending on disease progression and comorbidities.MethodsUnsupervised agglomerative clustering was applied to preprocedural data from echocardiography and right heart catheterization from 366 consecutively enrolled patients undergoing transcatheter aortic valve replacement for severe AS.ResultsCluster analysis revealed 4 distinct phenotypes. Patients in cluster 1 (n = 164 [44.8%]), serving as a reference, presented with regular cardiac function and without pulmonary hypertension (PH). Accordingly, estimated 2-year survival was 90.6% (95% CI: 85.8%-95.6%). Clusters 2 (n = 66 [18.0%]) and 4 (n = 91 [24.9%]) both comprised patients with postcapillary PH. Yet patients in cluster 2 with preserved left and right ventricular structure and function showed a similar survival as those in cluster 1 (2-year survival 85.8%; 95% CI: 76.9%-95.6%), whereas patients in cluster 4 with dilatation of all heart chambers and a high prevalence of mitral and tricuspid regurgitation (12.5% and 14.8%, respectively) died more often (2-year survival 74.9% [95% CI: 65.9%-85.2%]; HR for 2-year mortality: 2.8 [95% CI: 1.4-5.5]). Patients in cluster 3, the smallest (n = 45 [12.3%]), displayed the most extensive disease characteristics (ie, left and right heart dysfunction together with combined pre- and postcapillary PH), and 2-year survival was accordingly reduced (77.3% [95% CI: 65.2%-91.6%]; HR for 2-year mortality: 2.6 [95% CI: 1.1-6.2]).ConclusionsUnsupervised machine learning aids in capturing complex clinical presentations as observed in patients with severe AS. Importantly, structural alterations in left and right heart morphology, possibly due to genetic predisposition, constitute an equally sensitive indicator of poor prognosis compared with high-grade PH.     

Prognosis of Severe Low-Flow,Low-Gradient Aortic Stenosis by Stroke Volume Index and Transvalvular Flow Rate

ObjectivesThis study determined whether flow state classified by stroke volume index (SVi) or transvalvular flow rate (FR) improved risk stratification of all-cause mortality, hospitalization due to heart failure, and aortic valvular interventions for patients with severe aortic stenosis (AS).BackgroundSVi is a widely accepted classification for flow state in severe low-flow, low-gradient (LFLG) AS. Recent studies suggest that FR more closely approximates true AS severity and provides more useful prognostication than SVi.MethodsPatients with severe AS over a 7-year period were subclassified by echocardiographic parameters. LFLG-AS was defined as severe AS (aortic valve area index [AVAi]: <0.6 cm²/m²), with a mean transvalvular pressure gradient of <40 mm Hg in the setting of low flow state: SVi of <35 ml/m² and/or FR of <200 ml/s and subclassified into preserved (≥50%; paradoxical) or reduced (<50%; classical) left ventricular ejection fraction (LVEF).ResultsAmong 621 consecutive patients with severe AS, the proportions of patients classified as LFLG-AS were different between SVi and FR (p < 0.001). Classification using SVi, FR, and LVEF was a strong predictor of the composite endpoint at the 2-year follow-up. The addition of SVi to the echocardiographic and clinical model provided significant improvement in reclassification (net reclassification improvement: 0.089; 95% confidence interval [CI]: 0.045 to 0.133; p = 0.04), whereas addition of FR did not (net reclassification improvement: 0.061; 95% CI: 0.016 to 0.106; p = 0.17). C-statistics indicated improved risk discrimination when AVAi, LVEF, and SVi or FR were added as predictive variables to the clinical model (p = 0.006).ConclusionsLow SVi or FR was associated with adverse cardiovascular events and showed improvement in discrimination, but only SVi, not FR, significantly improved risk reclassification compared to other conventional clinical and echocardiographic predictors. This suggests that FR is not superior to SVi in distinguishing true severe from pseudosevere forms of AS and identification of patients with LFLG-AS who have worse outcomes.