Dobutamine Stress Echocardiography in Low-Gradient Aortic Stenosis.

IMPORTANCE: Guidelines recommend the use of Dobutamine stress echocardiography (DSE) in patients with low-gradient aortic stenosis (AS) and left ventricular ejection fraction (LVEF) <50%. However, a paucity exists in DSE data when LVEF>35%. OBJECTIVE: To examine the diagnostic accuracy of DSE, in patients with low-gradient AS with a wide range of LVEF and to examine the interaction between the diagnostic accuracy of DSE and LVEF. DESIGN, SETTING AND PARTICIPANTS: Patients with mean-gradient<40 mmHg, AVA<1.0 cm2, and stroke volume index≤35 mL/m2 undergoing DSE and Cardiac Computer Tomography (C-CT) were identified from three prospectively collected patient cohorts, and stratified according to LVEF; LVEF<35%, LVEF 35-50% & LVEF>50%. EXPOSURE: DSE and C-CT was performed on patients with low-gradient AS MAIN OUTCOMES AND MEASURES: Severe AS was defined as AVC score ≥2000 AU among men, and ≥1200 AU for women on C-CT. RESULTS: Of 221 patients included in the study, 78 (35%) presented with LVEF<35%, 67 (30%) with LVEF 35-50%, and 76 (34%) with LVEF>50%. Mean-gradient and Vmax during DSE showed significantly diagnostic heterogeneity between LVEF groups, being most precise when LVEF<35% (both AUC=0.90), albeit with optimal thresholds of 30 mmHg & 377 cm/s, and a limited diagnostic yield in patients with LVEF≥35% (AUC=0.67 & 0.66 in LVEF 35-50% and AUC=0.65 & 0.60 in LVEF≥50%). Using guideline thresholds led to a sensitivity/specificity of 49%/84% for all patients with LVEF<50%. CONCLUSION AND RELEVANCE: While DSE is safe and leads to an increase in stroke volume in patients with low-gradient AS regardless of LVEF, the association between DSE gradients and AS severity assessed by C-CT demonstrates important heterogeneity depending on LVEF, with highest accuracy in patients with LVEF<35%.

Grading of Aortic Valve Calcification Severity and Risk Stratification in Aortic Stenosis.

BACKGROUND: Thresholds of aortic valve calcification (AVC) to define hemodynamically moderate aortic stenosis (AS) from mild are lacking. We aimed to establish a novel grading classification of AVC as quantified by computed tomography and determine its prognostic value. METHODS AND RESULTS: This study included 915 patients with at least mild AS (mean age 70±12 years, 30% women) from a multicenter prospective registry. All patients underwent Doppler-echocardiography and noncontrast computed tomography within 3 months. Primary end point was the occurrence of all-cause death. Receiver operating characteristic curves analyses were used to determine the sensitivity and specificity of sex-specific thresholds of AVC to identify hemodynamically moderate AS. Optimal thresholds (ie, with best sensitivity/specificity) of AVC to distinguish moderate (aortic valve area 1.0-1.5 cm2 and mean gradient 20-39 mm Hg) from mild AS (aortic valve area >1.5 cm2 and mean gradient <20 mm Hg) were AVC ≥360 arbitrary units in women and ≥1037 arbitrary units in men. Based on the guidelines' thresholds for severe AS and the new thresholds in our study for moderate AS, 312 (34%) patients had mild, 253 (28%) moderate, and 350 (38%) severe AVC. During a mean follow-up of 5.6±3.9 years, 183 (27%) deaths occurred. In Cox multivariable models, AVC remained associated with an increased risk of death (adjusted hazard ratio per grade increase, 1.94 [95% CI, 1.53-2.56]; P<0.001). CONCLUSIONS: A novel grading classification of anatomic AS severity based on sex-specific thresholds of AVC provides significant prognostic value for predicting mortality. These findings support the complementarity of computed tomography-calcium scoring to Doppler-echocardiography to corroborate AS severity and enhance risk stratification in patients with AS.

Cardiac Damage in Early Aortic Stenosis: Is the Valve to Blame?

BACKGROUND: Despite the close association between aortic stenosis (AS) and cardiac damage (CD), it is unclear if CD is limited to patients with moderate and severe AS and which factors affect its progression. Although altered valvular hemodynamic status may drive the development of CD in AS, commonly occurring comorbidities may contribute. OBJECTIVES: The aim of this study was to determine the prevalence of and factors associated with CD in mild AS. METHODS: This retrospective study included 9,611 patients with mild AS (peak aortic valve velocity [Vmax] 2-3 m/s and description of abnormal aortic valve) from 2010 through 2021. CD was staged using the Genereux classification. RESULTS: All but 20% (n = 1,901; stage 0) of patients with mild AS demonstrated CD: 1,613 (17%) stage 1, 4,843 (50%) stage 2, 891 (9%) stage 3, and 363 (4%) stage 4. Patients with higher stages had more comorbidities (hypertension, heart failure, ischemic heart disease, stroke, peripheral arterial disease, chronic kidney disease, chronic pulmonary disease, and diabetes mellitus) but had valvular hemodynamic status similar to those without CD. CD stage did not worsen with higher Vmax range (stage >1 in 64% with Vmax <2.5 m/s vs 61% with Vmax ≥2.5 m/s) but increased with the number of comorbidities, with stage >1 occurring in 50%, 53%, 60%, 66%, 72%, and 73% in the presence of 0, 1, 2, 3, 4, and 5 or more comorbidities, respectively. CONCLUSIONS: CD was highly prevalent in patients with mild AS. Among patients with mild AS, there was no relationship between the degree of CD and AS severity; instead, CD was highly associated with comorbidities.

Low body mass index and risk of mortality after mitral transcatheter edge-to-edge repair procedure: The "obesity paradox".

BACKGROUND: Most patients undergoing the mitral transcatheter edge-to-edge repair (TEER) technique are elderly comorbid patients. Low body mass index (BMI) < 23 kg/m2 has been identified in other elderly populations as a risk factor, but has not been studied sufficiently in mitral TEER. AIMS: We aimed to study the impact of low BMI (23 kg/m2) on the outcome after mitral TEER. METHODS: Patients undergoing first-time TEER for mitral regurgitation at a single tertiary center were included, with the exclusion of patients with preprocedural hemodynamic instability or missing BMI. The primary endpoint was all-cause mortality. Secondary endpoints were long-term major bleeding or admission with heart failure. RESULTS: A total of 120 patients (mean age 76 ± 10 years, 76% men) were included in the study. Thirty-nine (31%) had low BMI. Patients with low BMI had a similar symptomatic benefit as patients with BMI ≥ 23 kg/m2 at 1 year regarding decrease in diuretics dose and decrease in New York Heart Association (NYHA) class (p > 0.05). In a multivariable Cox regression analysis, BMI as a continuous variable (hazard ratio [HR]: 0.93 [95% confidence interval, CI: 0.87-0.99], p = 0.03) and low BMI (HR: 1.99 [95% CI: 1.12-3.52], p = 0.02) were associated with the primary outcome. Low BMI was not significantly associated with major bleeding (subdistribution hazard ratio [SHR]: 2.39 [95% CI: 0.96-5.97], p = 0.06) or admission with heart failure (SHR: 1.06 [95% CI: 0.61-1.88], p = 0.83) during follow-up with univariable competing risk regression analysis. CONCLUSION: Low BMI is a risk factor for mortality after mitral valve TEER, confirming the presence of an "obesity paradox" in this population and should receive attention in patient selection.

Aortic Valve Calcification Density Measured by MDCT in the Assessment of Aortic Stenosis Severity.

BACKGROUND: Aortic valve calcification (AVC) indexation to the aortic annulus (AA) area measured by Doppler echocardiography (AVCdEcho) provides powerful prognostic information in patients with aortic stenosis (AS). However, the indexation by AA measured by multidetector computed tomography (AVCdCT) has never been evaluated. The aim of this study was to compare AVC, AVCdCT, and AVCdEcho with regard to hemodynamic correlations and clinical outcomes in patients with AS. METHODS: Data from 889 patients, mainly White, with calcific AS who underwent Doppler echocardiography and multidetector computed tomography within the same episode of care were retrospectively analyzed. AA was measured both by Doppler echocardiography and multidetector computed tomography. AVCdCT severity thresholds were established using receiver operating characteristic curve analyses in men and women separately. The primary end point was the occurrence of all-cause mortality. RESULTS: Correlations between gradient/velocity and AVCd were stronger (both P≤0.005) using AVCdCT (r=0.68, P<0.001 and r=0.66, P<0.001) than AVC (r=0.61, P<0.001 and r=0.60, P<0.001) or AVCdEcho (r=0.61, P<0.001 and r=0.59, P<0.001). AVCdCT thresholds for the identification of severe AS were 334 Agatston units (AU)/cm2 for women and 467 AU/cm2 for men. On a median follow-up of 6.62 (6.19-9.69) years, AVCdCT ratio was superior to AVC ratio and AVCdEcho ratio to predict all-cause mortality in multivariate analyses (hazard ratio [HR], 1.59 [95% CI, 1.26-2.00]; P<0.001 versus HR, 1.53 [95% CI, 1.11-1.65]; P=0.003 versus HR, 1.27 [95% CI, 1.11-1.46]; P<0.001; all likelihood test P≤0.004). AVCdCT ratio was superior to AVC ratio and AVCdEcho ratio to predict survival under medical treatment in multivariate analyses (HR, 1.80 [95% CI, 1.27-1.58]; P<0.001 compared with HR, 1.55 [95% CI, 1.13-2.10]; P=0.007; HR, 1.28 [95% CI, 1.03-1.57]; P=0.01; all likelihood test P<0.03). AVCdCT ratio predicts mortality in all subgroups of patients with AS. CONCLUSIONS: AVCdCT appears to be equivalent or superior to AVC and AVCdEcho to assess AS severity and predict all-cause mortality. Thus, it should be used to evaluate AS severity in patients with nonconclusive echocardiographic evaluations with or without low-flow status. AVCdCT thresholds of 300 AU/cm2 for women and 500 AU/cm2 for men seem to be appropriate to identify severe AS. Further studies are needed to validate these thresholds, especially in diverse populations.

Angiotensin II Receptor Blockers Are Associated With Reduced Valvular Fibrosis in Women With Aortic Stenosis.

BACKGROUND: Angiotensin receptor blockers (ARBs) may slow down the progression of aortic stenosis (AS) through their antifibrotic effect. Women present more valvular fibrosis than men, so ARBs may have more effect in females. Our aim was to assess the impact of ARBs on the remodelling of the aortic valve in men and women. METHODS: We included patients who had an aortic valve replacement with or without coronary bypass grafting from 2006 to 2013. Patients with missing echocardiographic or histologic data were excluded. Warren-Yong and fibrosis scores of the explanted valves were performed. Patients were divided into 4 phenotypes according to their Warren-Yong and fibrosis scores: mild calcification/fibrosis, severe calcification/fibrosis group, predominant fibrosis group, predominant calcification group. RESULTS: Among the 1321 included patients, the vast majority (89%) has severe AS. Patients in the predominant fibrosis group, compared with the predominant calcium group, were more often female (39% vs 31%; P = 0.008) with bicuspid valves (44% vs 34%; P = 0.002), and less often used ARBs (25% vs 30%; P = 0.046). Female sex was independently associated with being in the predominant fibrosis group (odds ratio 1.45, 95% confidence interval 1.08-1.95; P = 0.01), with a significant interaction between female sex and ARBs. Women taking ARBs compared with women not taking ARBs had significantly lower fibrosis scores (P < 0.001). This difference was not seen in men. CONCLUSIONS: In this large series of patients with moderate-severe AS, among the women there was a negative association between intake of ARBs and valvular fibrosis. Thus, the possible effects of ARBs may be sex specific, with a larger therapeutic role in women.

Atorvastatin and the influence on postoperative atrial fibrillation after surgical aortic valve replacement (STARC) in adults at Odense University Hospital, Denmark: study protocol for a randomised controlled trial.

INTRODUCTION: Atrial fibrillation (AF) is the most common postoperative complication after surgical aortic valve replacement (SAVR) and occurs in up to 50% of the patients. Development of postoperative AF (POAF) is associated with a 2-3 fold increased risk of adverse events, including stroke, myocardial infarction and death.Several studies have implied that prophylactic Atorvastatin therapy could prevent POAF in patients undergoing coronary artery bypass graft. These studies suggest that Atorvastatin has rapid and significant pleiotropic actions that reduce the risk of POAF. However, prophylactic treatment with statins has yet to be understood in SAVR. The aim of this study is to investigate whether prophylactic administration of torvastatin reduces POAF in patients undergoing SAVR. METHODS AND ANALYSIS: In this investigator-initiated, prospective, parallel-group, randomised, double-blind, placebo-controlled single-centre trial, 266 patients undergoing elective solitary SAVR with bioprosthetic valve, with no prior history of AF, and statin-naïve will be randomised (1:1) to treatment with Atorvastatin (80 mg once daily) or matching placebo for 1-2 weeks prior to and 30 days after surgery. The primary endpoint is POAF defined as an episode of irregular RR-intervals without a traceable p-wave of at least 30 s duration. After discharge and until day 30 after surgery, POAF will be documented by either rhythm strip or 12-lead ECG. ETHICS AND DISSEMINATION: Protocol approval has been obtained from the Regional Scientific Ethical Committee for Southern Denmark (S-20210159), The Danish Medicines Agency (2021103821) and the Data Protection Agency (21/65621).The trial is conducted in accordance with the Declaration of Helsinki, the ICH-GCP (International Conference on Harmonisation Good Clinical Practice) guidelines and the legal regulations of Denmark. Study findings will be shared via peer-reviewed journal publication and conference presentations. TRIAL REGISTRATION NUMBER: NCT05076019.

The effect of empagliflozin on contractile reserve in heart failure: Prespecified sub-study of a randomized, double-blind, and placebo-controlled trial.

BACKGROUND: Sodium-glucose co-transporter-2 inhibitors improve cardiac structure but most studies suggest no change in left ventricular (LV) systolic function at rest. Whether sodium-glucose co-transporter-2 inhibitors improve LV contractile reserve is unknown. We investigated the effect of empagliflozin on LV contractile reserve in patients with heart failure (HF) and reduced ejection fraction. METHODS: Prespecified sub-study of the Empire HF trial, a double-blind, placebo-controlled, and randomized trial. Patients with LV ejection fraction (LVEF) ≤ 40% on guideline-directed HF therapy were randomized (1:1) to empagliflozin 10 mg or placebo for 12 weeks. The treatment effect on contractile reserve was assessed by low dose dobutamine stress echocardiography. RESULTS: In total, 120 patients were included. The mean age was 68 (SD 10) years, 83% were male, and the mean LVEF was 38 (SD 10) %. Respectively 60 (100%) and 59 (98%) patients in the empagliflozin and placebo groups completed stress echocardiography. No statistically significant effect of empagliflozin was observed for the contractile reserve assessed by LV-GLS (adjusted mean absolute change, empagliflozin vs placebo, 0.7% [95% confidence interval {CI} -0.5 to 2.0, P = .25]) or LVEF (adjusted mean absolute change, empagliflozin vs placebo, 2.2% [95% CI -1.4 to 5.8, P = .22]) from baseline to 12 weeks. LV-GLS contractile reserve was associated with accelerometer-measured daily activity level (coefficient -24 accelerometer counts [95% CI -46 to -1.8, P = .03]). CONCLUSIONS: Empagliflozin for 12 weeks added to guideline-directed HF therapy did not improve LV contractile reserve in patients with HF and reduced ejection fraction.

Assessment of diastolic function in aortic stenosis: A comparison between 2009 and 2016 guidelines.

AIMS: New diastolic dysfunction (DD) guidelines were introduced in 2016 to replace the 2009 guidelines, but have not yet been evaluated in aortic stenosis (AS). We aimed to compare the 2009 and 2016 DD guidelines in severe AS patients in terms of association with left ventricular (LV) and left atrial (LA) remodeling, with pulmonary capillary wedge pressure (PCWP) at rest and exercise, and with prognosis. METHODS AND RESULTS: We included 212 patients with severe AS (112 undergoing AVR, 100 asymptomatic). Echocardiography, magnetic resonance imaging, and brain natriuretic peptides (BNP) were performed/measured. Thirty-nine asymptomatic patients had PCWP measured during rest and maximal exertion. Asymptomatic patients were followed for 3.1 years for the combined endpoint of death, AVR or admission with heart failure. The 2009 and 2016 DD guidelines agreed poorly with each other (Cohens' κ = .15). 2009 guidelines showed many ambiguous DD findings. With the 2016 guidelines, 20% of patients had indeterminate DD. DD grade 2 according to 2016 guidelines showed stronger association with symptom status, BNP, global longitudinal strain (GLS) and peak exercise PCWP than 2009 guidelines. For indeterminate DD patients according to 2009 guidelines, GLS above the median was associated with event-free survival (HR .11 (95% CI .02-.53)). For neither guideline was DD associated with the combined endpoint in asymptomatic patients. CONCLUSION: The 2016 guidelines show a stronger association with BNP, GLS, and exercise PCWP than the 2009 guidelines. The 2016 guidelines result in 20% of patients with indeterminate DD; however, these patients may possibly be stratified according to GLS.

First-phase ejection fraction: association with remodelling and outcome in aortic valve stenosis.

BACKGROUND: First-phase ejection fraction (EF1), the left ventricular (LV) ejection fraction (EF) until the time of peak transaortic velocity, is a novel marker of subclinical LV dysfunction able to predict adverse events in aortic stenosis (AS). This study investigated the association between end-systolic wall stress (ESWS) and EF1 in severe AS, as well as the prognostic value of EF1 in severe asymptomatic AS. METHODS: Two prospectively gathered cohorts of 94 asymptomatic patients and 108 symptomatic patients scheduled for aortic valve replacement (AVR), all with severe AS (aortic valve area <1 cm2) were stratified according to the median value of EF1 (33%). EF1 was defined as the EF at peak transaortic velocity. Asymptomatic patients were followed up for 3 years for the combined end-point of death, AVR or admission with heart failure. RESULTS: EF1 correlated with EF and was inversely associated with ESWS. In multivariate regression analysis, ESWS (p<0.001) and replacement fibrosis measured by MRI (p=0.02) were associated with EF1. Among asymptomatic patients, EF1 above the median was associated with the combined primary endpoint (HR=0.53 (95% CI 0.33 to 0.87)), while global longitudinal strain and EF were not. Among 42 patients with discordant AS (mean gradient <40 mm Hg), EF1 above median was associated with the primary endpoint (HR 0.28 (95% CI 0.12 to 0.61)). CONCLUSION: EF1 is an afterload-dependent measure that is associated with events in patients with asymptomatic severe AS. The afterload dependency of EF1 may be useful in timing of risk stratification in patients with discordant AS. TRIAL REGISTRATION NUMBERS: NCT02395107 and NCT02316587.

Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial.

Importance: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve outcomes in patients with heart failure and a reduced ejection fraction (HFrEF). The association with cardiac remodeling has not been investigated. Objective: To investigate the outcome of the SGLT2i empagliflozin, compared with placebo, on cardiac remodeling in patients with HFrEF. Design, Setting, and Participants: This exploratory post hoc analysis included participants with stable HFrEF and ejection fractions of 40% or less, who were randomly enrolled in an investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trial in Denmark. Enrollment commenced on June 29, 2017, and continued through September 10, 2019, with the last participant follow-up on December 20, 2019. Interventions: Randomization (1:1) to empagliflozin (10 mg once daily) or matching placebo in addition to recommended heart failure therapy for 12 weeks. Main Outcomes and Measures: Efficacy measures were changes from baseline to week 12 in left ventricular end-systolic and end-diastolic volume indexes, left atrial volume index, and left ventricular ejection fraction adjusted for age, sex, type 2 diabetes, and atrial fibrillation. Secondary efficacy measures included changes in left ventricular mass index, global longitudinal strain, and relative wall thickness. Results: A total of 190 patients were randomized (95 each receiving empagliflozin and placebo), with a mean (SD) age of 64 (11) years; 162 were men (85.3%), 97 (51.1%) had ischemic HFrEF, 24 (12.6%) had type 2 diabetes, and the mean (SD) latest recorded left ventricular ejection fraction was 29% (8%). Of the 190, 186 completed the study. Empagliflozin significantly reduced left ventricular end-systolic volume index (-4.3 [95% CI, -8.5 to -0.1] mL/m2; P = .04), left ventricular end-diastolic volume index (-5.5 [95% CI, -10.6 to -0.4] mL/m2; P = .03), and left atrial volume index (-2.5 [95% CI, -4.8 to -0.1] mL/m2; P = .04) compared with placebo at 12 weeks' follow-up, with no change in left ventricular ejection fraction (1.2% [95% CI, -1.2% to 3.6%]; P = .32). These findings were consistent across subgroups. Of secondary efficacy measures, left ventricular mass index was significantly reduced by empagliflozin (-9.0 [95% CI, -17.2 to -0.8] g/m2; P = .03). Conclusions and Relevance: In this small, randomized, short-term study, empagliflozin was associated with modest reductions in left ventricular and left atrial volumes with no association with ejection fraction. Effects beyond 12 weeks of SGLT2i use require further study. Trial Registration: ClinicalTrials.gov Identifier: NCT03198585.

Effect of Empagliflozin on Hemodynamics in Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Inhibition of the sodium-glucose cotransporter-2 (SGLT2i) improves outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but the mechanism by which they improve outcomes remains unclear. OBJECTIVES: This study aimed to investigate the effects of sodium-glucose cotransporter-2 inhibitor empagliflozin on central hemodynamics in patients with HF and HFrEF. METHODS: This investigator-initiated, double-blinded, placebo-controlled, randomized trial enrolled 70 patients with HFrEF from March 6, 2018, to September 10, 2019. Patients were assigned to empagliflozin of 10 mg or matching placebo once daily on guideline-driven HF therapy for 12 weeks. The primary outcome was ratio of pulmonary capillary wedge pressure (PCWP) to cardiac index (CI) at peak exercise after 12 weeks. Patients underwent right-heart catheterization at rest and during exercise at baseline and 12-week follow-up. RESULTS: Patients with HFrEF, mean age of 57 years, mean left-ventricular ejection fraction, 26%, and 12 (17%) with type 2 diabetes mellitus were randomized. There was no significant treatment effect on peak PCWP/CI (-0.13 mm Hg/l/min/m2; 95% confidence interval: -1.60 to 1.34 mm Hg/l/min/m2; p = 0.86). Considering hemodynamics over the full range of exercise loads, PCWP was significantly reduced (-2.40 mm Hg; 95% confidence interval: -3.96 to -0.84 mm Hg; p = 0.003), but not CI (-0.09 l/min/m2; 95% confidence interval: -0.14 to 0.32 l/min/m2; p = 0.448) by empagliflozin. This was consistent among patients with and without type 2 diabetes. CONCLUSIONS: Among patients with stable HFrEF, empagliflozin for 12 weeks reduced PCWP compared with placebo. There was no significant improvement in neither CI nor PCWP/CI at rest or exercise.

Induction of autoimmune abdominal aortic aneurysm in pigs - A novel large animal model.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a common disease with a high mortality. Many animal models have been developed to further understand the pathogenesis of the disease, but no large animal model has been developed to investigate the autoimmune aspect of AAA formation. The aim of this study was to develop a large animal model for abdominal aortic aneurysm induction through autoimmunity by performing sheep-to-pig xenotransplantation. METHODS: Six pigs underwent a xenotransplantation procedure where the infrarenal porcine aorta was replaced by a decellularized sheep aorta. In the following 47 days, the AP-diameter of the xenografts was measured using ultrasound once a week. All xenografts were harvested for histological analyses. RESULTS: All the xenografts formed aneurysms with a mean increase in AP-diameter of 80.98 ± 30.20% (p < 0.005). The ultrasound measurements demonstrated a progressive aneurysmal expansion with no sign of halting towards the end of the follow-up period. Histology showed destruction of tunica media and the elastic tissue, neointimal hyperplasia, adventitial thickening with neovascularization, infiltration of lymphocytes and granulocytes, and in some cases intramural haemorrhaging. CONCLUSION: We developed a novel large animal AAA model by infrarenal aortic sheep-to-pig xenograph transplantation resulting in autoimmune AAA induction with continuously progressive aneurysmal growth. This model can be used to provide a better understand the autoimmune aspect of AAA formation in large animals.