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An inflammatory process may increase the risk of arrhythmias after transcatheter aortic valve replacement (TAVR). In this single-centre, double-blind, placebo-controlled, randomized trial we investigated the efficacy of colchicine to reduce a composite of new-onset atrial fibrillation or atrioventricular conduction disturbances requiring the implantation of a permanent pacemaker at 30 days after TAVR. Between September 21, 2021 and April 25, 2024, 120 patients with aortic stenosis undergoing TAVR (mean age 80.6 ± 5 years, 64% male) were randomly allocated to treatment with colchicine ( n  = 60) or placebo ( n  = 60). The trial was prematurely stopped due to a higher rate of stroke in the experimental group in a pre-specified interim analysis (5 [8.3%] versus 0 at maximum available follow-up, p  = 0.022). In the intention-to-treat population, the primary endpoint occurred in 6 patients (10%) in the colchicine group and in 15 patients (25%) in the placebo group (risk-difference −15.0%, 95% CI −28.3 to −1.7, p  = 0.031). The prespecified imaging endpoint, subclinical leaflet thrombosis, was detected in 13 of 48 patients (27%) in the colchicine group versus 26 of 48 patients (54%) in the placebo group (risk difference −27.1%. 95% CI −46.0% to −8.2%, p  = 0.007). Here, we show that periprocedural treatment with colchicine may reduce the incidence of new-onset arrhythmias and subclinical leaflet thrombosis after TAVR. However, given the premature termination of the trial due to an unexpected increase in the stroke rate among patients treated with colchicine, confirmatory trials are warranted to corroborate the effect of anti-inflammatory treatment on the incidence of arrhythmias and subclinical leaflet thrombosis after TAVR. The trial was an investigator-initiated study supported by dedicated grants from the Bangerter-Rhyner Foundation and the Swiss Life Foundation. ClinicalTrials.gov Identifier: NCT04870424. An inflammatory process may increase the risk of arrhythmias after transcatheter aortic valve replacement. Here, the authors show that periprocedural treatment with colchicine may reduce the incidence of new-onset arrhythmias and subclinical leaflet thrombosis after transcatheter aortic valve replacement.

•Inflammation is a key driver in the pathogenesis of aortic valve stenosis (AS).•CHIANTI is a placebo-controlled, randomized trial of low-dose colchicine in AS.•Advanced CT and 18F-NaF PET-CT imaging offer new insights into AS pathophysiology. Aortic valve stenosis (AS) is one of the most common valvular heart diseases worldwide. Its prevalence increases with age and is expected to rise further as the population ages. Untreated severe AS carries a 2-year mortality rate exceeding 50%. Furthermore, surveillance and management of AS impose a significant burden on healthcare systems. Therefore, effective pharmacological strategies are urgently needed to slow or halt the progression of AS. Inflammation plays a central role in the pathogenesis of both atherosclerosis and AS. Anti-inflammatory therapy with low-dose colchicine reduces cardiovascular events in patients with coronary artery disease, but its efficacy has not been tested in AS. Colchicine and Inflammation in Aortic Stenosis (CHIANTI) is an investigator-initiated, placebo-controlled, double-blind, multicenter, randomized trial involving 150 patients with moderate AS. After confirming tolerance during a two-week run-in phase, eligible participants underwent coronary computed tomography (CT) angiography, 18F-sodium fluoride (18F-NaF) positron emission tomography (PET)-CT, and echocardiography. Thereafter, participants were randomized 1:1 to colchicine 0.5 mg once daily or a matching placebo. All baseline imaging is repeated after 24 months. The primary endpoint is the change in aortic valve calcium score on CT. Secondary endpoints are (1) the change in aortic valve 18F-NaF uptake on PET-CT and corrected for target-to-background ratio, and (2) the change in peak aortic jet velocity on echocardiography. The CHIANTI trial evaluates whether anti-inflammatory therapy with low-dose colchicine can slow or halt the progression of moderate AS. If successful, it would offer the first effective pharmacological treatment for AS. Registered on ClinicalTrials.gov (https://clinicaltrials.gov/), ID: NCT05162742.

In this randomized, placebo-controlled trial, the combination of simvastatin and ezetimibe had no effect on the progression of aortic stenosis, despite substantial lowering of low-density lipoprotein cholesterol. There was a reduction in the need for coronary bypass surgery in the simvastatin–ezetimibe group, but unexpectedly, active treatment was also associated with an increased incidence of cancer. The combination of simvastatin and ezetimibe had no effect on the progression of aortic stenosis, despite substantial lowering of low-density lipoprotein cholesterol. Unexpectedly, active treatment was also associated with an increased incidence of cancer. Aortic-valve stenosis is common in elderly persons, with a prevalence of 3 to 5% in the population over 75 years of age. 1 , 2 The condition has been shown to be an inflammatory process associated with cardiovascular risk factors, with histopathological changes in the valve leaflets that are similar to those in other atherosclerotic diseases. 2 – 19 Changes in the aortic valve are associated with an increased risk of death from cardiovascular causes and myocardial infarction, even in the absence of hemodynamic obstruction and signs of coronary disease. 20 – 22 The standard treatment is surgical replacement when the valve becomes severely stenotic. 23 , . . .

ObjectiveSex differences in risk factors of aortic valve calcification (AVC) by echocardiography have not been reported from a large prospective study in aortic stenosis (AS).MethodsAVC was assessed using a prognostically validated visual score and grouped into none/mild or moderate/severe AVC in 1725 men and women with asymptomatic AS in the Simvastatin Ezetimibe in Aortic Stenosis study. The severity of AS was assessed by the energy loss index (ELI) taking pressure recovery in the aortic root into account.ResultsMore men than women had moderate/severe AVC at baseline despite less severe AS by ELI (p<0.01). Moderate/severe AVC at baseline was independently associated with lower aortic compliance and more severe AS in both sexes, and with increased high-sensitive C reactive protein (hs-CRP) only in men (all p<0.01). In Cox regression analyses, moderate/severe AVC at baseline was associated with a 2.5-fold (95% CI 1.64 to 3.80) higher hazard rate of major cardiovascular events in women, and a 2.2-fold higher hazard rate in men (95% CI 1.54 to 3.17) (both p<0.001), after adjustment for age, hypertension, study treatment, aortic compliance, left ventricular (LV) mass and systolic function, AS severity and hs-CRP. Moderate/severe AVC at baseline also predicted a 1.8-fold higher hazard rate of all-cause mortality in men (95% CI 1.04 to 3.06, p<0.05) independent of age, AS severity, LV mass and aortic compliance, but not in women.ConclusionIn conclusion, AVC scored by echocardiography has sex-specific characteristics in AS. Moderate/severe AVC is associated with higher cardiovascular morbidity in both sexes, and with higher all-cause mortality in men.Trial registration numberClinicalTrials.gov identifier: NCT00092677

Observational studies indicate that low-density lipoprotein (LDL) cholesterol acts as a primary contributor to an active process leading to aortic stenosis (AS) development. However, randomized clinical trials have failed to demonstrate an effect of lipid lowering on impeding AS progression. This study explored if pretreatment LDL levels and AS severity altered the efficacy of lipid-lowering therapy. The study goal was evaluated in the analysis of surviving patients with baseline data in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial of 1,873 asymptomatic patients with mild-to-moderate AS. Serially measured peak aortic jet velocity was the primary effect estimate. Linear mixed model analysis adjusted by baseline peak jet velocity and pretreatment LDL levels was used to assess effect modifications of treatment. Data were available in 1,579 (84%) patients. In adjusted analyses, lower baseline peak aortic jet velocity and higher pretreatment LDL levels increased the effect of randomized treatment (p = 0.04 for interaction). As such, treatment impeded progression of AS in the highest quartile of LDL among patients with mild AS at baseline (0.06 m/s per year slower progression vs placebo in peak aortic jet velocity, 95% confidence interval 0.01 to 0.11, p = 0.03), but not in the 3 other quartiles of LDL. Conversely, among patients with moderate AS, there was no detectable effect of treatment in any of the pretreatment LDL quartiles (all p ≥0.14). In conclusion, in a non–prespecified post hoc analysis, the efficacy of lipid-lowering therapy on impeding AS progression increased with higher pretreatment LDL and lower peak aortic jet velocity (SEAS study: NCT00092677).

Calcific aortic stenosis, a relatively common problem in the elderly, has been found to be associated with atherosclerosis and hypercholesterolemia. This study found that, contrary to expectations, intensive lipid-lowering therapy with atorvastatin, which reduced low-density lipoprotein cholesterol levels to a mean of 63±23 mg per deciliter, had no effect on the progression of aortic stenosis (as measured by the aortic-jet velocity) or on aortic-valve calcification (as measured by helical computed tomographic scanning). Intensive lipid-lowering therapy with atorvastatin had no effect on the progression of aortic stenosis or on aortic-valve calcification. In the Western world, calcific aortic stenosis is the most common form of valvular heart disease, and its incidence increases with age such that 3 percent of adults over 75 years of age have aortic stenosis. 1 It is a gradually progressive disease, characterized by a long asymptomatic phase, lasting several decades, followed by a shorter symptomatic phase associated with severe narrowing of the orifice of the aortic valve. Once symptoms occur, the prognosis is poor and surgery is usually mandated. Calcific aortic stenosis is now the leading indication for valve replacement in North America and Europe. However, there are currently . . .

Renin-angiotensin system blockers (RASb) improve cardiac remodeling, but their clinical utility after surgical aortic valve replacement (SAVR) for aortic stenosis (AS) is unclear. We aimed to assess the impact of RASb on short- and long-term survival following isolated SAVR for severe AS. From January 2005 to January 2014, 508 consecutive patients had isolated SAVR for severe AS. Patients with RASb (n = 286; 53%) were more often female (p = 0.039), hypertensive (p < 0.0001), and diabetic (p = 0.004), with higher body mass index (p < 0.0001) and EuroSCORE II (p = 0.025), and lower mean aortic pressure gradient (p = 0.011). The 30-day mortality was similar in both groups (RASb: 3% vs no RASb: 5.8%, p = 0.13), but lower under angiotensin receptor blockers (ARB) than angiotensin-converting enzyme inhibitors (ACEi; 0.7% vs 5.6%, p = 0.017). Patients under RASb had a better 8-year survival than those without RASb (83 ± 3% vs 52 ± 5%, p < 0.0001), confirmed in a propensity score-matched pairs analysis (82 ± 4% vs 50 ± 7%, p < 0.0001). Regarding different types of RASb, patients under ARB had lower mortality than those under ACEi (87 ± 3% vs 79 ± 4%, p = 0.028). In multivariate analysis, the use of RASb was associated with improved survival (hazard ratio = 0.31, 95% confidence interval 0.20 to 0.47, p < 0.0001), with lower mortality under ARB than under ACEi (hazard ratio = 0.39, 95% confidence interval 0.18 to 0.85, p = 0.018). In this observational study, the use of RASb was associated with improved long-term outcome after isolated SAVR for severe AS. A randomized clinical trial is mandatory.

Objective Women with severe aortic valve stenosis (AS) have better LV systolic function and more concentric LV geometry than their male counterparts. However, sex differences in cardiovascular (CV) outcome during progression of AS have not been reported from a longitudinal prospective study. Methods Doppler echocardiography and CV events were recorded during a median of 4.0 years in 979 men and 632 women aged 28–86 (mean 67±10) years in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study. LV systolic function was assessed by EF and midwall shortening (MWS). Study outcomes were AS-related events, ischaemic CV events and total mortality. Results The annular cumulative incidence of AS events, ischaemic CV events and death was 8.1%, 3.4% and 2.8% in women, and 8.9%, 4.4% and 2.4% in men, respectively. Women and men had similar AS progression rate whether measured by peak jet velocity, mean gradient or valve area. In multivariate analyses, female sex independently predicted less reduction in LV MWS and EF during follow-up (both p<0.05). In time-varying Cox analyses, women had a 40% lower rate of ischaemic CV events (95% CI 21% to 54%), in particular, more than 50% lower rate of stroke and coronary artery bypass grafting, and a 31% lower all-cause mortality (95% CI 1% to 51%), independent of active study treatment, age and hypertension, as well as time-varying valve area, low systolic function and abnormal LV geometry. AS event rate did not differ by sex. Conclusions In the SEAS study, women and men had similar rates of AS progression and AS-related events. However, women had lower total mortality and ischaemic CV event rate than men independent of confounders. Trial registration number ClinicalTrials.gov identifier: NCT00092677.

Normalization of left ventricular (LV) hypertrophy is expected after successful aortic valve replacement (AVR) in patients with aortic valve stenosis (AS), but is not always observed. We tested the impact of body mass index (BMI) ≥30 kg/m2 on persistent post-AVR LV hypertrophy. In the present subanalysis of Simvastatin Ezetimibe in Aortic Stenosis study, clinical and echocardiographic data of 399 patients with severe AS who underwent surgical AVR were analyzed. All patients had a standardized pre- and post-AVR echocardiogram. Patients were grouped by BMI categories into BMI <25 kg/m2, BMI 25 to 29.9 kg/m2, and BMI ≥30 kg/m2. LV hypertrophy was defined as LV mass/height2.7 >49.2 g/m2.7 in men and >46.7 g/m2.7 in women. Predictors of persistent LV hypertrophy after AVR were identified in logistic regression analysis. After a median follow-up of 196 days after AVR, LV hypertrophy was more prevalent in patients with BMI ≥30 kg/m2 compared with those with BMI 25 to 29.9 kg/m2 and those patients with BMI <25 kg/m2 (71% vs 47% and 37%, p <0.01). BMI ≥30 kg/m2 patients also remained with lower LV midwall shortening post-AVR compared with patients with normal weight (p <0.01), independent of patient prosthesis mismatch. In multivariable logistic regression analysis, the presence of BMI ≥30 kg/m2 before AVR was associated with an almost fourfold higher prevalence of post-AVR LV hypertrophy independent of significant associations with higher systolic blood pressure and lower LV midwall shortening preoperatively (odds ratio 3.75 [95% confidence interval 2.04 to 6.91], p <0.001). In conclusion, the presence of BMI ≥30 kg/m2 before AVR in patients with severe AS was strongly and independently associated with persistent post-AVR LV hypertrophy.

IntroductionThere are a substantial number of patients developing heart failure after transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS), even though AS has been successfully treated. The purpose of this randomised controlled trial was to determine whether the addition of an angiotensin receptor–neprilysin inhibitor (ARNI), sacubitril/valsartan, is superior to conventional medications in lowering N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients undergoing TAVI for AS.Methods and analysisThe study design is a prospective, single-centre, open-label, randomised, parallel-group, two-arm study, in which participants will be randomised in a 1:1 ratio to receive either conventional medications plus ARNI or conventional medications only. In the ARNI group, if a patient was on an ACE inhibitor or angiotensin II receptor blocker before TAVI, it will be switched to ARNI 100 mg/day (50 mg two times per day) on the first postoperative day. If not, candesartan 4 mg/day will be started 1–2 days before TAVI, and switched to ARNI 100 mg/day on the first postoperative day. As the patient has tolerability to ARNI, dosage will be increased stepwise to 400 mg/day 2–4 weeks apart. ARNI will be continued until at least 6-month follow-up. In the control group, the patient will receive conventional medications. The primary endpoint is the serum NT-proBNP value at 6-month follow-up after TAVI. Each group includes 42 patients (84 total patients).Ethics and disseminationEthical approval for this study has been obtained from the Chiba University Hospital Certified Clinical Research Review Board (CRB3180015). The study is ongoing. Findings from this study will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberThis trial has been registered on the Japan Registry of Clinical Trials: jRCT1031220344.