Fortuin, F. David

Despite advances in lipid-lowering and antithrombotic therapy, patients with acute coronary syndromes remain at elevated risk for recurrent events due to persistent atherosclerotic inflammation. This review evaluates inflammation as a therapeutic target in secondary prevention and discusses established, investigational, and emerging strategies. Colchicine, now FDA-approved for cardiovascular risk reduction, lowered major adverse cardiovascular events in COLCOT and LoDoCo2. Canakinumab (IL-1β inhibition) reduced recurrent events in proportion to IL-6 and hsCRP suppression, while ziltivekimab (IL-6 inhibition) achieved profound biomarker reductions but remains investigational. Early-phase studies of anakinra (IL-1 receptor antagonist) and dapansutrile (oral NLRP3 inhibitor) showed anti-inflammatory effects in early trials, whereas varespladib and darapladib illustrated the challenges of targeting lipid-associated pathways. Beyond direct immunomodulators, GLP-1 receptor agonists and SGLT2 inhibitors provide both cardioprotective and anti-inflammatory benefits, reinforcing their expanding role post-ACS. Additional emerging avenues include triptolidiol, dasatinib, and BTK or JAK/STAT inhibitors, while novel approaches, such as nanozyme delivery systems and CRISPR-based editing, extend the therapeutic horizon. This review highlights the potential of inflammation-targeted therapies to advance secondary prevention in ACS by integrating current evidence and perspectives on future therapeutic developments.

Introduction: Mitral valve transcatheter edge-to-edge repair (M-TEER) has emerged as a minimally invasive option for high-risk surgical candidates with severe and symptomatic mitral regurgitation (MR), but post-procedure residual mitral valve (MV) dysfunction remains a significant concern. This study evaluates the clinical utility of combining artificial intelligence applied to electrocardiograms (ECG-AI) for diastolic dysfunction (DD) grading and the echocardiography-derived velocity time integral of the MV and left ventricular outflow tract ratio (VTIMV/LVOT) in predicting prognosis in patients post-M-TEER. Methods: A retrospective analysis of patients who underwent M-TEER between 2014 and 2021 was conducted. Patients were categorized based on VTIMV/LVOT and ECG-AI scores into three groups: both normal parameters, either abnormal parameter, or both abnormal parameters to compare outcomes (mortality, major adverse cardiovascular events [MACE], and the need for subsequent MV reintervention) using Kaplan–Meier analysis, multivariable Cox regression models, and net reclassification improvement. Results: Overall, 250 patients were included; the median age was 79.5 (IQR: 73.1, 84.6) and 66.4% were male. The combined abnormal VTIMV/LVOT (≥2.5) and ECG-AI score for DD (>1) was associated with higher risk of one-year mortality (adjusted HR: 4.56 [1.04–19.89], p = 0.044) and MACE (adjusted HR: 3.72 [1.09–12.72], p = 0.037) compared to patients with both normal parameters. Conclusions: This study highlights the potential additive value of integrating VTIMV/LVOT and ECG-AI scores as a prognostic tool for a personalized approach to the post-operative evaluation and risk stratification in M-TEER patients.

AbstractBackgroundDespite optimal medical therapy and cardiac resynchronization therapy (CRT), significant functional mitral regurgitation (MR) persisted in 30% of the patients and labeled as CRT nonresponders.AimsWe sought to study the impact of transcatheter edge‐to‐edge repair (TEER) in patients with symptomatic grade III and IV functional MR despite CRT.MethodsA retrospective analysis was conducted of all patients who had prior CRT for at least 6 months and underwent TEER for significant residual functional MR (grade ≥3) and symptomatic heart failure (HF) at our institution. The primary outcomes were the change in New York Heart Association classification (NYHA), MR grade, echo parameters, and NT‐ProBNP from baseline to 1‐year post‐procedure.ResultsA total of 28 patients were identified, mean age of 73 ± 6.7 years and 89% males. Procedure success was achieved in all patients. At 1‐year follow‐up, patients had lower MR grade (median 2, IQR 1 [1,2] vs. 4, IQR 1 [3,4]; p < 0.001), NYHA class (median 2, IQR 1 [2,3] vs. 3, IQR 1 [3,4]; p < 0.001), and NT‐ProBNP (7658 ± 11322 vs. 3760 ± 4431; p = 0.035) compared to before the TEER procedure. The left ventricular end‐diastolic volume (255 ± 59 vs. 244 ± 66 mm; p = 0.016) and the right ventricular systolic pressure (52 ± 14 mmHg vs. 37 ± 13 mmHg, <0.001) decreased.ConclusionPatients who remain symptomatic after CRT with severe functional MR had improved functional status and MR grade at 1‐year following TEER. There was a signal toward reverse remodeling.

Background: Conduction abnormality post-transcatheter aortic valve implantation (TAVI) remains clinically significant and usually requires chronic pacing. The effect of right ventricular (RV) pacing post-TAVI on clinical outcomes warrants further studies. Methods: We identified 147 consecutive patients who required chronic RV pacing after a successful TAVI procedure and propensity-matched these patients according to the Society of Thoracic Surgeons (STS) risk score to a control group of patients that did not require RV pacing post-TAVI. We evaluated routine echocardiographic measurements and performed offline speckle-tracking strain analysis for the purpose of this study on transthoracic echocardiographic (TTE) images performed at 9 to 18 months post-TAVI. Results: The final study population comprised 294 patients (pacing group n = 147 and non-pacing group n = 147), with a mean age of 81 ± 7 years, 59% male; median follow-up was 354 days. There were more baseline conduction abnormalities in the pacing group compared to the non-pacing group (56.5% vs. 41.5%. p = 0.01). Eighty-eight patients (61.6%) in the pacing group required RV pacing due to atrioventricular (AV) conduction block post-TAVI. The mean RV pacing burden was 44% in the pacing group. Left ventricular ejection fraction (LVEF) was similar at follow-up in the pacing vs. non-pacing groups (57 ± 13.0%, 59 ± 11% p = 0.31); however, LV global longitudinal strain (−12.7 ± 3.5% vs. −18.8 ± 2.7%, p < 0.0001), LV apical strain (−12.9 ± 5.5% vs. 23.2 ± 9.2%, p < 0.0001), and mid-LV strain (−12.7 ± 4.6% vs. −18.7 ± 3.4%, p < 0.0001) were significantly worse in the pacing vs. non-pacing groups. Conclusions: Chronic RV pacing after the TAVI procedure is associated with subclinical LV systolic dysfunction within 1.5 years of follow-up.

Abstract Aims Doppler mean gradient (MG) can underestimate aortic stenosis (AS) severity in patients with atrial fibrillation (AF) compared with patients with sinus rhythm (SR), potentially delaying intervention in AF. This study compared outcomes in patients with AF and SR following transcatheter aortic valve replacement (TAVR) and investigated delay in TAVR based on computed tomography aortic valve calcium score (AVCS). Methods and results Patients who underwent TAVR from 2013 to 2017 for native valve severe AS were identified from an institutional database. Baseline characteristics and overall survival were compared between those with SR and AF. There were 820 patients (mean age 81 years; 41.6% females) included in this study. AF was present in 356 patients. Patients with AF were older (82.2 vs. 80.5, P = 0.003) and had a lower MG compared with patients with SR (42.0 vs. 44.9, P = 0.002) with similar indexed aortic valve area (0.4 vs. 0.4, P = 0.17). Median AVCS was higher in AF (males: AF 2850.0 vs. SR 2561.0, P = 0.044; females: AF 1942.0 vs. SR 1610.5, P = 0.025). Projected AVCS, assuming the same age of diagnosis, was similar between AF and SR. Median survival post-TAVR was worse in AF compared with SR (3.2 vs. 5.4 years, log rank P &lt; 0.001). AF, lower MG, higher right ventricular systolic pressure, dialysis, diabetes, and significant tricuspid regurgitation were associated with higher mortality (P &lt; 0.05 for all). Conclusion Older age and higher AVCS in patients with AF compared with those with SR suggest that AS was both underestimated and more advanced at TAVR referral.

Background: Refractory angina(Ang) effects 150 –250,000 pts in the US alone. These individuals have exhausted options for revasc and continue to have lifestyle limiting ang despite optimal medical Rx. Pre-clinical studies provided evidence that human CD34+ cells(CD34) can stimulate new blood vessel formation in ischemic myocardium(Myo), improving perfusion and function. We performed a phase 2 study of intraMyo injection of autologous CD34 in pts with CCS Class 3 and 4 Ang to obtain evidence for feasibility, safety and bioactivity. Methods: A phase 2 randomized, double-blind, placebo-controlled clinical trial was performed at 26 centers in the United States. There were 3 treatment groups: placebo, low dose (1×10^5 CD34/kg body wt) and high dose (5×10^5 CD34/kg). All pts underwent mobilization with GCSF 5 mcg/kg/day SC for 5 d, followed by apheresis on d5 to collect mononuclear cells. On day 6 CD34 were purified from the collected cells using the Isolex 300i device. After lot release testing, CD34 were injected endocardially at 10 locations in the ischemic Myo using the Myostar catheter following NOGA mapping. Placebo injections consisted of identical volumes of the diluent only. Results: A total of 167 pts were randomized and completed the injection procedure and 162 completed the 6 mo evaluation. The mean age of subjects was 61.0±8.9, there were 22 female and 145 male subjects. Trop was elevated in 26 pts at baseline and in 71 at some point following GCSF or injection. At 6 mo CD34 treated pts showed more reduction in ang frequency (−8.6 placebo vs 14.2 low dose) and improved ETT time (+69 sec placebo vs. +138 low dose). At 12m CD34 treated continue to show more reduction in angina (−8.2 placebo vs. −15.0 low dose) and improved ETT (+58 sec placebo vs. + 139 sec low dose). For key endpoints the high dose group results were inferior to low dose. The 12m data set has been locked and is being analyzed and the results of the completed analysis will be presented. Conclusions: Autologous CD34 cell therapy was associated with improved exercise tolerance and reduced angina in no-option pts with intractable angina. Ongoing analysis will determine endpoints, sample size and suitability of this therapy for a phase III study in no-option pts with refractory angina.

Background Percutaneous heart valve procedures have been increasingly performed over the past decade, yet real‐world mortality data on valvular heart disease (VHD) in the United States remain limited. Methods and Results We queried the Centers for Disease Control and Prevention's Wide‐Ranging Online Data for Epidemiologic Research database among patients ≥15 years old from 1999 to 2020. VHD and its subtypes were listed as the underlying cause of death. We calculated age‐adjusted mortality rate (AAMR) per 100 000 individuals and determined overall trends by estimating the average annual percent change using the Joinpoint regression program. Subgroup analyses were performed based on demographic and geographic factors. In the 22‐year study, there were 446 096 VHD deaths, accounting for 0.80% of all‐cause mortality (56 014 102 people) and 2.38% of the total cardiovascular mortality (18 759 451 people). Aortic stenosis recorded the highest mortality of VHD‐related death in both male (109 529, 61.74%) and female (166 930, 62.13%) populations. The AAMR of VHD has declined from 8.4 (95% CI, 8.2–8.5) to 6.6 (95% CI, 6.5–6.7) per 100 000 population. Similar decreasing AAMR trends were also seen for the VHD subtypes. Men recorded higher AAMR for aortic stenosis and aortic regurgitation, whereas women had higher AAMR for mitral stenosis and mitral regurgitation. Mitral regurgitation had the highest change in average annual percent change in AAMR. Conclusions The mortality rate of VHD among the US population has declined over the past 2 decades. This highlights the likely efficacy of increasing surveillance and advancement in the management of VHD, resulting in improved outcomes.

Abstract Aims Cardiac amyloidosis (CA) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Cardiac amyloidosis has poor outcomes, and its assessment in all TAVR patients is costly and challenging. Electrocardiogram (ECG) artificial intelligence (AI) algorithms that screen for CA may be useful to identify at-risk patients. Methods and results In this retrospective analysis of our institutional National Cardiovascular Disease Registry (NCDR)-TAVR database, patients undergoing TAVR between January 2012 and December 2018 were included. Pre-TAVR CA probability was analysed by an ECG AI predictive model, with &gt;50% risk defined as high probability for CA. Univariable and propensity score covariate adjustment analyses using Cox regression were performed to compare clinical outcomes between patients with high CA probability vs. those with low probability at 1-year follow-up after TAVR. Of 1426 patients who underwent TAVR (mean age 81.0 ± 8.5 years, 57.6% male), 349 (24.4%) had high CA probability on pre-procedure ECG. Only 17 (1.2%) had a clinical diagnosis of CA. After multivariable adjustment, high probability of CA by ECG AI algorithm was significantly associated with increased all-cause mortality [hazard ratio (HR) 1.40, 95% confidence interval (CI) 1.01–1.96, P = 0.046] and higher rates of major adverse cardiovascular events (transient ischaemic attack (TIA)/stroke, myocardial infarction, and heart failure hospitalizations] (HR 1.36, 95% CI 1.01–1.82, P = 0.041), driven primarily by heart failure hospitalizations (HR 1.58, 95% CI 1.13–2.20, P = 0.008) at 1-year follow-up. There were no significant differences in TIA/stroke or myocardial infarction. Conclusion Artificial intelligence applied to pre-TAVR ECGs identifies a subgroup at higher risk of clinical events. These targeted patients may benefit from further diagnostic evaluation for CA.

Introduction: Cardiac amyloidosis (CA) has been suggested to be common (up to 16%) in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). CA has poorer outcomes and its assessment in all TAVR patients may be costly and challenging. Hypothesis: CA may be screened for with an artificial intelligence (AI) clinical predictive model applied to pre-TAVR ECGs, and high probability (>50%) for CA may be associated with worse clinical outcomes. Methods: In this retrospective analysis of the Mayo institutional National Cardiovascular Disease Registry (NCDR)-TAVR, patients undergoing a TAVR between Jan-2012 and Dec-2017 were included. Pre-TAVR ECGs were analyzed by the AI predictive model for CA embedded in the EMR. EMRs were reviewed to assess for a clinical diagnosis of CA in those identified as high probability (>50%) by the AI tool. Clinical outcomes on 1 year follow-up were extracted from the NCDR-TAVR database and Kaplan-Meier curves were created to compare patients with high CA probability (≥50%) versus those with low probability (<50%). Results: Of 1070 patients who underwent TAVR (mean age 81.1± 8.5 years, 58.2% male), 263 (24.6%) had ≥50% probability for CA on pre-procedure ECG. Only 18 (1.7%) of these had clinical diagnosis of CA. In the survival analysis, high probability of CA by AI tool was associated with higher all-cause mortality (HR 1.60, 95%CI 1.09-2.34, p=0.01) and greater HF admissions (HR 1.59, 95%CI 1.08-2.35, p<0.01). Neither TIA/stroke nor myocardial infarction were statistically significant. MACE (TIA/stroke, myocardial infarction, heart failure admissions) was higher in the ≥50% CA probability group (HR 1.68, 95%CI 1.17-2.40, p<0.01), (Figure) . Conclusion: CA is clinically underdiagnosed in patients undergoing TAVR. AI applied to pre-TAVR ECGs suggesting higher probability for CA identifies a subgroup at higher risk of clinical events, who may benefit from further diagnostic evaluation for CA.

Introduction: Doppler mean gradient (MG) can underestimate the severity of aortic stenosis (AS) in patients with atrial fibrillation (AF) compared to patients in sinus rhythm (SR). Patients with AF and severe AS may experience delayed diagnosis and more advanced disease at time of referral for transcatheter aortic valve replacement (TAVR). Methods: Patients who underwent TAVR from 2013 to 2017 for native valve severe AS were identified from an institutional database. MG and aortic valve calcium score (AVCS) at time of referral were compared in patients in AF and SR. Retrospective theoretical AVCS in AF patients were derived assuming an average progression of 152 AU/year (published data). Results: There were 820 patients included; mean age was 81.3+/- 8.2 years and 41.6% were female. AF was present in 356 patients at time of referral. Patients in AF were older (82.2 vs. 80.5, p = 0.003), had lower MG compared to SR patients (42.0 vs. 44.9, p = 0.002) and a lower peak velocity (4.1 vs. 4.2, p = 0.010) with a similar indexed aortic valve area (0.4 vs. 0.4, p = 0.17). Stratified by sex, the median calcium score for AF patients was higher (by around 300 AU) among both males (AF 2850.0 vs. SR 2561.0, p = 0.044) and females (AF 1942.0 vs. 1610.5, p = 0.025) ( figure 1 ). A density plot of retrospective theoretical AVCS in AF patients (projected assuming referral to TAVR approximately two years prior) resulted in nearly identical median AVCS between the two cohorts ( figure 2 ). Conclusions: Older age and higher AVCS in patients with AF compared to SR suggests that AS was both underestimated and more advanced at time of referral to TAVR. Patients in AF may have severe AS as early as 2 years prior to TAVR referral.