Nonfatal Stroke Research Articles

AI-ECG sex-estimation discordances predict cardiovascular events

Abstract Background Cardiovascular disease remains the leading cause of death and burden globally, warranting the need to explore novel predictors of major adverse cardiovascular events (MACE) using new technologies. Artificial Intelligence (AI)-enhanced ECG (AI-ECG) algorithms can provide information on cardiovascular health of individuals, independent of conventional risk factors. Purpose The current study aimed to understand whether a previously described AI-ECG sex estimation algorithm could be applied for risk stratification of major adverse cardiovascular events (MACE), with a focus on a population without previous history of MACE. Methods Patients having 12-lead ECGs between 2018-2019 were included and followed up until August 2023. Exclusion criterion was a prior history of MACE. AI-ECG sex estimation was determined using a previously described algorithm predicting sex based on 12-lead ECGs. The algorithm generates outputs ranging from 0 to 1, representing the estimated probability of being male. Outputs above 0.5 were considered as AI-ECG-estimated male, and below as AI-ECG-estimated female. This was compared with biological sex to determine whether the two matched. Inconsistency between AI-ECG estimated sex and biological sex was defined as discordance. MACE was defined as myocardial infarction, coronary revascularization, non-fatal stroke, and all-cause death. Results Among 80,578 subjects (mean age 59.1 ± 16.1 years, 52.4% female), 9.7% exhibited sex discordance in AI-ECG estimation. Discordance was associated with a 56% higher risk of MACE (HR, 1.56, 95% CI 1.46-1.65, p <0.001), and remained significant in multivariable analysis with traditional risk factors (HR 1.35, 95% CI 1.27-1.43, p <0.001) (Figure 1). Sex-specific analysis showed increased MACE risk in both discordant males and females (Figure 2). Conclusion In patients with no history of MACE, discordance in AI-ECG sex estimation is associated with increased risk of MACE. These findings suggest the potential of AI-ECG sex estimation algorithm for risk assessment, especially in patients with no history of MACE.Figure 1.Cox proportional hazard modelFigure 2.Kaplan-Meier of MACE by sex

Is the obesity paradox leading to a less stringent secondary prevention strategy in post-acute coronary syndrome patients?

Abstract Introduction Patients with acute coronary syndrome (ACS) are at very high risk of recurrent cardiovascular (CV) events. Despite being a major CV risk factor, obesity was associated with best survival in patients with ACS, the so-called "obesity paradox". It is uncertain if this finding is leading to a less stringent secondary prevention strategy in this group of patients, and whether it influences prognosis. Purpose To analyze the impact of obesity on outcomes after ACS and on other CV risk factor management. Methods Single-center, retrospective observational study that included all consecutive post-ACS patients enrolled in a phase 2 cardiac rehabilitation (CR) program in 2017, with a follow-up of 24 months. Patients were classified in 2 groups according to body mass index (BMI) at baseline: Group 1 (G1) were obese patients (BMI≥30 kg/m2), and Group 2 (G2) were non-obese patients (BMI<30kg/m2). Major adverse cardiovascular events (MACE) were defined as a composite of death, non-fatal ACS, non-fatal stroke, and unplanned revascularization. Results 198 patients were included (mean age of 60.3±10.7 years, 82% male) with a mean BMI of 27.7±4.2 kg/m2. Forty-seven patients (23.7%) had a BMI≥30 kg/m2. Patients in G1 were more likely to have hypertension (79% vs 55%; p=0.003) and diabetes (36% vs 20%; p=0.022). CR program was associated with smoking cessation, significant BMI (G1: -0.69 (95%CI: -0.40 to -0.10); G2: -0.39 (95%CI: -0.20 to -0.57) and LDL-Cholesterol (LDL-C) reduction (G1: -38 (95%CI: -25 to -50); G2: -29 (95%CI: -22 to -36), and functional capacity improvement (G1: +1.2 METs (95%CI: +0.9 to +1.5); G2: +1.1 METs (95%CI: +1.0 to +1.4) in both groups at 3 months, with similar magnitude of improvement. At 24 months, BMI had returned to baseline values in both groups, while the improvement in smoking status, LDL-C and functional capacity persisted. At 24 months, MACE occurrence was numerically increased in obese group (G1: 26.1% vs. G2: 17.2%, p=0.182), with a statistically significant higher incidence of non-fatal recurrent ACS in G1 (17% vs. 7.3%, p=0.048). Conclusions ACS patients with obesity have worse prognosis, despite the similar improvement in CV risk profile. Our data also suggests that, despite the short-term improvement in BMI, current treatment strategies are not effective at achieving a persistent weight control over 24-months.

Residual cardiovascular risk in patients with acute coronary syndromes: from hs-CRP and LDL-C to JCAD

Abstract Background Patients with a recent acute coronary syndrome (ACS) remain at high residual cardiovascular risk to which cholesterol, inflammation, and yet-to-be-identified pathways jointly contribute (1). The novel Junctional Protein Associated with Coronary Artery Disease (JCAD) protein drives incident cardiovascular events via pathways, among them fibrinolysis, that act independently from lipid metabolism and inflammation (2). Purpose Whether circulating JCAD provides predictive utility over and above established risk factors among ACS patients at residual lipid risk (RLR), residual inflammatory risk (RIR), or both (RILR), remains unknown. Methods Among patients participating in the multicentre SPUM-ACS study, patients at RLR (on-statin LDL-C ≥70.0 mg/dl), RIR (on-statin hs-CRP ≥2.0 mg/l) or both (RILR; on-statin LDL-C ≥70.0 mg/dl and CRP ≥2.0 mg/l),(1,3) and propensity-score matched (PSM) controls were identified, and the contributions of plasma hs-CRP, LDL-C and JCAD toward recurrent major adverse cardiovascular events (MACE; defined as a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) were studied by fitting uni- and multivariable-adjusted Cox proportional hazard regression models. Results Patients at RLR, RIR, or both (RILR) were at higher MACE risk compared to controls (hazard ratio [HR] per log2 increase, 1.51; 95% confidence interval (CI), 1.05-2.17; HR, 1.78; 95% CI, 1.23-2.58; and HR 1.75; 95% CI, 1.12-2.74; Figure 1). Among those at RLR, MACE risk increased with increasing levels of hs-CRP and JCAD, respectively, in uni- (HR, 1.17; 95% CI, 1.06–1.30; HR, 1.29; 95% CI, 1.03-1.62) and multivariable-adjusted models (adjusted [a]HR, 1.16; 95% CI, 1.03–1.30; aHR, 1.27; 95% CI, 1.01-1.60), whereas no association of LDL-C and future MACE risk was noted. Similarly, among patients at RIR, MACE risk increased by 1.28-fold per log2 increase in plasma JCAD (HR, 1.28; 95% CI, 1.03–1.59), which prevailed in multivariable-adjusted models accounting for potential confounders (aHR, 1.31; 95% CI, 1.04–1.65). In ACS patients at both residual inflammatory and lipid risk, MACE risk associated almost linearly with increasing JCAD levels (HR, 1.45; 95% CI, 1.09–1.92), independently of potential confounders (aHR, 1.47; 95% CI, 1.11–1.97). Meanwhile, no association of LDL-C or hs-CRP with MACE risk was identified among these high-risk patients (Figure 2). Conclusions ACS patients at RIR, RLR, or both are at high ischaemic risk, with JCAD ranking among the top predictors of MACE across the broad spectrum of residual risk. Our data highlight the importance of novel pathways to address residual cardiovascular risk, with JCAD ranking among most promising candidates.

Phenotype of patients with severe aortic stenosis and small aortic annulus: how does it impact on hemodynamics and on transcatheter aortic valve implantation outcomes

Abstract Background Discordant grading of severe aortic stenosis can result from a tight aortic valve area (<1cm2) with a low transvalvular mean gradient (<40 mmHg). Small aortic annulus dimensions and low flow status may contribute to discordant grading of severe aortic stenosis. However, the frequency of patients with small aortic annulus and discordant grading, along with their characteristics and outcomes after intervention, remains unknown. Purpose To investigate the frequency of discordant grading severe aortic stenosis in patients with a small aortic annulus and to evaluate their clinical characteristics, as well as outcomes after transcatheter aortic valve implantation (TAVI). Methods Patients with an aortic annulus diameter < 23 mm determined by cardiac computed tomography who underwent TAVI between 2018 to 2023 were retrospectively evaluated. Patients were followed for the occurrence of the composite endpoint of of all-cause mortality, rehospitalizations for heart failure, non-fatal myocardial infarction, and non-fatal stroke. Results Among 230 patients with severe aortic stenosis and a small aortic annulus, 52 (23%) had discordant gradient (24 with low flow low gradient (LFLG) and 28 with normal flow low gradient (NFLG)) while 120 (52%) exhibited normal flow high gradient (NFHG) and 58 (25%) had low flow high gradient (LFHG). The majority of the patients were female (Table 1). Differences were noted among the three groups regarding aortic transvalvular gradients, stroke volume index and ejection fraction. During a median follow-up of 2 years, the composite endpoint occurred in 20% of the total cohort. Patients with discordant grading severe aortic stenosis experienced the worse outcome (Figure1). Conclusions Most patients with severe aortic stenosis and small annulus have high gradient and only 23% of patients presented discordant grading. Patients with discordant grading severe aortic stenosis showed worse outcomes, suggesting potential delays in referral due to challenges in diagnosing severe aortic stenosis among patients with small aortic annulus.Basal clinical characteristicsKaplan-Meier survival curves

Cardiovascular events in patients treated with bempedoic acid vs. placebo: systematic review and meta-analysis

Abstract Aims Reduction of low-density lipoprotein cholesterol (LDL-C) decreases cardiovascular mortality and morbidity. Bempedoic acid represents a promising novel lipid modifying agent for patients who cannot reach guideline recommended LDL-C goals or statin-intolerant patients, but data on safety and cardiovascular outcomes are limited. We therefore aimed to systematically review randomized controlled trials investigating bempedoic acid versus placebo in patients with hyperlipidemia. Methods A systematic search on the databases PubMed, Web of Science, and Embase until 20 March 2023 was performed. All randomized trials comparing bempedoic acid (180 mg daily) with placebo in patients with an indication for lipid-lowering therapy were included. As primary endpoint we analysed three-point major adverse cardiovascular events (MACE) consisting of cardiovascular death, non-fatal myocardial infarction (MI) or non-fatal stroke. The analysis was carried out using the odds ratio as the outcome measure. Due to the expected heterogeneity across studies a random-effects model was fitted to the data. Results Out of 258 manuscripts, 10 manuscripts fulfilled the inclusion criteria. In total, these trials included 18,200 patients (9,765 on bempedoic acid, 8,435 on placebo). Bempedoic acid significantly reduced MACE compared to placebo (OR 0.84 [95% CI 0.76-0.96]; p<0.001; I2=0%). The endpoint reduction was driven by a lower rate of non-fatal MI, whereas bempedoic acid had no significant effect on stroke (OR 0.86 [95% CI 0.69-1.08]; p=0.20, I2=0%) and all-cause mortality (OR 1.19 [95% CI 0.73-1.93]; p=0.49; I2=18%). Conclusion Bempedoic acid reduced non-fatal MI in patients with hyperlipidemia, whereas it had no significant effect on stroke and all-cause mortality.Figure.Forest plot for three-point MACE

Measuring only sitting blood pressure without considering supine blood pressure underestimates cardiovascular risk in the elderly

Abstract Background and Objective Elderly individuals exhibit greater variability in blood pressure (BP) readings between sitting and supine positions. Nocturnal hypertension (supine position) is closely associated with cardiovascular diseases and mortality. However, the relationship between supine BP and cardiovascular risk remains unclear. This study aims to investigate the association between the occurrence of major adverse cardiovascular events (MACEs) with BP in sitting and supine positions. Methodologies A total of 3363 participants aged 65 years or older from the Northern Shanghai Study were included. Each participant is given 3 consecutive sitting SBP readings (SBP1, SBP2, SBP3) at 2-minute intervals, we then calculated the SBP1-2 (average of SBP1 and SBP2), SBP2-3 (average of SBP2 and SBP3), SBP1-2-3 (average of SBP1, SBP2 and SBP3). we also collected two supine BP readings (S-SBP1, S-SBP2). Kaplan-Meier and Cox proportional hazard regression were used to investigate the association of sitting and supine BP with MACEs (composite of nonfatal myocardial infarction, nonfatal stroke, or death). Results The mean age of participants was 71.5 years, and 1467(43.6%) were men. After a median of 6.4-year follow-up, a total of 362 events were recorded. Among 3 successive BP readings, SBP2-3 had strongest association with MACEs incidence (hazard ratio, 1.12 [1.00-1.26] per SD). Multiple cox proportional hazard regression showed supine BP had significant value in predicting MACEs, acute myocardial infarction (AMI) and mortality compared to sitting BP. Kaplan-Meier revealed significant differences in MACEs rates among participants without hypertension (HTN) in both sitting and supine positions, with HTN in both positions, or those with HTN in either position (Log rank P < 0.01). Compared to participants without HTN in both sitting and supine positions, those with HTN in both positions had a 1.4-fold (hazard ratio,1.40[1.08-1.82]) higher risk of MACEs and 2-fold (hazard ratio,2.01[1.24-3.26]) higher risk of stroke. Conclusion Supine BP measurements are more valuable than sitting BP in predicting MACEs in elderly individuals. Hypertension in both positions significantly increases the risk of MACEs. Taken together, supine BP may also need to be emphasized in the elderly.central illustration

Outcomes of post-acute coronary syndrome patients enrolled in a phase 2 cardiac rehabilitation program

Abstract Introduction Cardiac rehabilitation (CR) is a class I recommendation in the management of patients with acute coronary syndrome (ACS), namely ST-elevation myocardial infarction (STEMI) and non-ST acute coronary syndrome (NST-ACS). Reported mortality and recurrent cardiovascular (CV) events are still unacceptably high in these patients. Purpose To assess CV outcomes of patients enrolled in a CR program and its association with ACS presentation. Methods Single-center, retrospective observational study that included all consecutive post-ACS patients enrolled in a phase 2 CR program in 2017, with a follow-up of 24 months. Group 1 were patients with STEMI; group 2 were patients with NST-ACS. Major adverse cardiovascular events (MACE) were defined as a composite of death, non-fatal ACS, non-fatal stroke, and unplanned revascularization. Results Of the 202 ACS patients who attended the CR program in 2017, 4 were excluded due to missing data. Of the 198 patients analyzed (age 60.3±10.7 years, 82% male), 101 patients had a STEMI and 97 NST-ACS. STEMI patients were significantly younger (57±9.5 vs. 63±10, p<0.001), with fewer CV risk factors (diabetes 16% vs. 32%, p=0.008; hypertension 51% vs. 72%, p=0.002; obesity 17% vs. 31%, p=0.020; dyslipidemia 54% vs. 77%, p<0.001), except for active smoking (53% vs. 29%, p=0.001), and were less likely to have previous history of coronary artery disease (9% vs. 31%, p<0.001). During the 3-month CR program, both groups achieved significant reduction in body mass index, LDL-Cholesterol, functional capacity, and smoking cessation rates. At 3-, 12-, and 24-months evaluation, both groups showed no differences in risk factor management, nor differences in lipid-lowering therapy, namely percentage of high-intensity statin and ezetimibe use. STEMI patients were treated more frequently with ticagrelor (86% vs. 67%, p=0.001) at baseline. MACE occurrence was significantly lower in STEMI patients (11% vs. 28%, p=0.003), driven mainly by recurrent ACS (4% vs. 15%, p=0.006). Conclusions In our study, NST-ACS patients had significantly higher CV disease burden and worse outcomes at 24-month follow-up. Despite the heightened CV risk in this group, secondary prevention treatment intensity was similar in both groups.

Risk of recurrent ischaemic events in ACS patients with baseline LDL-C below guideline-recommended thresholds: insights from the prospective SPUM-ACS study

Abstract Introduction The 2023 European Society of Cardiology (ESC) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with acute coronary syndromes (ACS), adding ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) to achieve recommended target goals (LDL-C<55 mg/dL). Purpose This population-based, real-world study aimed to examine cardiovascular (CV) events in ACS patients with baseline LDL-C levels below current guideline thresholds. Methods ACS patients admitted to four Swiss University Hospitals and enrolled in the multicenter SPUM registry (NCT 01000701) between 2009 and 2017 were followed prospectively until 1 year. The composite primary endpoint was major adverse cardiac and cerebrovascular events (MACCE); i.e., non-fatal stroke, myocardial infarction (MI), and death) at 1 year. Multivariable-adjusted Cox proportional hazard regression models were fit to estimate ischaemic risk among those with LDL-C<55 mg/dL. Results Out of 4’787 ACS patients, 226 patients (4.7%) had baseline LDL-C<55 mg/dL. These patients were older (69.7±11.3 vs 63.4±12.4, p<0.001), more frequently male (20.8%vs 15.9%, p<0.001), had more often traditional CV risk factors (all p<0.001) and were more likely to have a complex history of CV disease, such as previous MI (37.2% vs 10.9%, p<0.001), prior percutaneous (47.8% vs 13.2%, p<0.001) or surgical (15.0% vs 3.5%, p<0.001) coronary revascularization. Inflammatory biomarkers were also higher (hs-CRP, 30.1±63.6 vs 10.7±25.8 mg/L), with most patients being on high-dose statin therapy (82.4% vs 38.7%, p<0.001). At 1 year, patients with LDL-C<55 mg/dL had a higher rate of MACCE (16.4% vs 7.0%, p<0.001), with individual components of the primary endpoint occurring more frequently among these patients (all p<0.001), except for a numerical increase in CE (2.7% vs 1.7%, p=n.s.), as shown in the figure (Panel A). The enhanced MACCE risk persisted after adjustment for potential differences in baseline characteristics, with a 51% (adj. HR 1.51, CI95% 1.05-2.17, p=0.026) increase in MACCE (Panel B). Diabetes, low eGFR and high hs-CRP levels remained independent predictors of MACCE in patients with low baseline LDL-C (all p<0.001). Conclusions Our real-world data confirm that even ACS-patients reaching currently recommended LDL-C thresholds have a substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to further reduce CV risk.Event-risk according to baseline LDL-C

OptiHeart: determinants and prognostic importance of optimal medical treatment in patients with heart failure discharged from the heart failure clinic

Abstract Background Heart failure (HF) is an increasing health problem globally. Current guidelines are based on studies with primarily male patients. Females are less likely to receive target dose of HF medication as recommended by the clinical guidelines. The reason for this is uncertain, but it has led to the question whether females might not need as high dosages as the males to achieve the beneficial effects of the HF medication. Aim To assess baseline predictors for achieving optimal medical treatment (OMT) and the prognostic importance of OMT for male and female patients who have attended a HF clinical program (HFCP). Methods OPTIHEART included 870 patients with left ventricular ejection fraction (LVEF) <45% leaving HFCP in 2018, 2019 or 2020 and followed in registers for a mean of 1083(SD 11.3) days. OMT was defined as receiving an angiotensin-converting-enzyme-inhibitor (ACEi), angiotensin-receptor blocker (ARB) or angiotensin-II-receptor blocker and nephrylisin-inhibitor (ARNI) AND a betablocker both in doses > 50% of target dose. Association between baseline data at referral and OMT at end of HFCP were calculated using logistic regression. The association between OMT and a 5-point Major Adverse Cardiovascular Event (a 5-Point MACE consisting of cardiovascular mortality, non-fatal acute myocardial infarction, non-fatal stroke, coronary revascularization, worsening of heart failure (both hospitalisation and re-referral to HFC)), were calculated and adjusted for other cardiovascular risk factors using multiple Cox-regression analyses. Results Achieving OMT was associated with male sex (OR: 2.05 95%CI 1.44-2.97; P<0.0001) independently of younger age, higher diastolic blood pressure (DBP), and lower creatinine at referral. A lower rate of 5-point MACE was associated achieved OMT (HR: 0.67 95%CI 0.50-0.89; P=0.006) independently of female sex (HR: 0.62 95%CI 0.47-0.82; P=0.002), younger age, never smoking and NYHA≤2. The beneficial effect of OMT was more pronounced in patients with BMI<26.5kg/m2 (HR=0.41[0.23-0.72] vs. HR=0.84[0.58-1.21], Pinteraction= 0.02), and insignificantly more pronounced in patients with male sex, older age, higher creatinine, and lower DBP. Conclusion OMT was more frequently achieved in patients with male sex independently of lower age, higher DBP, and lower creatinine. Achieving OMT was associated with less 5-point MACE independently of female sex, younger age, never smoking and NYHA≤2 and especially in patients with BMI<26.5kg/m2.Hazard RatioMedical treatment

Neutrophil-to-lymphocyte ratio can predict the clinical prognosis of patients with primary adosteronism

Abstract Background Excess aldosterone-mediated inflammatory response is thought to be a factor in the high risk of cardiovascular events in patients with primary aldosteronism (PA). Leucocyte related inflammatory parameters, especially NLR, were significantly independent of aldosterone (PAC) in PA patients. However, the impact of NLR on the long-term prognosis of PA patients is unclear. Objective To explore the predictive value of neutrophil-to-lymphocyte ratio (NLR) on the long-term prognosis of patients with primary aldosteronism (PA). Methods The data for this study were derived from the Tianjin Health and Medical Big Data Super platform, comprising a retrospective cohort of patients discharged from 72 hospitals in our city from 2010 to 2023. According to the inclusion and exclusion criteria, 570 patients were ultimately included in the statistical analysis. Each patient had laboratory measurements, including blood cell counts, taken after admission and before interventional treatment. The primary endpoint was major cardiovascular events (MACEs), defined as cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke. Results During a mean follow-up period of 5 years, 125（21.9%）MACEs were recorded. ROC curve analysis displayed that the best cut-off value of NLR for predicting MACEs was 4.87. The MACEs of the high NLR group at 1 year, 3 years, and 5 years were higher than those of the low NLR group（25.0% vs 9.4%，40.3% vs17.1% 和 40.3% vs 19.3%；P＜0.05).Kaplan-Meier survival curve analysis showed that the survival rate of the low NLR group was higher than that of the high NLR group (P<0.001). The results of multivariate Cox proportional hazards regression analysis showed that NLR was an independent risk factor affecting the prognosis of PA patients, and the difference was statistically significant (P<0.05). Conclusions Elevated NLR is associated with adverse prognosis in patients with PA. NLR can serve as a simple and practical indicator to evaluate the long-term prognosis of PA patients. These findings warrant external validation, preferably in a prospective design.

Incidental detection and quantification of coronary artery calcification in ungated thoracic computed tomography for prognostic assessment. Preliminary results from the ICARUS registry

Abstract Background Coronary artery calcium (CAC) score improves cardiovascular risk stratification in asymptomatic individuals. However, whether CAC can be quantified in ungated thoracic computed tomography (uTCT) performed for other indications, and if this CAC score associates with cardiovascular outcomes, hasn’t been confirmed yet. Purpose We aim to analyse the extension of CAC and its prognostic value in terms of major adverse cardiovascular events (MACE) in patients who underwent uTCT for other indications. Methods We analysed a preliminary sample of 115 uTCT performed in 2015 in our hospital. We studied the presence and extension of CAC and quantified the global CAC score by Agatston method using validated software. Patients were categorized according to Coronary Artery Calcium Data and Reporting System (CAC-DRS) categories. Cardiovascular risk factors, lipidic control and pharmacological therapy of the cohort were registered. We analysed the time to first 3P-MACE, defined as cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, whichever occurred first. A p-value <0.05 was considered statistically significant. Results Mean age of the cohort was 60.8±16.1 years (53% male, 53% smokers). Mean LDL-cholesterol was 121.67±34.91 mg/dL, and 35.1% received lipid-lowering therapy. In more than half (n=59, 51.3%) of the population CAC was detected. Mean CAC score was 312.99±774.48 Agatston units, and patients were categorized in CAC-DRS category 1 (n=19, 16.5%), category 2 (n=15, 13%) and category 3 (n=25, 21.7%). Patients with CAC were older (71±10.1 vs. 50.1±14.2 years, p<0.001), had higher burden of cardiovascular risk factors and prevalence of chronic kidney disease (CKD; n=8, 13.6% vs. n=1, 1.8%, p=0.03) and higher levels of triglycerides (143.2±80.5 vs. 106.8±36.2 mg/dL, p=0.004), but not LDL-cholesterol. Eleven (9.6%) patients presented 3P-MACE during a mean follow-up of 6.55±2.82 years. CAC score independently predicted 3P-MACE (HR 1.06 [1.01-1.11] per 100 Agatston units, p=0.02) along with CKD (HR 6.94 [1.58-30.46], p=0.01) and basal glucose levels (HR 1.03 [1.02-1.04] per mg/dL, p<0.001). Conclusions CAC can be incidentally detected in more than half of our unselected cohort of patients undergoing uTCT for other indications. CAC score quantification by Agatston method is feasible in uTCT and associates with a higher risk of MACE during follow-up.Incidental CAC detection in uTCT

Bioprosthetic versus mechanical prostheses in patients aged 50 to 70 years undergoing aortic valve replacement surgery: outcomes analysis from propensity score matching

Abstract Introduction Despite increasing use of bioprosthetic surgical aortic valve replacement (bAVR) in patients ≤70 years [1, 2], the relative benefits compared to mechanical valve replacement (mAVR) remain uncertain [3, 4]. Purpose The current study aims to compare mortality and other important clinical endpoints by prosthesis type for patients aged 50-70 years who received an AVR in a well-characterised Australian cohort. Methods A retrospective cohort study was designed utilising the WAVES Patient Registry and incorporating linked administrative outcome data including all patients who had an AVR in Western Australian public hospitals between 2010-2020. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular (CV) mortality, separately and combined with non-fatal myocardial infarction and non-fatal stroke (MACE), major bleeding, and days alive and out of hospital (DAOH). Outcomes were compared based on a propensity-matched analysis (including demographics, biometrics, and clinical characteristics). Results Within the initial cohort of 727 patients undergoing surgical AVR (mean age = 63 ± SD 6), a propensity-matched cohort identified 151 patients each with bAVR (mean age = 61 ± 4) and mAVR (mean age = 60 ± 5). Patients who received mAVR versus bAVR had improved all-cause survival (Hazard Ratio [HR] 0.50; 95% CI 0.25-0.99) but increased risk of major bleeding (HR 4.85; 95% CI 1.57-14.98). There were no significant differences in CV mortality (HR 0.58; 95% CI 0.19-1.74), MACE (HR 0.59; 95 % CI 0.32-1.07), or DAOH by prosthesis type (P = 0.452). Conclusions Patients aged 50-70 years who underwent mAVR had lower risk of all-cause mortality compared with bAVR, despite higher bleeding risk. Although risks of CV mortality and MACE were lower in mAVR, statistical significance was not reached, likely due to the small sample size. Larger studies are necessary to confirm these findings, which have important clinical implications.

A systematic assessment of myocardial involvement and cardiovascular events up to six months in patients hospitalised with COVID-19

Abstract Background Retrospective cohort studies indicate that myocardial injury occurs in approximately 25% of patients hospitalised with COVID-19. However, prospective studies with a systematic assessment of myocardial involvement and major adverse cardiovascular events (MACE) after COVID-19 are scarce. Purpose The primary objective was to determine the incidence of MACE within six months of hospitalisation. MACE was defined as a composite of cardiac death, sudden death, life-threatening ventricular arrhythmia's, heart failure, non-fatal myocardial infarction, and/or non-fatal stroke. The main secondary objective was to determine the frequency of other cardiac complications not covered by this definition. Methods We conducted a prospective multicenter cohort study in 13 Dutch medical centers. Adult patients hospitalised with COVID-19 were consecutively recruited (May 2021-April 2023). Exclusion criteria were age ≥70 years, a history of new cardiac disease in the past six months, or dependency in the activities of daily living. Cardiac involvement was evaluated by a standardised healthcare pathway that was implemented in participating hospitals. All patients received an electrocardiogram, transthoracic echocardiogram, and troponin measurement at admission and at six months follow-up. Furthermore, a questionnaire was distributed at three and six months after admission to collect information on post-COVID symptomatology. Results In total 190 patients were included, median age of 57 years [IQR 48; 64], mostly male (n=110, 60%) and white (n=136, 72%). Cardiovascular risk factors were present in 116 (61.1%) patients and 33 (17.4%) had a history of cardiac disease. At admission, troponin was above the upper limit of normal in 68 (35.8%) patients. Seven (3.7%) patients died during follow-up. The cumulative incidence of MACE was 2.6% at discharge with no additional events during follow-up. Other cardiac complications were detected in 18 (9.5%) patients during admission with 3 (1.6%) additional events at six months follow-up. Supraventricular tachycardias (n=8, 4.2%) were the most common cardiac complication. Other complications were myocarditis (n=2, 1.1%), pericarditis (n=1, 0.5%), non-sustained ventricular tachycardia (n=1, 0.5%), and other arrhythmias or conduction disorders (n=5, 2.6%). At six months follow-up, three (2.3%) patients reported chest pain, with one requiring a percutaneous coronary intervention. Palpitations and dizziness were experienced by 88.9% and 83.3% of patients three months after admission but the prevalence of these symptoms decreased to 9.8% and 11.8% at six months. Conclusion With a systematic assessment, one in three patients hospitalized with COVID-19 have elevated troponin levels at admission. However, the overall incidence of MACE within six months is low. Palpitations and dizziness are commonly reported after discharge but these symptoms disappeared for most participants within six months.

Association of cumulative systolic blood pressure load with cardiovascular events in patients undergoing percutaneous coronary intervention

Abstract Background Cumulative systolic blood pressure (SBP) load is a measure that considers both the magnitude and duration of elevated BP. The aim of this study was to evaluate the association between cumulative SBP load and the risk of cardiovascular events in patients following percutaneous coronary intervention. Methods Consecutive patients who underwent PCI between 2012 and 2016 were included. Cumulative SBP load was calculated as the area under the curve for SBP values ≥130 mm Hg divided by the total area under the curve for all measured SBP values during a 1-year period following PCI. The co-primary outcomes included net adverse clinical events (NACE) and major adverse cardiac and cerebrovascular events (MACCE) over a 3-year period. NACE was defined as a composite of MACCE (including all-cause death, non-fatal myocardial infarction (MI), non-fatal stroke, or any revascularization) or major bleeding. Results A total of 2,006 patients were included, among whom 253 (12.6%) experienced NACE during the follow-up period. Each 1-SD increase in cumulative SBP load was associated with a 28.7% increase in NACE (adjusted hazard ratio [aHR]: 1.287; 95% confidence interval [CI]: 1.160-1.428) and a 35.8% increase in MACCE (aHR: 1.358; 95% CI: 1.207-1.529). Furthermore, patients in the highest (third) SBP load group had a significantly higher risk of NACE (aHR: 1.672; 95% CI: 1.149-2.433) and MACCE (aHR: 1.722; 95% CI: 1.249-2.372) compared to those in the lowest (first) SBP load group. Conclusions Among patients undergoing PCI, there is a significant correlation between cumulative SBP load and clinical events. These findings emphasize the importance of accounting for both the magnitude and duration of elevated SBP in secondary cardiovascular prevention.

Insights into the reporting of major adverse cardiovascular events in coronary artery disease trials

Abstract Background and Purpose Major adverse cardiovascular event (MACE) is one of the most used composite outcomes in coronary artery disease (CAD) trials, though its lack of a standardised definition has led to ambiguity and challenges in its interpretation. This study aims to elucidate the definition of MACE and guide future interpretation of MACE in the context of CAD trials. Methods A systematic review was conducted by searching Medline, Embase and Cochrane for double-blind pharmacological randomized-controlled trials among participants with CAD from 2012 to 2022 that reported MACE outcomes. Qualitative reviews were conducted based on the components of MACE, composite definitions, composite rationale, and the reporting of MACE. Results 30 trials, consisting of 77,692 patients were included, from which a total of 41 MACE analyses were extracted. The most commonly included components were cardiac death (56%), unplanned revascularisation (56%), followed by fatal or non-fatal MI (54%), non-fatal MI (44%) and stroke (39%), with cardiac death, non-fatal MI and non-fatal stroke being the most commonly used conglomerate (14%). A third of trials did not provide definitions of MACE, and all MACE composites in included trials were determined within the investigating committees without justification nor citation from guidelines. Notably, 27% of studies constructed MACE outcomes post hoc, with 7% observing a resultant change in statistical significance of the overall results. A fifth of studies deviated from the original MACE definition that was proposed within their protocol. There were inconsistencies in the definitions of the composite components, with 22 trials (73%) failing to specify whether the MI component in MACE was fatal or non-fatal. Similarly, 16 trials (53%) did not specify if stroke was fatal. In terms of the timing of MACE in patients presenting with multiple events, the majority of the trials (77%) did not specify how the event was assessed with, seven trials (23%) described the approach to recording the time to the first MACE event, while none of the trials considered the time to the event that conferred greatest clinical significance, nor provided a definition for it. Conclusion There is substantial heterogeneity in MACE definitions within CAD trials, where rationale behind its adjudication is often inadequately described, with suboptimal specification, inconsistent reporting, and publication bias within and across studies. Clinicians should be cautious when interpreting conclusions related to MACE, as the intervention is unlikely to affect all components of MACE, due to the susceptibility to "cherry-picking" of components to improve statistical outcomes. Harmonising the MACE definition would enhance transparency in clinical trial reporting, ensuring a robust measure of intervention efficacy and safety that can be easily compared across different trials.

Remnant cholesterol predicts major cardiovascular events in coronary artery disease patients with NAFLD

Abstract Remnant cholesterol has attracted interest as a marker of cardiovascular event risk. The power of remnant cholesterol to predict major cardiovascular events (MACE) in patients with non-alcoholic fatty liver disease (NAFLD) is unclear and is addressed in the present study. We enrolled a high-risk cohort of 913 patients with coronary artery disease (CAD). NAFLD was diagnosed using the validated fatty liver index (FLI). Prospectively, MACE including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke were recorded over a mean follow-up period of 9.5±5.2 years. At baseline, remnant cholesterol was significantly higher in patients with NAFLD (n=419) than in patients who did not have NAFLD (30±28 mg/dl vs. 18±17 mg/dl; p<0.001). During follow-up, 379 of our patients suffered MACE. Remnant cholesterol in Cox regression models adjusting for age, sex, hypertension, smoking, diabetes mellitus, body mass index and LDL cholesterol independently predicted MACE in the total study population (standardized adjusted HR 1.18 [1.08-1.30], p<0.001), and both in patients with NAFLD as well as in those who did not have NAFLD (standardized adjusted HRs 1.19 [1.05-1.35], p=0.006 and 1.24 [1.03-1.49], p=0.023, respectively). From our data we conclude that remnant cholesterol is a predictor of MACE in patients with CAD with and without NAFLD.

A real-world data analysis investigating the cardioprotective effects of glucagon-like peptide-1 receptor agonists among people with type 2 diabetes in England

Abstract Background Cardiovascular disease (CVD) is a common and major complication of type 2 diabetes (T2D). Anti-diabetic therapy aims to lower blood glucose, with primary clinical trial endpoints for new antidiabetic entrants focused on HbA1c. Research suggests some glucose-lowering drugs, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), can have a cardioprotective effect in people with T2D.1,2 Purpose To compare the real-world risk of major adverse cardiovascular event (MACE) in people with T2D treated with GLP-1 RAs compared to dipeptidyl peptidase-4 (DPP-4) inhibitors or basal insulin. Methods We conducted a retrospective cohort study using linked primary care data from the Clinical Practice Research Datalink Aurum, secondary care Hospital Episode Statistics and Office for National Statistics death registrations. We included patients aged ≥18 years with T2D at high-risk or very-high-risk of CVD (as defined by the European Society of Cardiology) who had ≥2 prescriptions of either GLP-1 RA (dulaglutide, liraglutide, and semaglutide), DPP-4 inhibitor (as part of line 4 therapy) or basal insulin from 01/01/2014-31/12/2018. We excluded those pregnant at therapy initiation or with type 1 diabetes. Follow-up started at second prescription of relevant therapy and ended at the earliest of two years later, pregnancy, death, end of primary care record, or 31/12/2019. We used data from patients’ medical histories to define baseline characteristics. We calculated the incidence of MACE per 100,000 person-years (PY), defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. We used Cox proportional hazards regression, using LASSO to select confounding clinical variables including BMI, prior MACE and intercurrent antidiabetic treatments, to estimate risk difference of MACE among those treated with 1) GLP1-RA and DPP-4 inhibitor and 2) GLP1-RA and basal insulin. Results We included 63,237 patients, among whom the patients treated with GLP1-RA were younger and a higher proportion were obese or severely obese than those treated with DPP-4 inhibitor or basal insulin (Table 1). The incidence of MACE was highest in those treated with DPP-4 inhibitor (high-risk 1,503.0/100,000 PY; very-high-risk 6,000.7/100,000 PY) followed by basal insulin (high-risk 1,396.9/100,000 PY; very-high-risk 5,707.1/100,000 PY), and lowest in those treated with GLP1-RA (high-risk 377.1/100,000 PY; very-high-risk 1,946.1/100,000 PY). After adjustment, the risk of MACE among patients treated with GLP1-RA was still significantly lower than those treated with either DPP-4 inhibitor (high-risk aHR: 0.42, 95% CI 0.21-0.86 and very-high-risk aHR: 0.65, 95% CI 0.58-0.73) or those treated with basal insulin (high-risk aHR: 0.36, 95% CI 0.18-0.72 and very-high-risk aHR: 0.72, 95% CI 0.64-0.81). Conclusion(s) Our study supports clinical trial and other observational research studies which find a cardioprotective effect of GLP-1 RA use in people with T2D.

Clinical impact of serum cholinesterase level on clinical outcomes in patients with lower extremity artery disease undergoing endovascular treatment

Abstract Background Cholinesterase (ChE) has been used to be an indicator of the protein synthesis ability in the liver and nutritional status. Recent findings have identified low ChE levels as a prognostic factor for heart failure. However, the relationship between serum ChE levels and clinical outcomes in patients with lower extremity artery disease (LEAD) undergoing endovascular treatment (EVT) remains unclear. Purpose This study aimed to investigate the association between pre-procedure serum ChE levels and clinical outcomes in LEAD patients undergoing EVT. Methods The subjects were 283 consecutive LEAD patients who underwent EVT at our University Hospital were included. The primary outcome measure was the cumulative incidence of major adverse cardiovascular events (MACEs) within two years, defined as the composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke. Results The mean age of the cohort was 72.6±10.6 years, with 67.5% being male. Within two years, 45 patients experienced MACE, and Kaplan-Meier curves demonstrated the cumulative incidence of MACE within two years was 19.3%. Receiver operating characteristic curve analysis showed that serum ChE was a univariable factor that predicted MACE within two years with moderate accuracy (area under the curve = 0.693, 95% confidence interval (CI) 0.615–0.771), with an optimal serum ChE cutoff level of 284 units/L. According to the optimal cut-off value, patients were divided into low ChE (ChE ≤ 284 units/L, N=189) and high ChE ((ChE > 284 units/L, N=94) groups. In the baseline characteristics between the two groups, age was significantly higher in the low ChE groups than in the high ChE group. There were no significant differences in gender, the prevalence of diabetes mellitus, hypertension, and the proportions of previous stroke, and previous myocardial infarction between the two groups. In contrast, the proportions of hemodialysis (HD) and chronic limb-threatening ischemia (CLTI) were higher in the low ChE groups. Kaplan-Meier curves demonstrated a significantly higher cumulative incidence of MACE in the low ChE group compared to the high ChE group (log-rank p < 0.001). In multivariate analysis using Cox proportional hazards models adjusting for risk factors, including HD and CLTI, low ChE group was independently associated with MACE (low ChE group: hazard ratio (HR) 4.24, 95% confidence interval (CI) 1.24-14.49, p=0.021). In addition, Cox proportional hazards models using serum ChE level and HD revealed that patients with both low-ChE and HD showed a greater risk of MACE (HR 15.19; 95% CI 3.60–64.02; P < 0.001) after EVT as compared to patients with neither low-CHE nor HD. Conclusions In LEAD patients undergoing EVT, lower ChE levels were independently associated with a higher risk of MACE, regardless of HD. Assessment of serum ChE level may provide insights into identifying high-risk LEAD patients who need careful attention after EVT.

Identifying clinical phenotype clusters for coronary artery disease: a novel approach using clustering by unsupervised machine learning

Abstract Background Guideline recommendations for the prevention of cardiovascular (CV) events in patients with coronary artery disease (CAD) are one-size-fits-all. Clinically identifiable phenotypes needing specific considerations might exist. Purpose To identify phenotypes in patients with CAD based on clinical characteristics and their relationship with the risk of new CV events and treatment benefits. Methods Unsupervised machine learning through latent class analysis (LCA) was performed on patients with CAD included in the UCC-SMART cohort (n = 5,888) and SWEDEHEART registry (n = 67,428), to identify patient clusters (i.e., phenotypes) based on clinical characteristics: age, sex, body-mass-index, diastolic blood pressure, history of diabetes, myocardial infarction, atrial fibrillation, polyvascular disease, current smoking, non-high density lipoprotein cholesterol, estimated glomerular filtration rate, and C-reactive protein. Number of clusters was determined using the Bayesian information criterion. Event free survival and hazard ratios (HR) for major adverse cardiovascular events (MACE) as primary endpoint, including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, were estimated per cluster. The LCA were performed in each respective cohort and cross-validated in the other cohort to assess impact of variations in clustering variables on cluster reproducibility. In UCC-SMART, bootstrapping was performed the assess stability of the LCA model and impact on cluster assignment. Results In UCC-SMART four distinct phenotypes within the CAD population could be distinguished: Phenotype A (16%) of mostly males with isolated CAD, phenotype B (30%) of older patients with polyvascular disease, Phenotype C (28%) of only women with limited traditional risk factors and Phenotype D (27%) young, current smokers with a premature event (Figure 1). Cross-validation in SWEDEHEART identified roughly the same four phenotypes, i.e., phenotype A (39%) with 100% males and 3.8% polyvascular disease, phenotype B (8%) with average age of 71 years and 30% polyvascular disease, phenotype C (19%) with 100% women, and phenotype D (34%) 54 years and 25% current smokers. Notably, although age was comparable between phenotype A and C, MACE-free survival was worse for the female-only cluster. Similarly, although patients where on average 9 years younger in phenotype D when compared to phenotype A, MACE-free survival was worse (Figure 2). No significant changes in clustering models were observed in the bootstrap samples. Conclusion Phenotypes can be distinguished within patients with CAD. These phenotypes are related to differences in the risk of recurrent events. These findings suggest that specific guideline recommendations for these groups could be considered.Cluster interpretation in SMARTSurvival along cluster lines

Body weight variability as a predictor of cardiovascular outcomes in type 1 diabetes: A nationwide cohort study.

Intraindividual body weight variability (BWV), that is, the degree of weight fluctuations over time, is associated with an increased risk of cardiovascular diseases (CVDs) in multiple settings. The impact of BWV on cardiovascular risk in type 1 diabetes (T1D) remains unclear, despite the issues relative to weight management in individuals with this condition. Using data from the Swedish National Diabetes Register, we identified individuals with T1D and without CVD at baseline with at least three measurements of body weight taken over three consecutive years. We estimated BWV as quartiles of the standard deviation of weight measures and explored its longitudinal association with the incidence of CVD during a 12.7 ± 4.6 year follow-up through adjusted Cox regression models. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke and all-cause mortality. We modelled the function of risk in relation to the magnitude of BWV, testing also whether weight trends, that is, increasing, stable or decreasing, age, sex and glycaemic control modified the association between BWV and the outcome. Among the 36 333 individuals with T1D in the register, we identified 19 373 individuals with at least three measures of body weight and without CVD at baseline. Participants with the highest BWV had a 42% increased risk of reaching the primary endpoint compared to those with the lowest BWV (hazard ratio [HR] = 1.42, 95% confidence interval [CI]: 1.24-1.62). In addition, high BWV was significantly associated with a 51% increased risk of all-cause mortality (HR = 1.51, 95% CI: 1.28-1.78), a 37% increased risk of peripheral artery disease (HR = 1.37, 95% CI: 1.06-1.77) and a 55% increased risk of hospitalization for heart failure (HR = 1.55, 95% CI: 1.20-2.01). BWV showed a quasi-linear association with the primary endpoint. No interaction was observed when comparing subgroups for weight trends, sex or degree of glycaemic control. In the subgroup of elderly individuals, the association of BWV with the primary endpoint was no longer significant. High BWV is associated with an increased risk of CVD and all-cause mortality in individuals with T1D, independently of canonical risk factors. Weight trends, sex and glycaemic control do not modify such association while older age attenuates it.