Cardiovascular Risk Research Articles

How vaccination affects clinical outcomes of COVID-19 positive revascularized patients?

Abstract Background/Introduction Several vaccines are now available under emergency use authorization in globe and have demonstrated efficacy against COVID-19 positive patients. Our investigation centers on understanding the correlation between COVID-19 vaccine status and an extensive spectrum of risk factors, clarifying their impact on clinical outcomes in COVID-positive revascularized populations. Purpose This study clarified the multifaceted impact of the COVID-19 vaccine on individuals with a history of revascularization, highlighting the relationship between vaccination status and clinical outcomes. Methods We conducted a retrospective a cohort study COVID-19 positive (n=620) patients with revascularized two years prior to the pandemic, was categorized into unvaccinated (n=359) and vaccinated (n=261) groups. Comprehensive retrospective data on various risk factors, including hypertension, diabetes, smoking, stroke history, family history were collected. Clinical outcomes, intently documented, encompassed hospitalization, mortality, stroke and mechanical ventilation. Statistical analyses, including correlation assessments, were conducted, focusing on the COVID-positive subgroup. Results During the analysis of risk factors, between the unvaccinated and vaccinated groups the prevalence of smoking (32% vs. 31.4%, p=0.871), hypertension (81.3% vs. 78.2%, p=0.329), DM (42 .9% vs. 43.3%, p=0.921), HLP (14.8% vs. 13%, p=0.539), family history (21.7% vs. 17.6%, p=0.208)were not significantly different (Table 1). It showed a significant association with increased hospitalization(14.6% vs. 24.8%, p = 0.002) and death (2.3% vs. 8.1%, p = 0.002)rates in the unvaccinated group. In addition, it was associated with higher rate of mechanical ventilation in the unvaccinated group (2.6% vs. 10.1%, p = 0.153).Also, no significant difference was found between the two groups according to the type of revascularization, PCI (70.2% vs. 75.1%, p = 0.179), CABG (29.8% vs. 24.9%, p = 0.179) (Table 2). Conclusion(s) Our analysis within the COVID-positive subgroup of 620 revascularized patients revealed a significant correlation between COVID-19 vaccination status and clinical outcomes. Thus, a significant reduction in hospitalizations and deaths was recorded in the vaccinated group. This supports a potential positive effect of the vaccine on cardiovascular events in patients with COVID-19.Table 1Table 2

The impact of blood pressure guidelines on the cardiovascular event risk in Japanese patients with coronary artery disease in a real-world database using a multimodal data acquisition system

Abstract Background The European Society of Hypertension and the Japanese Society of Hypertension have established a blood pressure (BP) guideline for coronary artery disease (CAD): 130/80 mmHg. The impact of adhering to this BP guideline on the prognosis of Japanese patients with CAD after they have undergone percutaneous coronary intervention (PCI) is unclear. Purpose We investigated the impact of the current guideline-recommended BP value 130/80 mmHg on the prognosis of Japanese patients with CAD by using 'big data,' i.e., the Clinical Deep Data Accumulation System (CLIDAS) database. Methods We evaluated the data of 8,793 CAD patients who underwent cardiac catheterization at six university hospitals and Japan's National Cerebral and Cardiovascular Center (mean ± std. dev. 70 ± 11 years, 78% male, 43% with acute coronary syndrome [ACS]). We categorized the patients based on their BP management: those adhering to the guideline-recommended BP (<130/80 mmHg) and those under stricter BP control criteria (<120/70 mmHg and <110/60 mmHg). We compared the incidence of major adverse cardiovascular events (MACCEs) between these groups, with MACCEs being a composite endpoint (cardiovascular death, stroke, and myocardial infarction). We analyzed the relationship between BP classification and MACCE separately in two groups: the patients with ACS and those with chronic coronary syndrome (CCS). Results During an average follow-up period of 33 months, 710 MACCEs occurred, comprising 234 cardiovascular deaths, 305 strokes, and 270 myocardial infarctions, with some cases overlapping. No significant difference in the MACCE rate was observed between the group with BP below 130/80 mmHg and the group with BP above 130/80 mmHg (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.75–1.04, p=0.133). In the ACS group, the patients maintaining BP below 130/80 mmHg had a significantly lower MACCE incidence (HR 0.75, 95%CI: 0.59–0.95, p=0.017) and a significantly lower incidence of stroke (HR 0.47, 95%CI: 0.33–0.68, p<0.001), whereas no significant difference in the MACCE incidence was observed in the CCS group (HR 0.91, 95%CI: 0.73–1.13, p=0.393). Blood pressure values below 120/70 mmHg (HR 1.13, 95%CI: 0.97–1.31, p=0.109) and 110/60 mmHg (HR 1.23, 95%CI: 1.06–1.43, p=0.008), corresponded to an increased rate of MACCEs, becoming more pronounced at BP values <110/60 mmHg. Conclusion Achieving the BP guideline target of <130/80 mmHg is associated with improved outcomes in CAD patients, particularly regarding reducing the risk of stroke among patients with ACS. However, BP control at values that are too low may potentially worsen the prognosis for CAD patients.Kaplan–Meier curve

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.

10 years after treatment with renal denervation of the sympathetic nerves for resistant hypertension: what happened to the patients and their office blood pressure? An observational study

Abstract Background Catheter-based renal denervation of the sympathetic nerves (RDN) for resistant hypertension has long been controversial. A renewed clinical and scientific interest in defining the appropriate role of RDN in the treatment of resistant hypertension has become evident in recent years. The efficacy and safety of RDN treatment is mainly based on available data up to three years, whereas data concerning the long-term effect and safety are scarce. Purpose We therefore wanted to investigate the long time change in blood pressure (BP) in patients treated with RDN for resistant hypertension. Methods A review of data from the electronic patient journal concerning all RDN treated patients was initiated and completed in October 2023. Every registration of an office BP listed in the patient file, antihypertensive treatment, cardiovascular events, and renal function between 2012 and 2023 were registered. For each patient the average of all office post RDN blood were averaged for every year and for their complete follow-up. The outcome in blood pressure was the change in BP from baseline pre RDN office to follow-up Results Between January 2012 and October 2013, 19 consecutive patients underwent RDN treatment, 10 men and 9 women with a median age of 63 years (range 35-74 years). At baseline the median systolic office BP was 181 mmHg (range 162–230 mmHg) and the diastolic office BP 97 mmHg (range 82-123 mmHg) on a median of 5 (range 0-7 ) antihypertensive drugs. During follow-up the number of antihypertensive drugs were reduced in 7, unchanged in 10, and increased in 2 patients. Two patients left the outpatient clinic with normal BP after 2 years. Two patients developed heart failure after 7 years and were censored at that time-point. 15 (79%) patients had office BP recorded up to 9 or 10 years. In the 15 (79%) patients with available office BP 9 to 10 years after RDN the median systolic and diastolic office BPs were reduced by 39 mmHg (range -2 to - 66 mmHg) and 18 mmHg (range -11 to - 55 mmHg) respectively, relative reduction 22% (range 5-36%) and 20% (range 6-32), respectively. Conclusion During a follow-up of 9 to 10 years after RDN without a step-up in antihypertensive medication a relative decrease of ~20% in systolic and diastolic BP was observed.

Real-world analysis exploring the association between anti-hypertensive therapy with perindopril-based single-pill combinations (SPC) and cardiovascular outcomes and all-cause mortality in Italy

Abstract Background/Introduction A combination of blood pressure (BP)-lowering medications is recommended by guidelines as an effective strategy to obtain rapid and optimal BP control in hypertensive patients. However, the prescription of multiple BP-lowering medications increases the pill burden, potentially reducing medication adherence. Guidelines also recommend using single pill combinations(SPCs) containing ≥2 anti-hypertensive medications as a practical approach to simplify treatment schedules and possibly improve adherence. Yet, real-world evidence on the association between SPC or free combination of BP-lowering medications and hyperthensive patient outcome remains limited. Purpose We compared the association of SPC versus free-pill combination(free) on cardiovascular outcomes and all-cause mortality in hypertensive patients treated with perindopril(PER)-based therapies in real clinical practice in Italy. Methods A retrospective analysis was conducted using administrative databases covering 6.7 million health-assisted Italian residents. Among adults with hospitalization discharge diagnosis or exemption code for hypertension between 2010 and 2021, the study included patients prescribed with a combination of PER with amlodipine(AML) and/or indapamide(IND), either as SPC or free or mixed (SPC plus separate pill) combinations. Results The analysis included 24,476 hypertensive subjects receiving a PER-based therapy, 22,663 (93%) of them using SPC, 1458 (6%) free and 355 (1.4%) mixed. The last cohort was not included in the analysis due to the small sample size (N=355). The patients in the free cohort were significantly older than those in the SPC cohort (69.5±12.3 vs. 64.3±12.2 years, p<0.001), showed a higher number of pre-existing comorbidities (0.5±0.8 vs. 0.4±0.7, p<0.001), and received a larger number of different medications (pill burden: 1.2±1.7 vs. 0.7±1.3, p<0.001). To minimize selection bias, the groups were balanced with propensity score and inverse probability weighting (IPW), adjusting for baseline covariates, including comorbidity profile and pill burden. The IPW-adjusted Kaplan-Meier plots and Cox’s proportional hazard model (Table 1) revealed that, compared with SPC users, patients on free regimens had a significantly increased risk of all-cause mortality (36%, p<0.001), all cardiovascular events (45%, p<0.001), ischemic heart disease (29%, p<0.05), cerebrovascular events (84%, p<0.001), and occurrence of the composite outcome cardiovascular events/all-cause mortality (40%, p<0.001). Conclusions This real-world data from a large Italian administrative dataset suggested that PER-based anti-hypertensive therapy with SPC results in significant clinical benefits in terms of lowered risk of cardiovascular/cerebrovascular events and all-cause mortality. Reducing pill burden and simplifying therapeutic schedules is of crucial importance to maximize the potential benefits derived from the prescription of anti-hypertensive treatment.

Safety of COVID-19 vaccines regarding cardiovascular events: a systematic review and meta-analysis

Abstract Background Since the outbreak of COVID-19, extensive vaccination strategies have almost excelled in reducing the mortality and severity of COVID-19 infection; however, although there are several authorized vaccines thus far, vaccine hesitancy has risen among various populations. Cardiovascular adverse events have been among the highly reported adverse events of the vaccines. Herein, we aimed to systematically assess the studies that reported the safety of COVID-19 outcomes regarding cardiovascular outcomes. Methods Three online databases were comprehensively searched, including PubMed, Scopus, and Embase. Relevant observational/interventional studies and case reports/series were included. Study characteristics, demographic features of the populations, vaccine type and dosage, and outcomes of interest were extracted. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare the groups vaccinated and those that have not. Results From the 2960 initial searched records, 21 observational/interventional studies, and 110 case reports/series were included. Meta-analysis revealed that there is no difference between vaccinated and non-vaccinated regarding all new-onset cardiac disorders (RR 1.14, 95% CI 0.71 to 1.85, p-value=0.59). On the other hand, vaccinated patients had a higher risk of myopericarditis, compared to the general population by 74% (RR 1.74, 95% CI 1.56 to 1.94, p-value <0.01). There was no difference between the groups in terms of risk of myocardial infarction. Among 219 individuals reported in case reports and series, 193 were diagnosed with myocarditis and pericarditis. Notably, 95.34% of these patients were vaccinated with mRNA-based vaccines. Conclusion This systematic review and meta-analysis implied that there is no increase in overall new-onset cardiac adverse events, while there might be an increased risk of myopericarditis based on some studies’ findings. This highlights that since there is no added cardiovascular risk associated with COVID-19 vaccination, all individuals are encouraged to get vaccinated.Forest plots for meta-analyses

Cardiovascular events and consequent risk of death in hematopoietic stem cell transplant recipients

Abstract Background Hematopoietic stem cell transplant (HSCT) represents a potentially curative approach for various hematologic cancers and bone marrow disorders. Advancements in safety and efficacy have broadened the application of HSCT to older individuals and those with concurrent medical conditions predisposing them to cardiovascular (CV) issues. Despite the significant survival benefits offered by HSCT, it is accompanied by both short- and long-term complications, leading to considerable morbidity and mortality. CV complications, including heart failure, arrhythmias, acute thrombosis, pulmonary hypertension, and pericardial effusions, are among the potential adverse events following HSCT. Aim for the present registry is to determine how much CV complications are related to short-term survival in patients after HSCT. Methods Observational, monocentric cohort study consecutively enrolling all patients undergoing HSCT from 2019 to 2023. Inclusion criteria was >18 years, autologous or allogeneic HSCT, and written informed consent for the participation in the study. All patients underwent a complete cardiological examination, including 12-lead ECG, echocardiography, and cardiac biomarkers, before HSCT, and after 2,6 and 12-months. CV-related adverse events were defined as systolic dysfunction (even asymptomatic), thromboembolism (both VTE and PE), stroke, arrhythmias, pericarditis and hypertensive crises. Results 91 patients (34% female; mean age 54 +/- 12 years) were followed-up for a median of 2 years after HSCT. Major risk factors' prevalence was overall low (hypertension 28%, dyslipidaemia 33%, diabetes 9%, and only 11 patients (12%) had a positive history for CV events (6 atrial fibrillation, 4 coronary heart disease, 1 stroke) before HSCT. During follow-up, 26 patients (29%) experienced at least one CV-related adverse event, of which 7 (8%) were serious enough to require an hospital admission. CV adverse events included 5 new heart failure diagnosis, 5 new atrial fibrillation diagnosis, 10 episodes of VTE/PE, 4 pericarditis, one stroke and one hypertensive crisis. Twenty of all CV-related adverse events were reported within the first six months after HSCT (77%). Having a CV-related AE within the first six months after HSCT is associated with an increased risk of all-cause death (39% vs. 17%; log-rank p=.01; Figure 1). Conclusions CV-related adverse events are common in patients undergoing HSCT and strikes an overall young and healthy population. Having a CV-related adverse event in the six months following HSCT is a heavy prognostic factor for all-cause mortality. Therefore, an optimal prevention strategy including arrhythmia monitoring, echocardiographic follow-up and guideline-driven thromboembolic prophilaxis could improve patients' survival after HSCT.Figure 1

The role of fibrosis and inflammation for response and outcome prediction in candidates to cardiac resynchronization therapy: is response the right answer?

Abstract Background Cardiac resynchronization therapy (CRT) is an established treatment in selected patients suffering from heart failure with reduced ejection fraction (HFrEF). It has been proposed that myocardial fibrosis and inflammation could influence CRT "response" and outcome. Purpose Our study investigated the long-term prognostic significance of cardiac biomarkers in HFrEF patients with an indication for CRT. Methods 86 consecutive patients referred for CRT implantation were retrospectively evaluated. The soluble suppression of tumorigenicity 2 (sST2), galectin-3 (Gal-3), N-terminal portion of the B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured at baseline and after 1 year of follow-up. An echocardiographic reduction of LV end-systolic volume ≥15% was used to define a patient as responder to CRT. Multivariate analyses were performed to evaluate their correlation with the primary composite outcome of cardiovascular mortality and heart failure hospitalizations at a mean follow-up of 9 ± 2 years. Results 44% of patients experienced the primary outcome. the mean baseline values of NT-proBNP, Gal-3, and sST2 were significantly higher compared with the patients without cardiovascular events. At the multivariate analyses, baseline Gal-3 [cut-off: 38.5 ng/ml, AUC: 0.63, p=0.03, (OR 7.13 [1.12;45.41], p=0.03), together with TAPSE>17.5 mm (OR 10.86 [3.15;37.44], p<0.001) significantly correlated with the structural response to CRT in several prediction models. Baseline Gal-3 [cut-off: 16.6 ng/ml, AUC: 0.91, p<0.001, HR 8.33 (1.88–33.33), p = 0.005] and sST2 [cut-off: 35.6 ng/ml AUC: 0.91, p<0.001, HR 333 (250–1,000), p = 0.003] significantly correlated with the composite outcome in the prediction models with high likelihood (Table). At Kaplan-Meyer curve patients with both high baseline sST2 and Gal-3 had the lowest survival probability (Figure). Among the parameters evaluated at 1-year follow-up, sST2, eGFR, and the variation from baseline to 1-year of Gal-3 levels showed a strong association with the primary outcome [HR 1.15 (1.08–1.22), p < 0.001; HR: 0.84 (0.74–0.91), p = 0.04; HR: 1.26 (1.10–1.43), p ≤ 0.001, respectively]. Conversely, the echocardiographic definition of CRT response did not correlate with any outcome. Conclusion In HFrEF patients with CRT, sST2, Gal-3, and renal function were associated with the combined endpoint of cardiovascular death and HF hospitalizations at long term follow-up, while the echocardiographic CRT response did not seem to influence the outcome of the patients.

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.

Clinical Implications of NT-proBNP trajectory following Sacubitril/Valsartan initiation

Abstract Introduction Serum N-terminal pro–B-type natriuretic peptide (NT-proBNP) values after initiating Sacubitril/Valsartan is considered as a favorable prognostic factor, and widely used for risk stratification in patients with heart failure (HF). However, the relationship between the trajectory of serially measured NT-proBNP values and cardiovascular events in patients with HF who are treated with Sacubitril/Valsartan remains uncertain. Purpose This study aimed to reveal the prognostic association of an NT-proBNP trajectory after initiating Sacubitril/Valsartan and subsequent cardiovascular outcomes. Methods and Results A Japanese nationwide multicenter study was conducted on HF patients who initiated Sacubitril/Valsartan. Out of the 995 patients enrolled, we excluded 561 patients who were undergoing assessment of BNP or who lacked a complete set of NT-proBNP measurement. Finally, 434 patients included this study, and were divided into three groups based on NT-proBNP trajectory as follows; the ‘sustained-responder’ group (n = 129, 30%) : which exhibited a reduction of NT-proBNP by ≥10% at 1 month and further reduction of ≥10% at 3 months; and the ‘transient-responder’ group (n = 161, 37%), with ≥10% reduction at 1 month but not at 3 months; and the ‘non-responder’ group (n = 144, 33%), which did not achieve ≥10% reduction at 1 month. The mean age was 68 years, with females comprising 29%. In the ‘sustained-responder’ group, the age was significantly younger, and the duration of heart failure was significantly shorter. There were no significant differences in the mean systolic blood pressure, mean Sacubitril/Valsartan dose at each measurement points among the 3 groups. During follow-up of 456 (IQR, 371-549) days, the primary endpoint, which was either cardiovascular death or hospitalization of HF occurred in 78 of 434 patients (18%). The Kaplan-Meier analysis showed that the ‘sustained responder’ group experienced significantly lower event rate among the 3 groups (Log-rank p<.001). Additionally, an analysis that set a landmark time at 3 months post-initiation of Sacubitril/Valsartan showed that the ‘sustained-responder’ group experienced significantly fewer events than the ‘transient-responder’ group (Log-rank p=0.039) (Figure.1). Also, the ‘sustained responder’ was observed to have a better prognosis in a subgroup with LVEF<50%, but not in patients with LVEF ≥50%. (p value for interaction=0.035) (Figure.2). Conclusions This study revealed that sustained reduction of NT-proBNP was associated with a reduced risk of cardiovascular death or hospitalization for HF. The periodic NT-proBNP monitoring and the patterns of NT-proBNP during treatment with Sacubitril/Valsartan may be helpful in optimizing HF therapy and understanding the prognosis of HF.Figure.1Figure.2

Association of ethanolamine desaturase TMEM189-plasmalogen axis with the stability of atherosclerotic plaque and cardiovascular events after acute coronary syndrome

Abstract Background Patients with acute coronary syndrome (ACS) are still at high risk of recurring major adverse cardiovascular events (MACE). Disorders of lipid metabolism play an important role in the pathogenesis and progression of ACS. However, whether there are lipid components that can play an early warning role on the recurrence of MACE in patients with ACS and its potential mechanism is not yet known. Purpose To explore the changes of lipid profile before recurrent MACE in ACS patients, screen lipid molecules related to recurrent MACE, and explore their effects on pathological changes of atherosclerotic plaque. Methods We selected 44 Chinese ACS patients from the ‘Peking and Rotterdam on Mission to Reduce Coronary Artery Disease’ (PRoMISS) study. Among them, patients with recurrent MACE within 1 year after first onset of ACS were defined as MACE group, and the control group was recruited through 1:1 matching. The lipid profile of patients was analyzed by liquid chromatography-mass spectrometry. The effects of the screened potential lipid biomarkers and their synthesis enzymes were evaluated by real-time PCR, Western blot, IHC staining and ELISA. The enzyme knockout mice and ApoE knockout mice were hybridized and bred to obtain double gene knockout mice to determine whether the enzyme deficiency affects atherosclerotic plaque. Results Lipomic analysis showed that in the MACE group, plasmalogens and their 12 subtypes continued to decrease three months before the MACE recurrence. The most critical ethanolamine desaturase in the synthesis pathway of plasmalogen, transmembrane protein 189 (TMEM189) was also significantly lower in the MACE group than in the control group, and the level of TMEM189 was positively correlated with plasmalogen. Analysis of single-cell RNA sequencing results in human carotid artery plaques shows that TMEM189 is enriched in endothelial cells and smooth muscle cells (VSMC). In VSMC, treatment with oxLDL reduced TMEM189 expression. Overexpression of TMEM189 significantly improved oxLDL induced reduction in collagen synthesis, expression of alpha-smooth muscle actin (alpha-SMA) and smooth muscle protein 22 (SM22). Overexpression of TMEM189 in VSMC, significantly reduced the content of plasmalogens in the cells. After 12 weeks of feeding with high-fat and high-cholesterol diet, it was found that the content of smooth muscle cells and vulnerability index in the aortic plaque in TMEM189 -/-ApoE -/- mice were significantly decreased than in ApoE -/- mice. Conclusions Before the recurrence of MACE in ACS patients, the synthesis pathway of plasmalogen was gradually damaged, and the reduction of plasmalogen was a potential marker for predicting the recurrence of MACE in ACS patients. The deficiency of TMEM189 - plasmalogen axis aggravates atherosclerosis, it can regulate the phenotype transformation of smooth muscle cells, inhibit their collagen synthesis, and thus affect plaque stability.

Study of lipoprotein(a) and its impact on atherosclerotic cardiovascular disease: design, rationale, and first results of the Zabrze-Lip(a)R Registry

Abstract Aims Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. Increased Lp(a) concentration >30 mg/dl may cause faster atherosclerosis. There is a need to characterize further the clinical phenotypes in patients at risk for ASVD with high Lp(a) levels. Material The Zabrze-Lip(a)R Registry was created on the basis of data from 2,001 patients with high- and very high cardiovascular risk treated in a tertiary hospital, and the Registry patients will be followed for many years. Mortality and cardiovascular events, such as known death, MI, and stroke, will be assessed. Results The median Lp(a) concentration in the entire population was 6.6 mg/dl (mean 14.3 ± 19.4 mg/dl). Preliminary results of the study group showed that 540 (27%) patients had elevated Lp(a) levels above 30 mg/dl, mainly in patients with established ASCVD after MI and/or coronary revascularization. Patients with elevated Lp(a) levels are older and have higher hematocrit and NT-proBNP and CRP levels. Conclusions Extensive observational studies are essential for further work that objectively collects information on the risks associated with Lp(a) values and cardiovascular disease. Additionally, developing a deeper understanding of the impact of Lp(a) on prognosis will be valuable in how Lp(a) interacts with other established risk factors in improving cardiovascular risk prediction.Distribution of Lp(a) concentrationsComparison of pts with different Lp(a)

MiRNAs profile as a signature for cardiovascular disease in long-term breast cancer female survivors: a pilot study

Abstract Background/Introduction Cardiovascular diseases (CVD) is a matter of immediate concern among long term breast cancer (BC) survivors. An early identification of those patients who are at higher risk of developing CVD is warranted to tailor prevention strategies and improve their quality of life. Purpose To identify whether a specific miRNA signature exists in breast cancer female survivors who develop CVD in a long term follow up. Methods We performed cross-sectional comparison of miRNA expression between female BC survivors (i.e. individual with a diagnosis of invasive ductal carcinoma who were free from cancer at 10-year follow up and without known CVD before BC diagnosis) with CVD (n=11) and without CVD (n=11) matched for age, BC grade, treatment received and traditional cardiovascular risk factors. CVD was defined as the incidence of established atherosclerotic cardio- or cerebro-vascular diseases (i.e., ischemic heart disease, carotid endarterectomy, stroke, heart failure), atrial fibrillation or venous thromboembolism. Thirteen miRNAs were selected since they were involved in either BC and CVD. On plasma derived samples, miRNAs expression profile analysis was performed by retro-transcription and real-time PCR assays, using miRNA-specific probes. Results The BC female survivors (mean age 73 years, 70% hypertension, 60% histological grade 2 and 3) were treated with surgery. The majority (76%) received hormone therapy after surgery according to the BC receptor expression. In half of the cohort, radiotherapy was performed. Those female BC survivors developing CVD experienced more commonly cerebral or cardiovascular atherosclerotic events (70%). As reported in Figure 1, some miRNAs analyzed (miR-19a; miR-21; miR-24; miR-125b; miR-195) are upregulated in BC survivors who developed CVD. Of note miR-19a, miR-21 (and miR-195) increase is so significantly relevant to consider these miRNAs as candidate biomarkers. Conclusion(s) In this discovery cohort, a specific miRNA profile signature identified female BC survivors experiencing CVD. Validation of such signatures is needed in a larger cohort as well as mechanistic studies to understand what is the pathophysiological link between the miRNAs identified and vascular health. Nevertheless these miRNAs in both cancer and cardiac diseases are mainly associated with promotion of cell proliferation and inhibition of apoptotic processes. The clinical implications of using a specific miRNA profile as a likely early biomarker of adverse cardiovascular events are indeed of great interest to better preserve BC survivors' health.Figure 1

A comprehensive approach combining FFR, CFR, and IMR in order to predict adverse cardiovascular events in patients with non-obstructive coronary artery disease

Abstract Background Abnormal coronary circulation is linked to poor patient outcomes. The predictive values of comprehensive physiological assessments in patients with non-obstructive coronary artery disease (NOCAD) have not been fully investigated. Objectives The study aimed to evaluate the predictive value of a comprehensive approach that combines fractional flow reserve (FFR), coronary flow reserve (CFR), and index of microcirculatory resistance (IMR) in patients with NOCAD. Methods FFR, CFR, and IMR were measured in the left anterior descending artery of 226 patients with NOCAD. The primary endpoint was defined as adverse cardiovascular events including cardiovascular death, heart failure, coronary revascularization, cerebral infarction, and peripheral vascular events. Results Optimal cutoffs predicting the endpoint were 0.89 for FFR, 2.3 for CFR and 18.0U for IMR. Among the patients, 53 were negative for all indices, 80 positive for one, and 93 positive for two or three. During a median follow-up period of two years, 29 adverse events occurred, with the distribution as follows: 1 (1.9%) in patients with all negative indices, 5 (6.2%) in those with one positive index, and 23 (24.7%) in those with two or three positive indices. Kaplan-Meier curve analysis demonstrated significantly worse event-free survival in patients with an increasing number of positive indices (χ2=18.5, P<0.001). The presence of two or three positive indices was an independent predictor of the endpoint (hazard ratio 7.280, p<0.001). Conclusions Combining FFR, CFR, and IMR is an effective method for predicting cardiovascular events in patients with NOCAD.

Effect of pre-procedural blood pressure on one-year cardiovascular events after percutaneous coronary intervention in patients with acute myocardial infarction

Abstract Background Although high systolic blood pressure (SBP) and low diastolic blood pressure (DBP) are associated with adverse cardiovascular outcomes in coronary artery disease, their impact on patients with acute myocardial infarction (AMI) remains unclear. Methods This multicenter prospective study included 874 AMI patients undergoing percutaneous coronary intervention (PCI) with pre-procedural blood pressure recorded. Patients with cardiogenic shock and missing blood pressure data were excluded. The patients were categorized based on SBP (high ≥120 mmHg, low <120 mmHg) and DBP (high ≥70, low <70 mmHg) into four groups: high SBP and high DBP (HSHD), high SBP and low DBP (HSLD), low SBP and high DBP (LSHD), and low SBP and low DBP (LSLD) group. The primary endpoint was a composite of all-cause mortality, myocardial infarction, stroke, and major bleeding. Results The average age of the patients was 68.9 years, with a mean pulse pressure of 58 ± 19 mmHg. The Kaplan-Meier curves showed significant differences in the primary endpoints among the four groups (Log-rank test, p <0.001). At 12 months, the primary endpoint occurrence was highest in the HSLD group (13.3%) and lowest in the LSHD group (2.4%). Additionally, multivariate Cox regression analysis revealed that the HSLD group, compared to the HSHD group, was independently correlated with an increased risk of cardiovascular events (hazard ratio 2.43, 95% confidence interval 1.16-5.11; p = 0.019). Conclusion Pre-procedural HSLD serves as an independent predictor and is associated with one-year adverse cardiovascular outcomes in AMI patients.Patient diagramKaplan-Meier one-year outcome

From bench to bedside and back to bench: investigating the role of platelet heterogeneity in coronary artery disease

Abstract Background/Introduction Platelets exhibit considerable heterogeneity in RNA content, size, and thrombogenicity. Our preliminary investigation of the transcriptome of the RNA-rich reticulated platelets(RPs) in healthy donors revealed an enrichment of prothrombotic transcripts compared to mature platelets(MPs). Recently, we validated the prognostic role of elevated RPs at clinical level in a modern cohort of ACS patients treated with potent P2Y12 inhibitors. However, the pathophysiology of RP hyperreactivity remains unclear, particularly its correlation with adverse events and cardiovascular death. Purpose To study the biology of RPs in patients with chronic coronary syndrome(CCS) and to elucidate their role in disease progression. Methods RPs were isolated from peripheral blood of CCS patients(N=20) and compared with MPs. Cell viability and reactivity of RPs were quantified by FACS. Deep transcriptomic profiling was performed using post-sorting bulk RNA sequencing of RPs and MPs and analyzed with ad-hoc bioinformatic pipelines. Proteomic profiling using mass cytometry(CyTOF) was used to validate the transcriptomic findings with single cell resolution. Results FACS analysis confirmed RPs hyperreactivity showing increased P-Selectin expression upon activation with TRAP, ADP and Collagen(Fig. 1A). Total RNA-sequencing detected 2213 differentially regulated genes with an enrichment in RPs of key functional transcript such as, the von Willebrand Factor VWF(p=3.06*10-33), the thromboxane receptor TBXA2R(p=2.07*10-29) and the collagen receptor GP6(p=1.29*10-38, Fig. 1B-C). Gene ontology and gene set enrichment analyses detected an upregulation of relevant categories as "Regulation of platelet activation" and "Platelet aggregation"(Fig. 1D-F). In addition, we detected a novel alternative splicing event on the collagen receptor transcript GP6 upregulated in RPs(Fig. 1G). We detected 33 differentially regulated miRNAs, including miR-409, miR-134 and miR-432, which have been already linked to prothrombotic phenotypes(Fig. 1H). Additionally, we detected an enrichment of circular RNAs in RPs compared to MPs with several circular RNA upregulated in RPs, that have not been described before(Fig. 1I-K). Mass cytometry detected a significant upregulation in RPs of relevant proteins including the collagen receptor GPVI(p=8.98*10-12, Fig.2) and the thrombin receptor PAR1(p=5.21*10-11). Validation assays in an independent cohort detected an upregulation of the PI3K/AKT pathway in RPs which is downstream of the receptor PAR1 and GP6. Conclusion This study represents the first comprehensive multiomic characterization of RPs in CCS patients, providing insights into their prothrombotic phenotype and into their correlation with cardiovascular events. These findings suggest potential avenues for tailored therapeutic interventions targeting the identified upregulated pathways in patients with elevated RPs, warranting further investigation at the clinical level.

The potential effects of methotrexate on cardiovascular outcomes in rheumatoid arthritis patients: a multi-institutional analysis

Abstract Introduction and Purpose The association between rheumatoid arthritis (RA) and increased risk of developing cardiovascular disease has been previously described. Recent studies have also shown that methotrexate may reduce the risk of cardiovascular events in patients with RA but have been limited by small sample size and/or demographic constraints. Methotrexate is a first-line drug treatment for RA and works by suppressing multiple anti-inflammatory and immune reactions, thereby reducing the inflammation that promotes progression of cardiovascular disease in these patients. The goal of this study is to evaluate the potential benefit of methotrexate use on cardiovascular outcomes in patients with RA on a larger scale by utilizing a large international medical record database. Methods The TriNetX Diamond network was used for this study. Two cohorts were generated for comparison by using International Classification of Disease 10 (ICD-10) codes. Both cohorts included adult patients with a diagnosis of rheumatoid arthritis (M06) and both were excluded from being treated with the following biologic therapies: etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. One cohort was on active treatment with methotrexate while the other was excluded from being on it. The cohorts were then balanced for age, gender, race, ethnicity, presence of known coronary artery disease (I20-I25) and history of prior cardiovascular diseases (Z86.7) by propensity score matching and use of the greedy nearest neighbor algorithm. This resulted in 471,054 patients in each arm. They were then compared for the outcomes of acute myocardial infarction, chronic ischemic heart disease, congestive heart failure, and death at 5 years. Results Untreated RA patients were 11% more likely to develop myocardial infarction (RR 1.11, 95% CI (1.09,1.14), P value <0.0001) and 14% more likely to develop chronic ischemic heart disease (RR 1.14, 95% CI (1.13,1.15), P value <0.0001). CHF incidence was 21% higher (RR 1.21, 95% CI (1.19,1.22), P value <0.0001) in the untreated group, but 5-year mortality in the two groups was comparable at around 8.2% (RR 0.98, 95% CI (0.97,0.997), P value 0.016). Conclusion This study confirms that methotrexate is associated with fewer cardiovascular events in RA patients, especially congestive heart failure. Although the use of methotrexate in patients with RA did not result in a mortality benefit, treatment may offer substantial improvements in patient morbidity and healthcare system cost. These benefits were seen in a sample of greater than 900,000 patients representing every adult demographic. These data reaffirm the previously described association between RA and cardiovascular disease and support the initiation of treatment with methotrexate for any adult patient with RA. Watchful waiting is associated with a higher incidence of adverse events in this population.

A novel marker of cardiovascular risk stratification: the role of total cardiovascular calcium score using cardiac CT

Abstract Introduction It is widely accepted that coronary and valve calcification measured by cardiac CT, individually, are associated with cardiovascular events and mortality. However, the role of an encompassing marker of cardiovascular atherosclerosis could be more representative of the real cardiovascular risk. Objectives To determine the prognostic value of a combined coronary, valvular and aortic calcium score to predict long-term major adverse cardiac and cerebrovascular events (MACCE). Methods We conducted a single center study on 316 consecutive patients who underwent cardiac CT scan between January 2018 and December 2019. We excluded patients with poor imaging quality, constrictive pericarditis, prosthetic valves and/or devices. The calcium score of coronary arteries (CA), mitral valve (MV), aortic valve (AoV), ascending aorta (AAo) and aortic arch (AAc) were calculated from non-contrast ECG-gated CT using the Agatston method and were combined to derive a valvular (VA=MV+AoV), total cardiac (TC=CA+VA) and total cardiovascular (TCV=TC+AAo+AAc) calcium scores (Fig.1A). The primary endpoint was a composite of MACCE, defined as all-cause death, stroke, myocardial infarction and hospital admission for heart failure. Results A total of 275 CT scans were suitable for analysis. Mean age was 59.6±12.3 years, 48.4% were female. A total of 183 (66.7%) patients presented calcification in at least one location. Patients with calcification on any of the prespecified locations had higher prevalence of hypertension, dyslipidemia and type 2 diabetes mellitus (DM) than those without any calcium (p<0.05). After a median follow-up of 3.18 [IQR 2.84-3.69] years, 40 (14.5%) patients had met the primary endpoint. Regression analyses demonstrated that all CA, VA, TC and TCV scores were independent predictors of MACCE (p<0.05 for all). The best prediction models included calcium score (all combinations), age, sex, type 2 DM and smoking status (Fig.1B). The model with TCV score was the most powerful predictor of MACCE (χ2 47.8), followed by TC score (χ2 43.1). Of interest, the model with CA score had the poorest performance (χ2 35.4). Conclusion Coronary calcium score is a quick way to stratify risk in clinical practice, but its performance is too focused on coronary events. Total cardiovascular calcium score, however, is more encompassing, also quick to measure, and a more truthful depiction of the patient’s cardiac and cerebrovascular risk, potentially allowing a more tailored and timely approach to risk factors in clinical practice.

Does air pollution impact myocardial infarction incidence even in a city with fair air quality? Results from the EPIC-MI (Environmental Pollution and IncidenCe of Myocardial Infarction) Study

Abstract Background In light of recent research highlighting the potential association between air pollution and cardiovascular diseases, there remains a gap in data, particularly in cities characterized by relatively low pollution levels. The EPIC-MI Study endeavors to explore whether, even in a city boasting fair air quality such as our city, there exists a discernible impact of air pollution on the risk of cardiovascular events within an urban setting. Methods We analyzed all consecutive acute myocardial infarction (MI) patients admitted to our city heart center from March 2013 to December 2022. Air pollution data were meticulously gathered from 5 strategically positioned monitoring stations. Utilizing Poisson regression, the associations between these pollutants and the incidence of MI was analyzed. We also investigated the impact of pollution exceedance days and COVID-19 lockdown periods on MI incidence. Results Over nearly a decade, 18.798 MI cases were analyzed. The Poisson regression model revealed a significant independent association between the monthly average MI incidence and pollutant concentrations within the same month. Statistically significant independent effects were observed for CO (p<0.01), O₃ (p=0.03), SO₂ (p<0.01), and relative humidity (p<0.01) on MI incidence (Figure 1). Exceedance days were associated with a significant upswing in daily MI incidence. The MI incidence increased by 3.3% when PM10 exceeded 25 µg/m³ on the same day (5.19 ± 2.49 vs. 5.36 ± 2.50, p=0.03) and remained elevated over three days (5.19 ± 1.42 vs. 5.34 ± 1.46, p<0.01). For PM2.5, there was a 4.2% increase when exceeding 20 µg/m³ on the same day (5.20 ± 2.49 vs. 5.42 ± 2.52, p=0.02) and still elevated over three days (5.20 ± 1.42 vs. 5.40 ± 1.47, p<0.01). During the COVID-19 lockdown periods, a significant decrease was observed in air pollutant levels compared to non-lockdown years within the same timeframe (Figure 2). PM2.5 (9.89 µg/m³ vs. 12.76 µg/m³, p=0.02), PM10 (15.26 µg/m³ vs. 18.7 µg/m³, p<0.01), SO2 (1.16 µg/m³ vs. 1.77 µg/m³, p<0.01), and NO2 (14.42 µg/m³ vs. 19.53 µg/m³, p<0.01) exhibited significant reductions. Concurrently, a 22.5% reduction in daily MI incidence was observed compared to non-lockdown years within the same timeframe (4.16 vs. 5.37, p<0.01). Conclusion The study demonstrates an enduring influence of air pollutants on cardiovascular events, even in a city with fair air quality, such as our city. Elevated concentrations of air pollutants, especially on days with excessive levels, were significantly associated with an increased incidence of MI. The reduction in MI cases observed during the COVID-19 lockdown period underscores the potential cardiovascular benefits associated with improved air quality. These findings emphasize the importance of sustained efforts to mitigate air pollution for the enhancement of cardiovascular health in urban environments.