Systolic Blood Pressure Research Articles

Prognostic significance of pre-procedure wall shear stress in the ascending aorta in patients with aortic stenosis undergoing transcatheter aortic valve replacement

Abstract Background Accurate prognostication before the procedure is challenging in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Recently, blood flow dynamics assessed by four-dimensional flow cardiovascular magnetic resonance imaging (4D-flow CMR) showed a significant reduction in average wall shear stress (WSS) in the ascending aorta (AAo) after TAVR. However, the prognostic value of pre-procedure average WSS in the AAo is controversial. Purpose We aimed to investigate whether pre-procedure average WSS was associated with clinical outcomes in patients with AS undergoing TAVR. Methods We prospectively examined 159 consecutive AS patients who underwent TAVR (57 males, mean age 83.6 ± 4.7 years, median left ventricular ejection fraction 63.4%) between May 2018 and May 2022. We assessed average WSS in the AAo before TAVR using 4D-flow CMR. We divided the patients into high WSS (≥6.60 Pa, n = 79) and low WSS (<6.60 Pa, n = 80) groups according to the median value of pre-TAVR WSS. The primary outcome of interest was a composite of all-cause death and hospitalization for worsening heart failure. Results Patients with high WSS had lower age compared to those with low WSS. There were no significant differences on sex, body mass index, systolic blood pressure, hemoglobin, serum albumin, N-terminal pro b-type natriuretic peptide, left ventricular ejection fraction, mean transaortic valvular gradient, annulus area in aortic valve and AAo diameter between the groups. During a median follow-up period of 19.8 months (interquartile range 6.0-37.1), the primary outcome more frequently occurred in patients with low WSS than in those with high WSS (28% vs 5%, P <0.001) (Figure 1). A multivariable Cox regression showed that lower WSS independently associated with increased risk of the primary outcome (hazard ratio 0.69, 95% confidence interval [CI] 0.53-0.91, P <0.001), even after adjustment for significant prognostic covariates including age, sex, serum albumin, history of chronic obstructive pulmonary disease, peripheral artery disease and malignancy, and estimated glomerular filtration rate. Predictive performance for the primary outcome was improved when adding the value of WSS in the AAo to representative prognostic factors (c-index 0.81 95%CI 0.72-0.90 vs. 0.77 95%CI 0.67-0.88) (Figure 2). Conclusions In patients with AS who underwent TAVR, lower average WSS in the AAo before procedure was associated with higher risk of worse clinical outcomes, suggesting that pre-TAVR average WSS in the AAo would be a surrogate marker and useful for the risk stratification.Survival analysis for primary outcomePredictive performance

Comparison of procedural analgosedation in patients undergoing pulsed field ablation or cryoballoon ablation for atrial fibrillation

Abstract Background Pulsed field ablation (PFA) has emerged as a novel technology that is increasingly applied for the catheter ablation (CA) of atrial fibrillation (AF) with similar efficacy to established, thermal energy sources. Data solely focussing on analgosedation compared to established single-shot modalities, such as cryoballoon (CB) ablation are scarce. Aim The aim of this study was to assess differences of analgosedation requirement, procedural cardiopulmonary stability, and analgosedation-associated complications between PFA and CB ablation. Methods This study was a retrospective single-centre comparison of analgosedation in patients with paroxysmal, persistent, and long-standing persistent AF undergoing pulmonary vein isolation (PVI) with either PFA or CB from March 2021 until April 2022. The primary study endpoints were the requirements of analgosedation medications (propofol, midazolam and sufentanyl), cardiorespiratory stability measured as decreases in oxygen saturation and systolic blood pressure and analgosedation-associated complications. Secondary endpoints were acute procedural success, procedure time and overall complication rates. Results A total of 100 patients were included {PFA n=50, CB n=50, mean age 66 ± 10.6, 61% male patients, 65% paroxysmal AF). The body weight – and procedure time-adjusted requirement of all analgosedation medications was significantly higher in the PFA group compared to CB {Propofol 0.14 ± 0.04 mg/kg/min in PFA versus 0.11 ± 0.04 mg/kg/min in CB (p=0.001); midazolam 0.00086 ± 0.0004 mg/kg/min in PFA versus 0.00063 ± 0.0003 mg/kg/min in CB (p=0.002) and sufentanyl 0.0013 ± 0.0007 µg/kg/min in PFA versus 0.0008 ± 0.0004 µg/kg/min in CB (p<0.0001)}. Procedural cardiorespiratory stability did not differ between groups (maximum blood pressure decrease PFA 53.4 ± 20.9 mmHg, CB 50.3 ± 18.6 mmHg, P=0.28 and maximum decrease in oxygen saturation: PFA group 4.8 ± 5.3 %, CB group 3.5 ± 2.6 %, P=0.12). Analgosedation-associated complications did not differ between both groups (PFA n=1/50 mild aspiration pneumonia, CB n=0/50, p=0.99). There was no significant difference in acute procedural success (100% n=50/50 in both groups, p>0.99), non-analgosedation associated complications (PFA: n=2/50, 4%, CB: n=1/50, 2%, p=0.99) and procedure times (PFA 75 ± 31, CB 84 ± 32 mins, p=0.18) between groups. Conclusions Pulsed field ablation is associated with higher sedation and especially analgesia requirement compared to cryoballoon ablation, however, the safety of analgosedation does not differ significantly to cryoballoon ablation.

Acute echocardiographic assessment of patients with ST-elevation myocardial infarction in detecting clinically hidden hemodynamic deterioration

Abstract Background Transthoracic echocardiography (TTE) offers an immediate non-invasive assessment of cardiac morphology and function that can be performed bedside. Acute TTE in the catheterization laboratory (cath.lab.) may be helpful to identify markers of subsequent development of cardiogenic shock (CS) in patients with ST-elevation myocardial infarction (STEMI) in addition to the previously validated ORBI risk score. This relationship has not been investigated thoroughly previously. Purpose To investigate the association between acute TTE estimates of left ventricular (LV) function prior to primary percutaneous coronary intervention (pPCI) in STEMI patients and pro-B-type natriuretic peptide (proBNP) as a proxy associated with of CS development. Method From September 2023 all non-CS STEMI patients at one tertiary heart center underwent acute bedside TTE in the cath.lab. and ORBI risk score assessing the risk of CS development aiming for inclusion of 500 patients. The 5 minutes TTE-protocol consisted of LV ejection fraction (EF), LV outflow tract velocity time integral (LVOT VTI), mitral inflow (E and E/A), mitral deceleration time, and mitral annular early diastolic velocity é lateral. The primary endpoint was proBNP measured 24 hours (h) after pPCI (12-36h) stratified in quartiles (Q4 vs. Q1-3). The correlation between proBNP and TTE measurements and proBNP and ORBI risk score was examined using univariate linear regression models. Results Until now 153 STEMI patients (mean age 64 years, 25% female) were studied. Anterior STEMI was present in 36%, and median time from cath. lab. arrival to first wire over the culprit lesion was 28 minutes (IQR 24; 37). Patients with high proBNP level (Q4 vs. Q1-3) had significantly higher heart rate (median 84 bpm vs. 72 bpm) and Killip Class>1 (16% vs. 0%) at admission, but similar lactate levels (1.8mM vs. 1.5mM), systolic blood pressure (130 mmHg vs. 137 mmHg), and out-of-hospital cardiac arrest (11% vs. 12%). Patients with high proBNP levels (Q4 vs. Q1-3) had significantly lower LVEF (35% vs. 50%), higher E/é lateral (median 11.4 vs. 7.9), and higher ORBI risk score (median 8 vs. 4). LVEF, LVOT VTI, E/é lateral, and ORBI risk score were significantly associated with proBNP (Figure 1). Two patients developed CS after the pPCI; one with high proBNP level Q4, and one deceased prior to proBNP measurement. Conclusion Acute TTE is an easy tool for assessment of the acute hemodynamic status in STEMI patients bedside in the cath.lab., and it can be without delaying time to revascularization. LVEF, LVOT VTI, E/é lateral, and ORBI were all parameters associated with increased levels of the hemodynamic biomarker proBNP, and may together with the ORBI risk score improve the assessment and risk stratification of STEMI-patients at risk of CS-development.Figure 1.

Trajectories of lipid profile during adolescence and risk of subclinical atherosclerosis in early adulthood: a two-decade population-based study

Abstract Background/Introduction Recent studies have shown the highest burdens of premature cardiovascular diseases (CVDs) in the Middle-eastern, and North Africa (MENA) region. The role of dyslipidemia, as a major metabolic disturbance, in the progression of subclinical atherosclerosis and subsequently premature CVDs, indicated by carotid intima-media thickness (cIMT), must not be overlooked, specifically in young adults. Purpose To examine the impact of early-life lipid profile trajectories in adolescence on subclinical atherosclerosis, evidenced by cIMT in adulthood. Methods In this trajectory analysis, with 1006 participants (472 male, mean age=14.72±3.23 years), latent class growth modeling, particularly Group-based multi-trajectory modeling (GBMTM) was used to analyze the heterogeneity in the longitudinal lipid alterations (total cholesterol [TC], triglycerides [TG], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and non-HDL-C). The trajectories were named based on direction (rising/decreasing) and slopes of the associated trends in lipid alterations (stable/ slow/ rapid). The association between lipid trajectories, and cIMT values, both as continuous and categorical variables, were evaluated using multivariate regression analysis adjusted for age, sex, body mass index, and systolic blood pressure at the baseline, as well as antihypertensive and lipid-lowering drug use, smoking, physical activity, and desired lipid parameter at the nearest survey to cIMT measurement. Results During a median follow-up of 17.6 years, the "Rising" trajectories of TC, TG, LDL-C, and non-HDL-C were linked to elevated cIMT values (in the fully-adjusted model beta-coefficients [βs]=0.08 [-0.01,0.14], 0.11 [0.05,0.17], 0.13 [0.05,0.21], and 0.12 [0.06,0.18], respectively). The "Rapid-Rising" trajectories of TG, LDL-C, and non-HDL-C notably amplified the risk (in the fully-adjusted model odds ratios (OR)=2.05 [1.46-2.75], 1.99 [1.35-2.92], and 2.02 [1.45-2.77], respectively). Conversely, the "Decreasing" trajectories of TC, LDL-C, and TG were associated with lower cIMT measures (βs =-0.09 [-0.16,-0.03], -0.11 [-0.17,-0.01], and -0.08 [-0.14,-0.02], respectively); also "Decreasing" trajectories of TC and LDL-C lowered the risk by at least 30% in the fully-adjusted model (ORs=0.59 [0.39-0.81] and 0.68 [0.41-1.02], respectively). While HDL-C "Rapid-Decreasing" trajectory doubled the risk of elevated cIMT (OR=1.98 [1.47-2.68]). Conclusion The findings showed the unfavorable trajectory alterations in all lipid parameters were significantly associated with higher cIMT values, underscoring the need for sustained efforts to monitor lipid levels from early adolescence.

A standards-based software tool to support prognostic modelling: application to exemplar heart failure risk scores

Abstract Introduction Heart failure prognosis is an active research area, with the development of several new risk scores each year. While risk score derivation and evaluation have become common practices, these processes currently lack standardisation. Purpose We aimed to: i) develop a standards-based software tool to support prognostic modelling; and ii) apply the tool to derive, evaluate and compare exemplar heart failure risk models to address a hypothetical question of whether using only non-invasive measurements provides similar prognosis value compared to adding invasive measurements. Methods A software tool was developed based on a prognostic modelling workflow defined using the Common Workflow Language and containing 7 steps: univariate Cox proportional hazard (PH) regression, multivariable Cox PH regression with assessment of proportional hazards and linearity with outcome (Schoenfeld and Martingale residuals), derivation of points per risk factor, risk calculation and stratification, discrimination and calibration assessment. Using data from the PEOPLE heart failure cohort [1], two integer-based risk scores were developed to predict 2-year all-cause mortality. The first model utilised 12 variables available at recruitment informed by prior analysis of the PEOPLE cohort to provide a benchmark for comparison, while the second model is based on 9 non-invasive parameters. The analysis was conducted on cases with complete data (n=781), with no internal or external validation. Results By inputting the dataset and indicating the variables of interest for each model, our software tool automatically generated the patient-specific risk scores, risk strata, c-index, and discrimination and calibration plots. A 12-parameter model based on age, sex, ejection fraction, hypertension, diabetes, atrial fibrillation, ischaemic history, NYHA class, heart rate, systolic blood pressure, creatinine and NT-proBNP yielded reasonable discrimination (c-index=0.77). Graphical assessment of risk strata and calibration (Fig. 1.a and c) revealed good performance overall, apart from the highest risk decile where survival was overestimated. The reduced 9-parameter model excluded creatinine, NT-proBNP, and automatically dropped diabetes status for non-linearity. It showed a substantial drop in discrimination (c-index=0.67), confirmed in graphical assessment of risk strata (Fig. 1.b). Calibration was more variable per decile than seen with the 12-parameter model but was more robust to survival overestimation (Fig. 1.d). Conclusion Our software tool ensures the uniformity and comparability of the two risk models derived by a common statistical process. In this example, we showed how the addition of NT-proBNP, creatinine, and diabetes status improves discrimination for predicting heart failure survival. This tool can be leveraged to test new hypotheses in a standardised and reproducible manner to enhance research in heart failure prognosis.

Incident HFpEF and time-dependent changes in markers of LVDD severity in women and men with pre-clinical LVDD

Abstract Background Over time, left ventricular diastolic dysfunction (LVDD) can progress towards heart failure with preserved ejection fraction (HFpEF). Yet, the identification of those at high risk of progression is challenging, and guidance on follow-up or preventive treatment is lacking. Purpose To study the incidence of HFpEF and changes over time in markers of LVDD severity in women and men with pre-clinical LVDD. In addition, we evaluate whether blood pressure and kidney function affect progression of LVDD. Methods We reinvited 146 participants from the HELPFul study (58% women and 42% men) with pre-clinical LVDD after a median follow-up of 4.3 [IQR: 3.9-4.7] years (Figure 1). The follow-up measurements were similar to baseline and encompassed a structured interview, physical examination, blood draw, electrocardiogram and (exercise) echocardiography. We determined HFpEF incidence and report changes over time in cardiovascular risk factors as well as echocardiographic characteristics and biomarkers of LVDD. Additionally, we studied whether changes in blood pressure and kidney function affected LVDD progression using generalized mixed models. LVDD progression was defined as an increase in plasma NT-proBNP levels and HFA-PEFF major functional and morphological abnormalities. All analyses were performed for women and men combined as well as stratified by sex. Results Fifteen (10%) of the 146 participants developed HF of whom 13 had HFpEF (9 women and 4 men) during follow-up. Over time, systolic and diastolic blood pressure levels remained stable while mean kidney function (eGFR) declined from 89±14 to 81±17 mL/min/1.73m2. Median NT-proBNP plasma levels increased from 71 [IQR: 44, 120] to 100 [IQR: 51, 157] pg/mL. The prevalence of major functional abnormalities according to the HFA-PEFF score increased from 84 to 91%, while the prevalence of morphological abnormalities increased from 25% to 39% (Figure 2). A higher systolic blood pressure in women and a higher diastolic blood pressure in men was associated with an increase in NT-proBNP plasma levels over time. Additionally, lower eGFR levels were related to increased NT-proBNP plasma levels over time in both men and women. There was a significant rise in the prevalence of major functional and morphological abnormalities with time, but blood pressure and kidney function did not affect this change over time. Conclusions A small proportion of women and men with preclinical LVDD developed incident HF over a 5-year follow-up period. High blood pressure and reduced kidney function were associated with increased levels of NT-proBNP over time. This highlights the need to further explore cardiorenal protection as a method to prevent HFpEF.Study design and HF outcomesLongitudinal changes in LVDD markers

Association of a history of acute kidney injury with major adverse cardiovascular events in chronic kidney disease patients

Abstract Background/introduction Acute kidney injury (AKI) is strongly associated with major adverse cardiovascular events (MACE), particularly heart failure, in both general and critically ill populations. A recent study questioned whether this association holds true only for patients without chronic kidney disease (CKD). Purpose To evaluate the association of a history of AKI with MACE in a large real-world CKD population defined using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Methods A retrospective cohort study was conducted using Merative® Explorys electronic health records (>54 million patients) from Jan 2010 to Dec 2019. Six cohorts of CKD patients (diagnosed or not) were created, one for each stage (1-5). Patients were required to have two consecutive abnormal eGFR, uACR/uPCR results within 3-18 months to determine CKD stage, to have at least a 12-months lookback period, and no history of end-stage kidney disease. CKD classification was not mutually exclusive (individual patients could contribute to multiple stages). Index date was the date of the second abnormal test. History of AKI was defined using ICD diagnosis codes, not through biological changes. We followed each patient until the occurrence of a composite of MACE including death, coronary events [acute coronary syndrome + coronary revascularization], any stroke, hospitalization for heart failure, or loss to follow-up, or for up to 5 years. We used multivariable Cox proportional hazards regression to estimate associations between the history of AKI and the risk of MACE during follow-up, adjusted for the following confounders: age, sex, ethnicity, systolic blood pressure, eGFR, BMI, CV history, diabetes, and any CKD diagnosis at baseline. Results Most of the 969,394 patients included in at least one CKD stage cohort were in stage 3a (see table) and Caucasian. Mean ages were 57-75y and 42%-64% were females across the 5 CKD stages. The prevalence of pre-existing CV disease increased from 24% in stage 1 to 57% in stage 4. The proportion of patients with a history of AKI increased from 4% in stage 1 to 36% in stage 4, as well as, the proportion of patients with a ICD code for CKD diagnosis at baseline (3% to 44%). The 5-year incidence of the composite of MACE increased from 25.1% in stage 1 to 65.8% in stage 5. Death was the most frequent event across all stages. In multivariable analysis, a history of AKI was associated with increased risk of MACE (hazard ratios, HR 1.19 to 1.32), all-cause death (HR 1.12 to 1.86), and hospitalization for Heart Failure (HR 1.59 to 1.98) for all CKD stages, and coronary events for stage 2 to 5 (HR 1.14 to 1.22), but not stroke. Conclusion Patients with CKD and a history of AKI are at higher risk of adverse CV outcomes, especially hospitalization for heart failure. This study suggest that these patients should receive cardio -protective intervention.

Dapagliflozin reduces epicardial adipose tissue in patients with heart failure with reduced ejection fraction and type 2 diabetes

Abstract Introduction Epicardial adipose tissue (EAT) accumulation is associated with adverse outcome in heart failure with preserved ejection fraction, however its role in HF with reduced ejection fraction (HFrEF) is less clear. The relationship between EAT thickness and their impact on patients who have diabetes and heart failure remains unclear. SGLT2 inhibitors such as dapagliflozin improve outcomes in heart failure and diabetes, however their mechanism of benefit is not well understood. The aim of our study was to assess whether dapagliflozin reduced EAT in patients with type 2 diabetes and HFrEF. Methods We performed an analysis of individuals with type 2 diabetes and HFrEF who were randomised to receive either dapagliflozin or a placebo for 12 months as part of the REFORM trial. Participants had cardiac magnetic resonance (CMR) scans at baseline and at 12 months. Epicardial fat was measured utilizing 4-chamber cine images to quantify adipose tissue between the myocardium and the visceral layer of the pericardium. This assessment was carried out using the single end-diastolic image, with measurements conducted by evaluators blinded to the randomisation status of participants. Results 47 participants completed the stud. At baseline, not only EAT thickness and BMI level (placebo: 33, dapagliflozin 32, p=0.49) but also heart rate (74.39 bpm vs. 77.61 bpm, p=0.35), systolic blood pressure (132.75 mmHg vs. 135.00 mmHg, p=0.63), diastolic blood pressure (71.39 mmHg vs. 74.04 mmHg, p=0.33) and age (67 vs. 66, p=0.79) were comparable between the two groups. 23 randomised to placebo and 24 to dapagliflozin. Baseline EAT was similar in both groups (placebo: 11.54 cm², dapagliflozin 11.74 cm², p=0.414). After 12 months of treatment dapagliflozin caused a significant reduction in EAT compared to placebo (1.21 cm² vs. 0.09 cm², p=0.007). Conclusion Dapagliflozin significantly reduced epicardial adipose tissue compared to placebo in patients with type 2 diabetes and HFrEF. The reduction in EAT may play a role in the beneficial effects of dapagliflozin in heart failure patients.4 Ch CMRBox plot

Sex differences in RNA transcripts in dilated cardiomyopathy

Abstract Introduction Dilated cardiomyopathy (DCM) is the most common cardiomyopathy and a major cause of heart failure. Differences in clinical presentation and phenotype exist in men and women but the reason for this is not clear. The analysis of the RNA transcripts (mRNA sequencing) offers an opportunity to provide a link between the genome, the proteome, and the phenotype. The aim of this study was to explore sex differences using mRNA sequencing in patients with DCM. Method Our database, an observational prospective cohort study, includes patients referred for suspected cardiomyopathy. The database includes data on patients’ characteristics, symptoms, diagnostic procedures, treatments, cardiac devices, and outcome. Endomyocardial biopsy from the right ventricle was collected and total RNA, including miRNA and other small RNA, was isolated. RNA sequencing and library preparation was performed. Following quality check, reads were aligned to GRCh38 reference genome by STAR (v2.7.10a). Sex-specific differential expression analysis between individuals diagnosed with DCM (cases) versus non-confirmed cardiomyopathy (controls) was performed using DESeq2 (v.1.38.3) adjusting for age, RNA integrity number and systolic blood pressure. After controlling for multiple testing using the Benjamini-Hochberg method, genes with a corrected P-value < 0.05 were considered as being differentially expressed. Gene-set enrichment analysis on differentially expressed genes was performed via Enrichr tool using Descartes cell types and tissues, KEGG biological pathways, DisGeNET, and Gene Ontology Biological Processes (GOBP). Results Patients´characteristics in women and men with DCM is presented in table 1. There was no difference in outcome in men and women (data not shown). Differential expression analyses with transcriptomic data comparing DCM (n=43) versus controls (n=22) stratified by sex (DCM n= 9, (20.9%) women and controls n=7, (30.4%) women) was performed. There was no overlap between differentially expressed genes between sexes (Figure 1). In men gene set enrichment analyses showed that differentially expressed genes were related to pathways involved in dilated and hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (KEGG). Interestingly, these analyses revealed an enrichment of genes related to platelet biology, namely precursors (Descartes), activation (GOBP, KEGG) and platelet disorder (DisGeNET). In women, HLA-DQB1 was more expressed in DCM. HLA-DQB1 is associated with celiac disease, narcolepsy, and type 1 diabetes. Consistently, the enrichment analyses showed an enrichment of genes involved in autoimmune diseases (DisGeNET). Conclusion Women and men with DCM exhibit differently activated RNA transcripts although no difference in phenotype was observed. This may indicate that although DCM can be caused by similar factors in women and men the transcriptome is differently activated which warrants further investigation.Table 1.

Usefulness of left ventricular mechanical dyssynchrony for predicting atrial fibrillation and adverse outcomes following first atrial fibrillation event

Abstract Background Left ventricular mechanical dyssynchrony (LVMD) has shown to predict many cardiovascular outcomes including ventricular arrhythmias. Our hypothesis is that LVMD can reveal early atrial dysfunction. Purpose The aim of this study was to investigate whether LVMD can be used to predict atrial fibrillation (AF) and adverse outcomes following first AF event in individuals from the general population. Methods A total of 3785 individuals (mean age 55±17 years, 57% women) from the general population free of AF, heart failure (HF) and prior stroke had an echocardiographic examination performed including two-dimensional speckle tracking echocardiography. LVMD was calculated as the standard deviation of the regional time-to-peak strain from the three apical views. The primary endpoint was AF, and the secondary endpoint was complicated AF as assessed by the occurrence of either stroke or HF after the diagnosis of AF. Results During a median follow-up of 5 years (interquartile range, 4.4-6.2 years), 142 (4%) individuals were diagnosed with AF, and of these 22 (15%) individuals developed HF or stroke. LVMD was a univariable predictor of AF (per 10ms increase: HR 1.03; 95% CI (1.02-1.05), p<0.001, Figure). The association remained significant even after multivariable adjustment for age, sex, body mass index, diabetes, hypertension, heart rate, previous ischaemic heart disease, systolic blood pressure, diastolic blood pressure, smoking, left ventricular ejection fraction, global longitudinal strain, left atrial volume index (LAVI), and E/e’ (per 10ms increase: HR 1.02; 95% CI (1.00-1.04), p=0.042). LVMD also predicted complicated AF, and the association remained significant even after multivariable adjustment (per 10ms increase: HR 1.05; 95% CI (1.01-1.09), p=0.026). Furthermore, LVMD provided incremental prognostic information over the LAVI with regard to predicting AF (Harrell’s C-statistics 0.66 vs. 0.70, p=0.012). Conclusion In a low-risk general population, LVMD provides prognostic information on the risk of AF. Additionally, LVMD can identify individuals with complicated AF defined as occurrence of either stroke or HF following the diagnosis of incident AF. Furthermore, LVMD provides incremental prognostic information over the LAVI in predicting AF.

Deficiency of transcription factor E4BP4 suppresses neointimal formation after vascular injury

Abstract Aim In addition to traditional risk factors such as hypertension, diabetes, and dyslipidemia, chronic inflammation is deeply involved in the onset and pathogenesis of atherosclerotic diseases. Furthermore, diurnal fluctuations are observed in the rupture of atherosclerotic plaques and the onset of myocardial infarction. There are still many patients for whom medical treatments such as statins and antihypertensive drugs do not respond adequately, and new treatment methods are expected. E4BP4 (also known as NFIL3) is a basic leucine zipper (bZIP)-type transcription factor associated with circadian rhythms and cell viability, and it has been reported that E4BP4 regulates inflammation. Therefore, to investigate how the circadian transcription factor E4BP4 which is involved in inflammation, we decided to examine the role of E4BP4 in neointimal formation after vascular injury. Methods and Results Using E4BP4-deficient (E4BP4−/−) and wild-type (WT) mice, we investigated neointimal formation 2 weeks after femoral artery injury induced by an external vascular cuff model. Intimal and medial area were measured, and the intima/media ratio was calculated. Systolic blood pressure was similar between groups (WT mice: 92 ± 5 mmHg [n = 5] vs. E4BP4−/− mice: 90 ± 4 mmHg [n = 5]). And there was no significant difference in baseline body weight between groups (WT mice: 22.4 ± 0.8 g [n = 5] vs. E4BP4−/− mice: 22.0 ± 1.1 g [n = 5]). The mean intimal area and the intima/media ratio of E4BP4−/− mice decreased by 86 % (WT mice: 3,683 ± 512 μm2 [n = 10] vs. E4BP4−/− mice: 521 ± 363 μm2 [n = 10]; P < 0.0001) and 97% (WT mice: 0.33 ± 0.05 vs. E4BP4−/− mice: 0.01 ± 0.03; P < 0.0001), compared with WT mice. However, we observed no significant difference in the medial area (WT mice: 11,019 ± 358 μm2 vs. E4BP4−/− mice: 11,281 ± 401 μm2; P = NS) between groups (Figure). Immunohistochemistry for NK cell (NKp46) revealed the percentage of NKp46 positive area in the adventitia of E4BP4−/− mice was significantly lower compared with WT mice at 14 days post-injury (P <0.05). Furthermore, the positive area of IL-6 (P<0.05), TNF-α (P<0.05) and IFN-γ (P<0.05) in the intima of E4BP4−/− mice tended to be much smaller than those of WT mice. Our findings indicate that E4BP4 might induce vascular inflammation following vascular injury. Conclusions Deficiency of E4BP4 reduced the inflammatory cytokines and suppressed neointimal formation after injury. We also observed a decrease in NKp46, suggesting that NK cell development is impaired by E4BP4 deficiency. The present study is the first to demonstrate that E4BP4 plays an important role in the increase of neointimal formation after injury in vivo, thus suggesting that E4BP4 inhibition may represent a useful strategy to inhibit vascular inflammation.Neointimal formation after cuff injury

Impact of appendicular skeletal muscle mass on effect of intensive blood pressure control

Abstract Background Appendicular skeletal muscle mass (ASM) is associated with cardiovascular diseases (CVDs) and chronic kidney diseases (CKDs). However, whether low ASM affects the efficacy of intensive systolic blood pressure control is currently uncertain. Purpose To examine the impact of low ASM on the effects of intensive SBP control on cardiovascular and kidney outcomes. Methods Data from the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trials was used. The primary outcome was a composite of myocardial infarction, acute coronary syndrome without myocardial infarction, stroke, heart failure, and cardiovascular death. The prespecified incident CKD was defined as a >30% decrease in estimated glomerular filtration rate to a value <60 mL/min/1.73 m2. Results A total of 14,017 patients were included in this study, 2203 (15.7%) of whom had low ASM. Over a median follow-up of 3.26 years, 1,032 primary outcomes and 460 incident CKD were observed. Patients with low ASM had a significantly higher risk of primary outcome and CKD. Intensive SBP control effects on cardiovascular outcomes were not significantly different on a relative scale or absolute scale. But low ASM significantly amplified the increased risk of CKD associated with intensive SBP control, on an absolute scale (P for interaction = 0.04). Conclusions Low ASM is one of the markers of increased risk of CVD and CKD, and it did not affect the cardiovascular benefits of intensive treatment, but significantly amplified the increased risk of CKD associated with intensive SBP control.

Zibotentan in microvascular angina: a randomized, placebo-controlled, crossover trial

Abstract Background/Introduction Microvascular angina is a chronic condition characterized by abnormal myocardial blood flow leading to ischemic symptoms. Endothelin-1, a peptide secreted by endothelial cells, is a highly potent constrictor of the human coronary arterioles. Microvascular angina is associated with elevated circulating concentrations of endothelin-1, and prolonged exposure to ‘excess’ endothelin causes vasoconstriction and vascular remodelling. The chronic elevation of circulating endothelin-1 in microvascular angina may be influenced by genetic factors. Purpose Zibotentan, the most selective antagonist of the endothelin A receptor with no off-target binding to the endothelin B receptor, was evaluated in oncology trials and did not improve survival. We identified zibotentan as a potential disease-modifying therapy for patients suffering from microvascular angina. We hypothesized that zibotentan 10 mg daily for 12 weeks in addition to background medical therapy could be an efficacious and safe treatment for patients with microvascular angina. We further hypothesized that the SNP regulator of EDN1 gene expression, rs9349379 (G allele), could be a novel theragnostic biomarker. Methods The trial involved a prospective, multicentre, randomized, double-blind, placebo-controlled, sequential crossover design to assess the effects of zibotentan 10 mg or matched placebo, once daily for 12 weeks. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The secondary outcomes included exercise test parameters, health status questionnaires, safety (frequency and severity of severe adverse events (SAEs) and adverse events), feasibility (withdrawal rate), and biomarkers of efficacy (pharmacokinetics, pharmacodynamics). Results The study found no significant difference in exercise duration with zibotentan (-4.26 seconds; 95% CI: -19.60 to 11.06; P=0.5871). There was no effect on the secondary outcomes. However, for exploratory (mechanistic) outcomes, zibotentan increased plasma big endothelin-1, endothelin-1, and global myocardial blood flow, while reducing hemoglobin, diastolic, and systolic blood pressure (all p<0.001). Adverse events were more common during the zibotentan period (60.2%) compared to placebo (14.4%, p<0.001). Conclusion(s) In conclusion, daily administration of 10 mg zibotentan for 12 weeks did not enhance exercise duration and was commonly associated with adverse effects related to fluid retention. Further trials exploring lower zibotentan doses in combination with agents to mitigate fluid retention, and longer treatment durations, are warranted.

Impact of dapagliflozin on supraventricular and ventricular arrhythmias, assessed by Holter ECG, in patients with heart failure with reduced ejection fraction

Abstract Background & Introduction Dapagliflozin has significantly reduced morbidity & mortality in patients with heart failure with reduced ejection fraction (HFrEF) (1). Some studies reported supraventricular & ventricular arrhythmia suppression, but Holter ECG was underused, hindering precise assessment of arrhythmia burden. Purpose We aim to assess the impact of dapagliflozin on reduction of arrhythmia in HFrEF at 1 year follow-up (FU) by Holter ECG. Methods This is a single center, prospective study. We have screened 219 HFrEF patients, but only 156 patients were enrolled with LVEF <40% in sinus rhythm from December 2021 to July 2023. All patients had dapagliflozin 10 mg once/day tablet with the standard HF therapy. Clinical evaluation, NYHA evaluation, 6-minute walking test (6MWT), echocardiogram, 24-hours Holter ECG and laboratory work-up were done at baseline, and FU at 6 months and 12 months. Results Males constituted 61.5% of study population; mean± SD participants’ age was 56.8 ± 8.6 years. The most common comorbidities were: ischemic etiology (63.3%), dilated cardiomyopathy (28.1%), hypertension (27.3%), smokers (14.7%), and type II diabetes (31.4%). LVEF was ≤ 35% in 85.9% of patients. We have reported (7.69%) deaths during 1-year FU, and 4 patients (2.56%) didn't complete 1-year FU. Main clinical and echocardiographic findings (baseline vs. 1-year FU): NYHA FC III& ambulant IV dropped from (42.9 to 32.9%), P value<0.05. Distance walked in 6MWT improved from 191.52 ± 75.37 to 219.35 ± 71.51 mean± SD meters, P value<0.05. E/e improved (9.4 to 8.3 cm/s, P value <0.01), LVEF improved (31.3 to 36.4%, P value<0.05). HF emergency: [HF visits dropped (23.7 to 19.2%) and HF hospitalization dropped (11.1 to 7.8%)], P value<0.05. Holter ECG (baseline vs. 1-year FU): Supraventricular Arrhythmia: [Paroxysmal AF reduced (56.2 to 47.6%), frequent PACs (≥ 10%) dropped (3.8 to 1.4%) & Intermittent 1st degree heart block dropped (12.5 to 7.3%)] P value <0.01. Ventricular Arrhythmia: [PVCs >5%-<10% dropped (16% to 9.3%), Frequent PVCs >10% dropped (3.2 to 1.4%), and NSVT dropped (7.8 to 3.1%)], P value <0.01. Stepwise logistic regression multivariable model aiming to predict the occurrence of ventricular and supraventricular arrhythmias has indicated a direct linear correlation with male gender, smoking, body mass index, left atrial volume, and a history of myocardial infarction. Conversely, there is an inverse relationship with systolic blood pressure, 6MWT distance, LVEF, and the administration of dapagliflozin (OR 0.72 [0.61 - 1.07], P value <0.01) concerning the likelihood of supraventricular and ventricular arrhythmias. Conclusions Dapagliflozin has demonstrated significant improvement in functional and echocardiographic parameters in HFrEF patients. Furthermore, it has effectively decreased the incidence of supraventricular and ventricular arrhythmias, identified through 24-hour Holter ECG monitoring during 1-year follow-up.

Adverse prognostic implications of increased left ventricular force in hypertrophic cardiomyopathy

Abstract Background The left ventricular (LV) force, also known as elastance, serves as a load-independent indicator of contractility and can be noninvasively assessed through echocardiography. In hypertrophic cardiomyopathy (HCM), the heightened presence of the active state of myosin heads results in an increased LV force. Purpose To assess the prognostic value of increased LV elastance at rest in patients with HCM. Methods We enrolled 1420 HCM patients (age 50±16 years, 907 males, 64%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 10 quality-controlled labs from 7 countries. TTE assessment included peak left ventricular outflow tract gradient (LVOTG), EF, and LV force (systolic blood pressure + LVOTG/LV end-systolic volume assessed with 2-D, mmHg/mL). All patients were followed up. All-cause death was the outcome measure. Results At a median follow-up of 83 months, 150 deaths occurred (Group 1). At study entry, Group 1 patients had the same ESC-Sudden cardiac death score compared to survivors (Group 2). In Group 1 compared to Group 2, TTE showed higher values of MR severity, E/e’ , left atrial volume index, estimated systolic pulmonary artery pressure, and force (see table). At multivariable Cox analysis, only age (HR =1.08, 95% CI=1.03-1.14, p=0.001) and force > median value of 5.3 mmHg/mL (HR = 2.14, 95% CI 1.53-2.99, p=0.020) were independent predictors of mortality. Ten-year survival was 95% in the pooled first (<3.8 mmHg/mL) and second (3.8-5.2 mmHg/mL) quartiles vs 80% in the pooled third (5.3-7.8 mmHg/mL) and fourth quartiles (>7.8 mmHg/mL), see figure. Conclusion HCM patients with higher values of resting LV elastance show a worse survival, highlighting the dark prognostic side of an excess of force in these patients. Table Legends E/e’, early mitral inflow to early mitral annulus motion ratio, EF, left ventricular ejection fraction, LAVI, left atrial volume index; LVOTG, left ventricular outflow tract peak gradient, MR, mitral regurgitation; MWT, maximal wall thickness, NYHA, New York Heart Association classification, RWT, relative wall thickness; SCD risk, risk score for sudden cardiac death in hypertrophic cardiomyopathy, SPAP, systolic pulmonary arterial pressure.Table.Clinical and TTE findingsFigure.Survival in the force quartiles

Prevention of dementia using mobile phone applications (PRODEMOS): a multinational randomised controlled effectiveness-implementation trial

Abstract Background The expected increase of dementia prevalence in the coming decades will mainly be within low-and middle-income countries and those with low socioeconomic status (SES) in high income countries. Forty percent of dementia is associated with modifiable, lifestyle-related cardiovascular risk factors. Mobile health interventions with remote coaching can help reach underserved high-risk populations globally. Methods This open label, blinded endpoint, hybrid effectiveness-implementation randomised controlled trial (RCT) investigated whether a coach-supported mHealth intervention can reduce dementia risk in persons aged 55-75 years of low SES in UK or from the general population in China with at least two dementia risk factors. The primary effectiveness outcome was change in CAIDE dementia risk score (including age, education, sex, systolic blood pressure, total cholesterol, BMI, physical exercise) after 12-18 months of intervention. Main implementation outcomes were coverage, acceptability, appropriateness, adoption, feasibility, sustainability, fidelity, and costs using a mixed methods approach. Findings Between 15th January 2021 and 18th April 2023, 1,488 persons were included and randomised (734 intervention, 754 control), with 1,229 (82·6%) available for analysis of the primary effectiveness outcome. After a mean follow-up of 16 months, the mean CAIDE score improved by 0·16 points in the intervention group vs. 0·01 in the control group (Mean Difference (MD) 0·16, 95% Confidence Interval (CI) 0·03-0·29). The effect was larger in those who adhered to the intervention (MD 0·27, 95%CI 0·12-0·44) and those planning to change lifestyle (MD 0·33, 95%CI 0·10-0·57). Ten percent of those invited participated; of these, 81% adopted the intervention and 50% continued active participation throughout the study. For the individual components of the CAIDE score, there were no statistically significant differences for systolic blood pressure, total cholesterol and BMI, but in the intervention group physical inactivity was reduced more than in the control group (MD 6·7%, 95%CI 2·1 to 11·2) and more participants quit smoking (MD -3·1%, 95%CI -4·8 to -1·5). Interpretation A coach-supported mHealth intervention to improve lifestyle is modestly effective in reducing dementia risk factors in those with low SES in the UK and any SES in China. Implementation is challenging in these populations, but those reached actively participated. Whether this will result in less cognitive decline and dementia requires a larger RCT with long follow-up.

Left atrial reservoir strain measured by three-dimensional echocardiography is associated with major adverse cardiovascular events in the general population

Abstract Background Left atrial (LA) strain measured by three-dimensional (3D) echocardiography (3DE) is a novel way of evaluating LA function. The prognostic value of LA strain by 3DE in incident heart failure (HF) and cardiovascular (CV) death has not previously been documented. Purpose We south to investigate whether 3D LA strain measures were associated with incident heart failure (HF) and cardiovascular (CV) death in a population at low risk of CV events. Methods A total of 1,934 participants from a prospective longitudinal cohort study of the general population underwent a comprehensive transthoracic echocardiographic examination including 3DE where LA reservoir strain (LASr), conduit strain (LAScd) and contraction strain (LASct) were quantified. All participants were at sinus-rhythm during 3DE. The endpoint was a composite of HF and CV death. Cox proportional hazards regression was applied. Multivariable adjustments were made for the ARIC-HF risk score (age, gender, heart rate, systolic blood pressure, antihypertensive medication, diabetes, ischemic heart disease, smoking, and body mass index) and left atrial volume index. Results Mean age was 54±17 years, 43% were male. During a median follow-up time of 4.8 years (interquartile range 4.3-5.4 years), 89 participants (4.6%) either developed HF or died of a CV cause. In univariable analysis, LASr and LAScd, but not LASct were significantly associated with the outcome, but after multivariable adjustment only LASr remained significantly associated with outcome (HR 1.04 (95% CI: 1.01-1.08), p=0.016, per 1% decrease) while LAScd and LASct did not. LASr provided incremental prognostic information beyond the ARIC-HF risk score (continuous NRI 0.21±0.11, p=0.027). Compared to participants with a LASr in the 1st tertile (LASr>32%) Participants with an LASr in the in the 3rd tertile (LASr<26.5%) had an almost 7-fold increased risk of HF or CV-death (HR 6.93 (95% CI 3.29-14.58; p=0.001)(Figure). Conclusion LA reservoir strain assessed by 3DE was independently associated with incident HF and CV death, which was not the case for LA conduit and contraction strain. In addition, LA reservoir strain added incremental value beyond clinical risk scores.

Unsupervised machine learning identifies distinct phenotypes in cardiac complications of pediatric patients treated with anthracyclines

BackgroundAnthracyclines are essential in pediatric cancer treatment, but patients are at risk cancer therapy-related cardiac dysfunction (CTRCD). Standardized definitions by the International Cardio-Oncology Society (IC-OS) aim to enhance precision in risk assessment.ObjectivesCategorize distinct phenotypes among pediatric patients undergoing anthracycline chemotherapy using unsupervised machine learning.MethodsPediatric cancer patients undergoing anthracycline chemotherapy at our institution were retrospectively included. Clinical and echocardiographic data at baseline, along with follow-up data, were collected from patient records. Unsupervised machine learning was performed, involving dimensionality reduction using principal component analysis and K-means clustering to identify different phenotypic clusters. Identified phenogroups were analyzed for associations with CTRCD, defined following contemporary IC-OS definitions, and hypertensive response.ResultsA total of 187 patients (63.1% male, median age 15.5 years [10.4–18.7]) were included and received anthracycline chemotherapy with a median treatment duration of 0.66 years [0.35–1.92]. Median follow-up duration was 2.78 years [1.31–4.21]. Four phenogroups were identified with following distribution: Cluster 0 (32.6%, n = 61), Cluster 1 (13.9%, n = 26), Cluster 2 (24.6%, n = 46), and Cluster 3 (28.9%, n = 54). Cluster 0 showed the highest risk of moderate CTRCD (HR: 3.10 [95% CI: 1.18–8.16], P = 0.022) compared to other clusters. Cluster 3 demonstrated a protective effect against hypertensive response (HR: 0.30 [95% CI: 0.13– 0.67], P = 0.003) after excluding baseline hypertensive patients. Longitudinal assessments revealed differences in global longitudinal strain and systolic blood pressure among phenogroups.ConclusionsUnsupervised machine learning identified distinct phenogroups among pediatric cancer patients undergoing anthracycline chemotherapy, offering potential for personalized risk assessment.

Comparative analysis of muscle sympathetic nerve activity in patients afflicted with orthostatic hypertension versus conventional hypertension

Abstract Introduction Standing places a significant hemodynamic burden on the cardiovascular system. In healthy individuals, neurohumoral reflex mechanisms, particularly the arterial baroreflex, maintain blood pressure during standing. However, in some cases, the counterregulatory response can be excessive, resulting in a condition known as orthostatic hypertension (OrthoHT), which appears to be linked to an increased cardiovascular risk. Epidemiologically, orthostatic hypertension has been reported in 5-30% of hypertensive patients. Furthermore, in recent years, it has garnered attention as a responder group in renal denervation therapy. Purpose In hypertensive patients, sympathetic hyperactivity is expected to exacerbate cardiovascular risk. However, the relationship between OrthoHT and sympathetic nerve activity remains poorly understood. This study aims to assess the differences in sympathetic nerve activity between OrthoHT and conventional hypertensive patients using muscle sympathetic nerve activity (MSNA) measurements. Methods We conducted an examination of hypertensive patients undergoing drug treatment at our clinic between April 1, 2023, and June 30, 2023, to identify cases of OrthoHT. Only patients with essential HT were included in the HT group; patients diagnosed with secondary HT were excluded. HT patients with other active CV diseases (i.e., symptomatic cerebral/coronary artery diseases or heart failure) and/or severe renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m2) were also excluded. OrthoHT was defined as a sustained increase in systolic blood pressure ≥20 mmHg and/or diastolic blood pressure ≥10 mmHg within 3 minutes of standing. MSNA was recorded from the left peroneal nerve using a tungsten microelectrode at supine position. We measured MSNA in the cases for which consent was obtained. Statistical analyses were performed using SPSS software. Results Among the 183 cases, 31 were diagnosed with OrthoHT, and 7 of them consented to MSNA measurement. Of the 11 cases of hypertensive patients who consented, two groups were well age-matched. We assessed body mass index, resting systolic blood pressure, diastolic blood pressure, heart rate, blood glucose level, creatinine, cholesterol, brain natriuretic hormone, and ejection fraction measured by echocardiography, but found no significant differences between the two groups. OrthoHT patients exhibited elevated MSNA burst frequency (28.3 +/- 5.7 vs. 38.4 +/- 12.2 bursts/min, P < 0.05) and burst incidence (44.6 +/- 11.1 vs. 61.1 +/- 21.3 bursts/100 heartbeats, P < 0.05) at rest. Conclusions OrthoHT is associated with sympathetic hyperactivity compared to normal hypertensive patients, contributing to an increased cardiovascular risk.

Non-lipid metabolomic biomarkers are associated with adverse cardiac remodelling and cardiovascular outcomes

Abstract Background Metabolomics is the detailed profiling of circulating metabolites including carbohydrates, lipids, amino and fatty acids, and ketones, all of which are substrates used in energy metabolism by cardiomyocytes. Purpose The role of cholesterol fractions with cardiovascular risk is well-established. This novel study examines the association between non-lipid circulating metabolites and markers of cardiac remodelling as assessed by cardiovascular magnetic resonance (CMR) imaging. Metabolites associated with adverse remodelling were taken forward to examine their impact on incident cardiovascular disease (CVD); ischaemic heart disease (IHD) and heart failure (HF). Methods This study used data from the UK Biobank. After exclusions (prevalent IHD, HF; outliers), there were a maximum of 34,727 individuals for CMR analyses and 262,536 individuals for incident CVD analysis. For CMR analyses, outcome variables were LV end-diastolic volume (EDV), LV mass, LV mass:volume ratio (MVR), LV global longitudinal strain (GLS) and native T1. Separate regression models were built for each of the 40 scaled metabolite biomarkers. Each model incorporated one metabolite at a time with additional covariates: age, sex, ethnicity, systolic blood pressure, cholesterol medication use, type 2 diabetes, dietary intake, smoking status, fasting time, and time between recruitment and CMR examination. A Bonferroni-corrected significance threshold of 2.4x10-4 was used. To account for correlation between metabolites, Lasso regression with 10 fold cross-validation to identify the most important predictors was performed for LV MVR, LV GLS and native T1 whereby all metabolites and above covariates were included in the model. Metabolite predictors of adverse remodelling were included in an adjusted logistic regression model with incident CVD as an outcome. Results Metabolites demonstrating significant (p < 2.4x10-4) associations with CMR parameters are presented in Fig 1. For higher LV MVR and more positive LV GLS, the metabolites with the largest effect were monounsaturated fatty acids and glycoprotein acetyls. Higher omega-6:omega-3 ratio was associated with higher T1 values. The Lasso model identified 8 important predictors for adverse cardiac remodelling. Of these, two were routine biomarkers (creatinine, glucose). Of the remainder, monounsaturated fatty acids, glycoprotein acetyls and apolipoprotein B:apolipoprotein A1 ratio were significantly associated with increased risk of incident CVD (Fig 2). Current evidence regarding monounsaturated fatty acids in CVD is mixed. Glycoprotein acetyls are implicated in vascular inflammation. Apolipoproteins are thought to be a potential therapeutic target for CVD risk reduction. Conclusion This study demonstrates a role of non-lipid metabolites on subclinical CVD as assessed by adverse remodelling with CMR as well as associations with incident CVD. We highlight potential novel biomarkers for identification of CVD.Metabolite association with LV MVR/GLSMetabolite association with incident CVD