Heart Failure Death Research Articles

The underestimated risk of prediabetes on cardiovascular outcomes in heart failure with reduced left ventricular function

Abstract Background The global prevalence of prediabetes and diabetes is increasing, highlighting an urgent public health challenge. While the cardiovascular (CV) risk of diabetes is well studied, profound data on the CV risk of prediabetes in patients with heart failure (HF) remain scarce in current literature. Therefore, we aimed to investigate the relationship of prediabetes and diabetes with common HF associated events such as all-cause, CV death and hospitalization for HF (HHF) in patients with HF with reduced ejection fraction (HFrEF). Methods Patients with HFrEF who were admitted to a tertiary academic center between 01/2005 and 07/2019 were included in the present analysis and then stratified according to their glycemic state. Prediabetes was defined as an HbA1c value between 5.7% and 6.4% and the absence of diabetes mellitus. The primary outcome was a composite of CV death and HHF. Secondary outcomes were the individual components of the primary outcome and all-cause death. We used cox regression models adjusted for age, sex, chronic kidney disease, body mass index, prior myocardial infarction, hypertension, CRP, and LDL-C. Results In total, 1,777 patients (median age 69 years, 24.3% female) were included in the present analysis and followed over a median of 4 years. Among them, 35.2% were diabetic, 18.7% prediabetic, and 46.1% showed non-impaired glucose metabolism. NT-proBNP levels were comparable between all glycemic groups. Both prediabetes and diabetes were found to significantly increase the risk of CV-death or HHF compared to those with normal glucose metabolism, with adjusted hazard ratios (HR) of 1.41 (95% Confidence Interval [CI]: 1.05-1.89) and 1.52 (95% CI: 1.17-1.97), respectively. This elevated risk applied to both components of the primary outcome, as illustrated in Figure 1. Notably, the increased risk of all-cause mortality was statistically significant only among diabetic patients (adj. HR 1.75; 95%CI: 1.30-2.36), with prediabetic patients showing a trend towards increased risk but not reaching statistical significance (adj. HR 1.40; 95%CI: 0.99-1.97). Conclusion The findings of this study underscores the independent associations between both prediabetes and diabetes with increased risks of cv-death and HHF in patients diagnosed with HFrEF. This emphasizes the critical role of glycemic status in the prognostication and management of HFrEF. The associations suggest that prediabetes is not merely a transient or benign state but has significant implications for cardiovascular health, particularly in the context of HF. In light of these findings, screening of prediabetes in patients with HFrEF might help to identify patients at risk who are susceptible for the development of HF related adverse events.Forest plot for all study endpointsKaplan-Meier curves for CV-death/HHF

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

The condition of myocardium reserves score from a cloud-based analytics platform of Holter ECG data indicates better cardiometabolic function in heart failure

Abstract Introduction Cardiometabolic dysregulation, particularly type 2 diabetes mellitus (T2DM), is associated with subtle myocardial pathologies, even in individuals without known cardiovascular disease. These subclinical changes, often undetectable by standard electrocardiogram (ECG) analytics, can offer valuable insights into the relationship between metabolic health and cardiac function. Novel ECG markers, developed through machine learning and artificial intelligence (AI), may provide the sensitivity needed to detect such changes. Aim This study aims to evaluate novel composite cardiac parameters from an analytics platform in the context of heart failure (HF), seeking to understand their relationship to cardiometabolic dysregulation. Methods Data from the MyoVasc study, a prospective cohort on HF, were analysed. Participants underwent extensive clinical phenotyping, including a Holter ECG assessment. Holter ECG data was processed based on machine learning and AI models on a cloud-based analytics platform (Cardiolyse, Helsinki, Finland), generating both traditional and proprietary ECG, and heart rate variability cardiac health markers. LASSO-penalized logistic regression adjusted for sex and age was performed to select the marker most strongly associated with T2DM. The identified marker was then evaluated in relation to cardiac function and structure as well as HF-related outcome. Results A total of 953 subjects (mean±SD age 64.6±10.5 years; 35.7% women) were included in the analyses. Symptomatic HF stage C/D was present in 54.8% (n=522) of subjects and diabetes mellitus in 22.4% (n=213). The Condition of Myocardium Reserves Score (CMRS) was the novel composite cardiac parameter selected based on its relationship with T2DM. In a Poisson regression model with robust variance adjusted for sex and age, a lower score was associated with T2DM (Prevalence ratio per SD 1.24, 95% confidence interval [1.14;1.36], P=0.0002). In multivariable linear regressions adjusted for traditional cardiovascular risk factors, comorbidities, and medication, a higher CMRS was associated with better global longitudinal strain (β per SD –0.82 [–1.11;–0.53], P<0.0001), diastolic function (left ventricular E/e’; β per SD –0.04 [–0.06;–0.01], P=0.0059) and systolic function (LV ejection fraction; β per SD 2.06 [1.46;2.67], P<0.0001). A lower CMRS independently predicted all-cause death (Hazard ratio per SD 1.25 [1.09;1.45], P=0.0020) and worsening of HF (HR per SD 1.44 [1.21;1.72], P<0.0001) in Cox regression analysis adjusted for the same confounders. Conclusion The Condition of Myocardium Reserves Score exhibited a strong association with cardiometabolic dysregulation. A higher CMRS indicated preserved cardiac function, while a lower score independently predicted increased risk of all-cause death and worsening HF. This novel score offers potential as a non-invasive tool for assessing cardiometabolic health and stratifying risk in patients with HF.

The prognostic interplay of heart failure and chronic kidney disease in atrial fibrillation, focus on cardiorenal outcomes

Abstract Background Heart failure (HF) and chronic kidney disease (CKD) create a mutually reinforcing cycle, escalating disease development, and increasing morbidity and mortality rates. Both are common comorbidities promoting atrial fibrillation (AF) and contributing to heightened symptom burden and poorer outcomes in AF. Purpose To investigate the relationship of HF and CKD with cardiorenal outcomes in patients with AF. Methods For this analysis we included patients with known AF, treated at a tertiary centre between 01/2005 and 07/2019. The primary endpoint was a composite of cardiovascular (CV) death and hospitalization for HF (HHF). Secondary outcomes were renal death and dialysis. The multivariate model has been adjusted for age, sex, body mass index, HF, diabetes mellitus, CKD, coronary artery disease, previous myocardial infarction, and C-reactive protein. Results We included in total 7412 patients (median age 70 years, 39.7% female) with AF and followed them over a median of 4.5 years. A total of 1668 patients (22.5%) were diagnosed with HF, 806 (10.9%) with CKD and 372 (5.0%) were suffering from both conditions. Both CKD (adjusted HR 1.87, 95% CI 1.55-2.25) and HF (adjusted HR 2.57, 95% CI 2.22-2.98) were significantly associated with the composite of CV death/ HHF after multivariable adjustment. There was a significant stepwise increase in 5-year’s event rates of CV death/ HHF (no CKD & no HF: 23%, HF: 61%, CKD: 63%, CKD & HF: 82%; P-logrank <0.001). These results remained significant in the multivariate analysis, showing the highest increase in risk in patients with both HF and CKD with an adjusted HR of 3.96 (95% CI 3.34-4.68), followed by patients with only HF (adjusted HR 2.53, 95% CI 2.26 to 2.84) and only CKD (adjusted HR 2.22, 95% CI 1.87-2.63, p-value of <0.001, respectively). Regarding renal death/ dialysis we could observe a similar distribution of the 5-year’s event rates (no CKD & no HF: 1.5%, HF: 4.0%, CKD: 11.8%, CKD & HF: 17.7%; P-logrank <0.001). Both conditions, CKD and HF, remained independently associated with the combined endpoint of renal death/ dialysis after multivariable adjustment (only HF: adjusted HR of 2.80, 95% CI 1.84 to 4.25; only CKD: adjusted HR of 5.31, 95% CI 3.22 to 8.76; CKD & HF: adjusted HR of 7.47, 95% CI 4.70 to 11.87; Figure 1). Conclusions Both CKD and HF significantly increase the risk of CV death and HHF, as well as renal death and dialysis in patients with AF. Risk assessment should expand beyond stroke and bleeding to cardiorenal complications including HHF, CV and renal death, as well as kidney failure in an unselected AF patient population.

Left atrial reservoir strain and global longitudinal strain associates with re-hospitalization and mortality in patients admitted for acute heart failure

Abstract Background Left atrial reservoir strain (LAr) and global longitudinal strain (GLS) have emerged as useful parameters for the assessment of left ventricular diastolic function and the estimation of left ventricular filling pressures. Yet, there remains a gap of knowledge regarding the possible association of LAr and GLS with re-hospitalization and mortality in patients with acute heart failure (HF). Aims This study aims to investigate the association between LAr and GLS with re-hospitalization and mortality in patients admitted for acute HF. Methods Out of 526 enrolled patients admitted for acute HF, 142 (mean age 71, 25% women) were systematically evaluated for LAr and GLS using speckle tracking echocardiography. Multivariable Cox regression analyses, adjusting age, sex, current smoking prevalent atrial fibrillation, hypertension, kidney disease and plasma glucose, were used to assess the associations between continuous values of LAr and GLS with all-cause mortality and HF-related re-hospitalization. Results The median follow-up time to death of any cause and HF rehospitalization was 39 (interquartile range 14-66) and 22 (4-51) months, respectively. During follow up, 63 (44%) patients died, and 63 (44%) were re-hospitalized due to HF. Lower values of LAr were significantly associated with higher risk of mortality (HR 0.93; 95%CI 0.89-0.98, p=0.008). Similarly, lower GLS was associated with higher risk of mortality (HR 0.94; 95%CI 0.89-0.99, p=0.045). Only lower values of LAr were associated with higher risk of HF re-hospitalization in the multivariable model (HR 0.93; 95%CI 0.88-0.98, p=0.004). Conclusion In this prospective, long-term follow-up study of patients with acute heart failure, lower values of LAr and GLS showed prognostic significance, with lower values being indicative of poorer outcomes. Notably, LAr was associated with higher risk of both death and rehospitalization for heart failure, whereas GLS was solely associated with higher mortality risk. These echocardiographic parameters could be further investigated for risk assessment of patients with heart failure in order to identify those at higher risk of rehospitalization and death, thereby facilitating targeted interventions to improve their prognosis.KM-curves for or the Quartiles of LAr

Right atrio-ventricular strain as a predictor of death in left-sided heart failure

Abstract Background Right ventricular (RV) strain is an established outcome predictor in heart failure (HF). However, the role of right atrial (RA) strain in the setting of left-sided HF is incompletely understood. Purpose We sought to evaluate the RV, RA and combined right atrio-ventricular (RAV) strain using speckle-tracking echocardiography in a cohort of patients with left-sided HF and to assess their prognostic role. Methods 121 consecutive patients (mean age 59±14 years, 74% men) with HF with reduced ejection fraction (HFrEF) referred to our echocardiography department were prospectively enrolled. The main endpoint was all-cause death. RV strain was measured as the average longitudinal strain of the basal, mid, and apical segments of the RV free wall and was reported as a positive value, thus a lower RV strain reflecting a greater longitudinal dysfunction. RA strain was defined as the maximal longitudinal displacement of the atrial wall at end-systole, corresponding to atrial reservoir function. RAV strain was defined as the sum of RV strain and RA strain. Results During a median follow-up of 19±11 months, 26 patients (21%) died. Patients who reached the endpoint had lower left ventricular ejection fraction (LVEF) (21±7% vs. 26±7%, p=0.001), lower tricuspid annular plane systolic excursion (16±3 vs. 18±5, p=0.02) and lower RA strain (13± 10% vs. 18±11%, p=0.03). In univariable Cox regression, RV, RA and RAV strain were all predictors of death: HR=1.05 [95% CI, 1.00-1.11], p=0.045 for RV strain, HR=0.95 [95% CI, 0.91-0.99], p=0.02 for RA strain, HR=0.97 [95% CI, 0.94-0.99], p=0.01 for RAV strain. We constructed a multivariable model with well-established event predictors in HFrEF and one strain index at a time. After adjustment for LVEF, maximal left atrial volume, tricuspid regurgitation severity and pulmonary artery systolic pressure, only RAV strain remained an independent predictor of death (HR=0.97 [95% CI, 0.94-1.00], p=0.04), while RV strain and RA strain did not (p=0.07 for both). LVEF did not emerge as a predictor of death in multivariable regression (p=0.57). Conclusion In left-sided HF, RV and RA strain were predictors of death. Combining the longitudinal strain of both right heart chambers might improve risk stratification, since RAV strain remained the only independent predictor of adverse outcome after adjustment for confounders.

Dynamics and prognostic role of persistent angina in chronic coronary syndrome with clinical, angiographic and stress CMR evidence of ischemia

Abstract Background In patients with established chronic coronary syndrome (CCS), the significance of myocardial ischemia is a controversial issue. Persistent angina within the first year after treatment intervention has ranged widely in previous studies and its association with subsequent hard clinical events is unclear. We aim to evaluate the long-term dynamics of angina class and the prognostic role of persistent angina in symptomatic chronic coronary syndrome (CCS) patients with abnormal stress cardiovascular magnetic resonance (CMR) and altered angiography. Methods We analyzed 486 CCS patients with Canadian Cardiovascular Society angina class ≥2, perfusion deficit in stress CMR and severe lesions in angiography submitted to treatment intervention (medical therapy plus, if feasible, CMR-guided revascularization). The dynamics and association of persistent angina at 6 months post-intervention with subsequent cardiac death, myocardial infarction, and admission for heart failure were investigated. Results All patients displayed angina class ≥2 (mean: 2.7±0.7), abnormal stress CMR (mean ischemic burden: 6.2±3 segments) and severe angiographic lesions. Most underwent CMR-guided revascularization (n=392, 81%). The angina resolution rate was 78% at 6 months, and 79%, 77%, and 75% at 1, 2, and 5 years respectively. Compared with medical treatment alone, CMR-guided revascularization was associated with less persistent angina (19% vs. 35%; HR 0.42 [0.2–0.7]; p=0.003). During an 8.3-year median follow-up, persistent angina was independently associated with higher subsequent cardiac death rates (18% vs. 4%; HR 10.9 [4.1–29.2]; p<0.001), myocardial infarction (24% vs. 6%; HR 5.8 [3.2–10.4]; p<0.001), and admission for heart failure (31% vs. 14%; HR 2.7 [1.7–4.2]; p<0.001). Conclusions In CCS patients with robust diagnostic evidence by symptoms, stress CMR and angiography, sustained improvement of anginal symptoms can be achieved in most patients after treatment intervention. Angina resolution is more frequent in patients treated with CMR-guided revascularization and is associated with fewer cardiac events.Central Figure.Persistent angina and MACE risk

Prognostic implication of right ventricular - pulmonary arterial coupling in patients with non-valvular atrial fibrillation

Abstract Background The clinical importance of right ventricular (RV) - pulmonary arterial (PA) coupling has been reported in various cardiac diseases such as right heart failure, pulmonary hypertension, and valvular dysfunction. However, there is limited data on patients with non-valvular atrial fibrillation (AF). We aim to investigate whether RV-PA uncoupling affects the clinical outcome in patients with non-valvular AF. Methods A total of 807 consecutive patients with non-valvular AF who underwent echocardiography (mean age 70 ± 12 years, 39% female) were included. We excluded patients with significant (at least moderate degree) valvular diseases, left ventricular ejection fraction (LVEF) <50%, cardiac implantable electronic devices, previous cardiac surgery, and poor echocardiographic image for RV analysis. RV-PA coupling was assessed by the ratio of RV global longitudinal strain (GLS) to PA systolic pressure (PASP), and decreased RV-PA coupling was defined as less than 0.52 %/mmHg based on on the receiver operating characteristic analysis. The primary outcome was the composite of all-cause death and hospitalization for heart failure. Results Over a mean of 4.7 ± 3.5 years of follow-up, 178 (22%) patients had experienced primary outcomes. Among them, 107 (13%) patients were hospitalized for HF and 90 (11%) patients died. Patients with decreased RV-PA coupling were older (73 ± 11 vs. 68 ± 12 years, p<0.001), had a higher prevalence of females (51 vs. 33%, p<0.001) and diabetes (33 vs. 23%, p=0.003), lower left ventricular ejection fraction (60 ± 5 vs. 61 ± 5%, p=0.011), higher E/e’ (14 ± 5 vs. 11 ± 4, p<0.001), larger left atrial volume index (78 ± 37 vs. 62 ± 22 ml/m2, p<0.001) and larger RV end-systolic area (11 ± 4 vs. 10 ± 3 cm2/m2, p=0.001) compared to those with preserved RV-PA coupling. In multivariate Cox regression analysis, decreased RV-PA coupling was associated with worse clinical outcomes even after adjusting for age, diabetes, E/e’, and RV end-systolic area (Hazard ratio [HR] 1.50, 95% Confidence interval [CI] 1.09 – 2.07, p=0.014) (Figure 1). Conclusions In patients with non-valvular AF, RV-PA coupling was associated with clinical outcome, suggesting that it may provide additional information for predicting future cardiovascular risk in this population.

The effect of treatment srategy for acute myocardial infarction complicated by cardiac shock using Impella in accordance with institutional protocol

Abstract Backgrounds Team-based care for cardiogenic shock (CS) using mechanical circulatory support (MCS) including Impella in accordance with standardized protocol was reported to improve the prognosis of patients with CS. Methods Between February 2018 and September 2022, we performed percutaneous coronary intervention (PCI) in 63 patients with acute myocardial infarction (AMI) complicated by CS using Impella. We introduced institutional protocol (Figure 1) to standardize the treatment strategy for CS from June 2019, in which early Impella implantation preceding PCI was recommended. We retrospectively examined the incidence of Impella implantation preceding PCI, in-hospital outcomes including the rates of survival to Impella weaning and to discharge, and the incidence of major cardiovascular events (MACE) including all death, MI, and hospitalization for heart failure at 1-year before and after protocol introduction. Results The patients have a mean age of 67.1±13.2 years and 53 patients (84.1%) were male. The patients in preceding period were 16 cases, while 47 in latter period. The rate of Impella implantation preceding PCI was significantly higher in latter period than that in preceding period (61.7% vs. 25%, p=0.027) (Figure 2A). The rate of survival to Impella weaning was significantly higher in latter period than that in preceding period (83% vs. 56.3%. p=0.043). There was no difference in the rate of survival to discharge between each period (50% in preceding period vs. 68.1% in latter period, p=0.236). However, the cumulative MACE free survival rate was significantly higher in latter period than that in preceding period (56.9% vs. 31.3%, Log-rank p=0.020) (Figure 2B). Conclusion The introduction of institutional standardized protocol of MCS use might improve 1-year outcomes of patients with AMI complicated by CS treated with Impella.Figure 1Figure 2

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.

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.

Changes and prognostic impact of right ventricular-to-pulmonary artery coupling after transcatheter aortic valve replacement

Abstract Background The ratio of tricuspid annular plane systolic excursion to systolic pulmonary artery pressure (TAPSE/sPAP), a good noninvasive approach for right ventricular to pulmonary artery (RV/PA) coupling, is of prognostic significance in many cardiovascular diseases. Yet, data regarding RV/PA coupling in transcatheter aortic valve replacement (TAVR) remain sparse. Aims: To assess the change in TAPSE/sPAP between pre- and post-TAVR as well as its long-term prognostic value. Methods: All patients who underwent TAVR for severe aortic stenosis between 2002 and 2022 at a university hospital, with an available TAPSE/sPAP assessed by echocardiography before and after procedure were included in this study. When available, TAPSE/sPAP was correlated with invasive right heart catheterization data. The primary endpoint was 5-years all-cause death or hospitalization for acute heart failure. C-tree analysis was used to find the best TAPSE/sPAP cut-off to be associated with the primary outcome. Results: Two hundred and sixty-nine patients were included in this analysis (median age 85 years, 57% women, 63% NYHA III-IV). Balloon expandable valves was implanted in 90% of cases. TAPSE/sPAP was significantly improved by TAVR (0.52 vs 0.58 mm/mmHg, p=0.02). The lower the TAPSE/sPAP, the higher the NYHA functional class (p=0.0017), the higher the NTproBNP level (p <0.001) and the higher the logistic EuroSCORE (p<0.001). TAPSE/sPAP had a good correlation with pulmonary artery elastance (r=-0.61, p<0.001). Using C-tree analysis, TAPSE/sPAP ≤0.55 mm/mmHg was the best cut-off associated with the primary outcome (p=0.002). In multivariable Cox regression analysis, TAPSE/sPAP remained independently associated with the primary outcome even after adjustment with echocardiography, comorbidities or logistic EuroSCORE (Table 1). Both from baseline and follow-up assessment, patients with TAPSE/sPAP ≤0.55 mm/mmHg had worse event-free survival (Figure 1A-B). Interestingly, change in TAPSE/sPAP provided important prognostic value (Figure 1C). Conclusion: This study emphasizes the prognostic value of TAPSE/sPAP in the field of TAVR and suggest considering RV/PA coupling assessment not only before or after procedure but also the change in TAPSE/sPAP to identify patients at higher risk of worse outcome.Table1.Multivariable Cox analysisFig1.Kaplan meier curves

Impact of heart failure diagnosis on recorded healthcare resource use by older people in Wales; is primary care shouldering a hidden burden?

Abstract Background Heart failure (HF) is associated with high healthcare resource use and mortality. Most of the evidence focuses on hospital admission data. The impact on primary care interactions and outpatient attendance is less well described, but this information is important in understanding resource utilisation, patient pathways, and in planning services. Purpose To examine how a diagnosis of HF impacts healthcare resource use and outcomes for older people in Wales. Methods We conducted a retrospective, population-level, observational study using linked anonymised electronic health record (EHR) data in Wales (2015-22). 737,230 individuals were aged 65y+ in the study period in primary and secondary care data. Of these, 65,010 had a code for HF in their primary or secondary care records. To evaluate changes in resource use, we excluded 13,990 individuals with fewer than 12 months health data pre- and post-diagnosis. We summarised general practice (GP) interactions, emergency department (ED) attendance, outpatient (OP) attendance, inpatient (IP) episodes and days, time between HF diagnosis and death, and place of death. Results The final cohort comprised 51,020 individuals 65y and over with a diagnosis of HF between 2015-2022. Incidence and prevalence of HF increased across the study period (1.4-1.5% and 8.5-9.1% respectively). Figure 1 shows the percentage change in healthcare resource use for the cohort when HF was diagnosed (12 months pre-and post-diagnosis comparison). Table 1 shows the average number of healthcare utilisation events per person. After a diagnosis of HF, there are fewer ED attendances (-28.2%) and IP admissions (-9.3%) but more OP appointments (31%) and GP interactions (20.3%). When admissions occur, hospital stays tend to be longer (55.4%). Median time (IQR) from HF diagnosis to death from any cause was 247(34-840) days, and with HF listed as a cause 186(25-780) days. In this cohort, the place of death was recorded as NHS establishment (20,379, 67.8%), community (5,450, 18.1%), non-NHS establishment (3,789,12.6%) and unknown (450, 1.5%). Conclusions In Wales, a diagnosis of HF in those 65y+ increases primary care interactions and OP attendances. The change in volume of primary care interactions is considerable (increase from 1,047,920 to 1,315,080). Longer hospital stays may suggest difficulty in managing patients or discharging back to community settings. Majority of those with HF die in NHS establishments. It is unclear whether this reflects deficits in end-of-life care. These results are important in planning effective health service delivery and in establishing baseline data from which to monitor quality improvements.

Heart failure risk assessment using biomarkers in patients with atrial fibrillation: analysis of 32,041 patients from the COMBINE-AF study

Abstract Introduction Heart failure (HF) is one of the most common comorbidities in patients with AF, resulting in a clinical need for robust risk assessment. Purpose To investigate the incremental value of adding NTproBNP, high-sensitivity cardiac troponin T (hs-cTnT), and growth-differentiation factor-15 (GDF-15) to clinical predictors for HF risk stratification in patients with AF, and the individual contribution of each biomarker accounting for inter-biomarker correlation. Methods We used pooled individual patient data from 3 large RCTs investigating DOACs versus VKAs (ARISTOTLE, ENGAGE AF-TIMI 48, RE-LY) from the COMBINE-AF cohort and included all patients with available biomarkers at baseline. The composite primary endpoint was hospitalization for HF (HHF) or CV death (CVD), with HHF as secondary endpoint. We employed analyses of absolute risk and Cox-regression adjusting for clinical factors to assess the association of the individual biomarkers with both endpoints, testing incremental discrimination with the likelihood ratio test from nested models. To address the inter-biomarker correlation, weighted quantile sum (WQS) regression analysis summarizing the adjusted risk of all biomarkers (per quartile) in one index was applied, thereby exploring the individual and additive contribution of each biomarker to risk assessment. Results Data were available in 32,041 patients (median age 71 [IQR 64-77] years, 36.7% female, 23.0% with paroxysmal AF, 41.6% with established HF). Higher biomarker values were associated with a graded increase in absolute risk for HHF/CVD and HHF (Figure 1). In a model adjusting for clinical variables and all biomarkers, hs-cTnT (HR per 1-SD 1.39 [95% CI 1.33-1.44]), NT-proBNP (HR 1.67 [95% CI 1.58-1.76]), and GDF-15 (HR 1.20 [95% CI 1.15-1.25]) were associated with HHF/CVD. The c-index increased with addition of biomarkers (0.70 [0.69, 0.70] to 0.77 [0.76, 0.78]; Likelihood ratio test p<0.001). Results were similar for HHF alone. NTproBNP was significantly correlated with hs-cTnT (r=0.40, p<0.0001) and GDF-15 (r=0.36, p<0.001). To address this correlation, WQS regression analysis was conducted (Figure 2). NTproBNP and hs-cTnT contributed nearly equally to the risk assessment for HHF/CVD and HHF, with GDF-15 providing statistically significant but less contribution to risk assessment (Figure 2). Conclusion Hs-cTnT, NT-proBNP and GDF-15 contribute individually and additively to the risk assessment for HHF/CVD and HHF in patients with AF. Our analysis suggests that hs-cTnT is as important as NTproBNP for HF risk assessment, with significant but less contribution of GDF-15. Our findings support the possible future routine use of biomarkers to distinguish patients with AF at low or high risk for HF and could guide the introduction of therapies to mitigate the risk of HF events in this growing population.Event incidence by biomarker quartilesWeighted quantil sum regression analysis

Impact of global longitudinal strain and anemia for predicting cardiovascular mortality in patients hospitalized for acute heart failure with atrial fibrillation

Abstract Background Iron deficiency is a prognostic factor in heart failure (HF) with reduced ejection fraction (EF). In patients with atrial fibrillation (AF) and HF, left ventricular EF (LVEF) measurements are imprecise due to irregular tachycardia, but it is unclear whether global longitudinal strain (GLS) and anemia assessment are prognostic. Purpose We examined whether GLS and anemia predict cardiovascular death (CD) in patients with acute HF complicated by AF. Methods We retrospectively enrolled patients aged 18 years or older with acute HF complicated by AF who were consecutively admitted to our hospital from January 2014 to December 2018. Exclusion criteria were acute coronary syndromes, no transthoracic echocardiogram performed within 30 days before or after admission, and missing data. All patients were followed up from admission to CD (due to myocardial infarction, HF, stroke or sudden death), or were censored at the date of last contact or 3 years. Anemia was defined as hemoglobin < 12 g/dL in females and hemoglobin < 13 g/dL in males. Patients were divided into four groups according to median GLS and anemia status. Results A total of 320 patients (mean age 79 ± 12 years, 163 females) were included in the analysis. The median duration of AF was 1.2 years; 11% (36/320) had paroxysmal AF. The median brain natriuretic peptide value was 623 pg/ml, and 52% of the patients (165/320) were in New York Heart Association functional class 4. During a median follow-up of 528 days, 24% (77/320) patients were observed with CDs: 2 myocardial infarctions, 51 HF-related deaths, 6 strokes, and 18 sudden cardiac deaths. At the 3-year follow-up, the survival rate by the Kaplan-Meier curve was 89% (95% confidence interval (CI) 76%-95%) in the no anemia group with high GLS (< -10%) and 40% (95% CI 25%-54%) in the anemia group with low GLS (≥ -10%) (p < 0.001, log-rank test). In multivariate Cox regression analysis, GLS (adjusted hazard ratio (aHR) 1.06, 95% CI 1.01-1.14, p = 0.017) and hemoglobin (aHR 0.85, 95% CI 0.76-0.96, p = 0.009) were independent factors for CD, with a significantly increased risk in the anemia group with low GLS compared to the no anemia group with high GLS (aHR 4.11, 95% CI 1.59-10.6, p = 0.004). The results were consistent with no interaction by gender or LVEF 50%. Conclusions Anemic patients with low GLS with AF and HF may have poor prognosis. Prospective studies are needed to determine whether iron supplementation improves prognosis in such patients.

Efficacy of native T1 mapping for patients with non-ischemic cardiomyopathy and ventricular functional mitral regurgitation undergoing transcatheter edge-to-edge repair

Abstract Background The objectives of this study were to investigate the efficacy of LV myocardial damage assessment by native T1 mapping obtained with cardiac magnetic resonance (CMR) for symptomatic heart failure (HF) patients with non-ischemic cardiomyopathy (NICM) and ventricular functional mitral regurgitation (VFMR) undergoing transcatheter edge-to-edge repair (TEER). Methods We studied 40 symptomatic HF patients with NICM and VFMR undergoing TEER. LV myocardial damage was defined as the native T1 Z-score which was converted from native T1 value obtained with CMR before TEER. The primary endpoint was defined as first re-hospitalization for HF or cardiovascular death over a median follow-up period of 12 months after TEER. Results Multivariable Cox-proportional hazards analysis showed that a native T1 Z-score was the only independent parameter associated with cardiovascular events (hazard ratio: 3.40, 95% confidential interval: 1.51-7.67), and patients with native T1 Z-score < 2.41 experienced significantly fewer cardiovascular events than those with a native T1 Z-score ≥ 2.41 (log-rank P = 0.001). Moreover, such a low native T1 Z-score and more severe VFMR in an effective regurgitant orifice area (EROA) ≥ 0.30 cm2 was associated with fewer cardiovascular events than for a high native T1 Z-score of ≥ 2.41 and less severe VFMR of EROA < 0.30 cm2 (log-rank P = 0.002). Conclusion Assessment of baseline LV myocardial damage by means of native T1 Z-score obtained with CMR without the use of gadolinium-based contrast media is a valuable additional parameter for better management of symptomatic NICM patients with reduced LVEF and VFMR following TEER.

The association between endogenous erythropoietin levels and the risk of heart failure in a Chinese community-based population

Abstract Background Patients with heart failure (HF) often have elevated endogenous erythropoietin (EPO) levels, which are associated with disease severity and prognosis. Previous studies have indicated that in the special population elevated endogenous EPO levels are associated with HF and cardiovascular death. However, whether endogenous EPO levels are associated with the risk of HF in the general population remains to be elucidated. Purpose Our study aims to investigate the association between endogenous EPO levels and the risk of HF admission in the general population. Methods We conducted a prospective cohort study on subjects from a Beijing community in China who had no history of stroke or myocardial infarction. Endogenous EPO levels were measured at baseline for all participants. The endpoint of interest was admission with HF. Cox proportional hazard regression models were used to analyze the relationship between endogenous EPO levels and the occurrence of the endpoint. Results A total of 4870 participants were included. Among all participants, the mean (±SD) age was 56.72 ± 8.78 years, with 1802 (37.0%) being men. The median (interquartile range, IQR) EPO level was 13.19 (9.47-18.20) IU/L. During a mean 9.57-year follow-up, a total of 176 (3.6%) subjects experienced heart failure. Subjects were grouped in quintiles according to baseline endogenous EPO levels. Higher and lower endogenous EPO levels were both associated with increased risk of HF (Figure 1A). The Kaplan–Meier curves showed significant differences in cumulative hazards of heart failure among EPO quintiles (log-rank test: P＜0.05) (Figure 1B). After adjusting for covariates, including demographics, traditional risk factors for cardiovascular disease, renal function, and hemoglobin levels, and using the middle quintile (Q3) (11.72-14.94IU/L) of EPO levels as a reference, we found that the highest quintile (Q5) (>19.86 IU/L) was associated with a 159% increased risk of HF admission (HR 2.59, 95% CI 1.57-4.28, P = 0.0002). Similarly, the lowest quintile (Q1) (<8.66 IU/L) was associated with a 94% increased risk (HR 1.94, 95% CI 1.11-3.41, P = 0.0210) (Table 1). Conclusion There exists a "U-shaped" relationship between endogenous EPO levels and HF admission in the general population. Both higher and lower endogenous EPO levels were associated with an increased risk of HF admission in the community population. These findings differ from previous studies, so further research may be needed to explore the underlying pathophysiological mechanisms of endogenous EPO and HF.

Clinical value of multiple sensors contributing to a composite heart failure ICD monitoring index

Abstract Background The HeartLogic algorithm integrates data from various implantable defibrillator (ICD) sensors to predict impending heart failure (HF) decompensation. The algorithm computes worsening in its sensors and weighs them based on a risk level. These sensors include accelerometer-based first (S1) and third (S3) heart sounds, intrathoracic impedance (TI), respiration rate (RR), the ratio of respiration rate to tidal volume (RSBI), and night heart rate (NHR). Objective This study assessed the relative worsening of ICD sensors at the onset of HeartLogic alerts, their association with patient characteristics and subsequent outcomes. Methods The HeartLogic feature was activated in 568 ICD patients (410 with CRT-D) across 26 centers, with a median follow-up of 26 months [25th–75th percentile: 16–37]. Results During the follow-up, 1200 HeartLogic alerts were recorded in 370 patients. The sensor with the highest worsening (SHW) at the alert onset was S3 (27% of alerts), followed by S3/S1 (25%), TI (16%), RR (15%), and NHR (11%), RSBI (6%). Patients with atrial fibrillation (AF) at implantation and those with chronic kidney disease (CKD) had higher alert prevalence (AF 84% vs. no-AF 58%, CKD 72% vs. no-CKD 59%; both p <0.05) and higher alert rates (AF 1.51/patient-year vs. no-AF 0.88/patient-year, CKD 1.30/patient-year vs. no-CKD 0.89/patient-year; both p <0.05). AF patients had alerts with every sensor as SHW, while CKD patients had alerts primarily with TI, RR, and RSBI as SHW (Figure). In 85% of cases among 247 patients with >1 alert, the SHW changed between successive alerts. Of the 88 (7%) alerts resulting in HF hospitalizations or deaths, a greater proportion featured RR or RSBI (11%) and NHR (11%) as SHW, followed by heart sounds (5%) (both p <0.05). Clinical events were more common with the first alert (12.6%) than subsequent alerts (5.2%, p <0.001). Conclusion HeartLogic alerts are predominantly associated with the highest worsening in heart sounds. Nevertheless, recurrent alerts often involve other sensors, suggesting varied HF progression mechanisms and potential divergent outcomes. The frequency of alerts and the pattern of worsening in ICD sensors are linked to patient characteristics.

Unleashing the potential: early evaluation of blood pressure control with novel measurements in patients with hypertension

Abstract Objective To assess the prognostic value of two novel blood pressure measurements——short-term cumulative systolic blood pressure (SBP) load and Time in Target Rang (TTR) in major adverse cardiovascular outcomes and all-cause mortality. Method This is a post-hoc analysis of the SPIRNT (Systolic Blood Pressure Intervention Trial). Participants with complete record of BP values and no adverse events occurred in the initial 90-days follow-up were enrolled. Short-term cumulative SBP load and TTR were calculated by the 3-month SBP values in the follow-up period (Fig 1). The primary outcome was major adverse cardiovascular events (MACEs), defined as the composite of myocardial infarction, stroke, heart failure and cardiovascular death. Secondary outcomes were the components of the primary outcomes and all-cause mortality. Results The study population included 8639 adults (median [IQR]or mean (%) baseline age, 67 [61,76] years; 2940 women (35.1%); Median follow-up time 3.8[3.3-4.4] years). 559 MACEs were occurred. Participants categorized by tertiles of cumulative SBP Load (T1: [0,0.1572]; T2: (0.1572 ,3.5946]; T3: (3.5946 ,30.2949]) showed a significant increase hierarchical trend (P for trend <0.05) in the incidence of MACEs and stroke. For Participants grouped by SBP TTR (T1: [0,21.2657]; T2: (21.2657 ,71.1462]; T3: (71.1462 ,100]), it indicated a decrease hierarchical trend (P for trend <0.05) in the incidence of MACEs and MI (Fig2 and Fig3). Both short-term cumulative SBP Load (HR: 1.117(1.033-1.208)) and TTR (HR: 0.861(0.785-0.945)) were correlated with MACEs independently(tabal1). According to C-statistics and Net Reclassification Indexes (NRI), short-term cumulative SBP Load and TTR both outperformed mean SBP and SBP standard derivation (SD) on the prognosis value of MACEs. Moreover, our results showed that the coefficient of cumulative SBP Load under penalty decreased to 0 with the largest log(lambda),which indicted a major role across 4 different measures in models. (Fig 4). Conclusions Both short-term cumulative SBP load and TTR had an independent prognosis value for MACEs superior to mean SBP and SBP SD in hypertension patients without diabetes. This study provided the evidence of novel BP measurements for early assessment of BP levels after antihypertensive treatment.

Ferric derisomaltose versus usual care in patients with heart failure, reduced ejection fraction, and iron deficiency: a short-term UK cost-utility analysis based on the IRONMAN RCT

Abstract Background In the IRONMAN trial, patients with heart failure (HF), a reduced ejection fraction and iron deficiency who were randomly assigned to ferric derisomaltose (FDI), rather than usual care, had a lower rate of the composite of hospitalization for heart failure (HHF) and cardiovascular (CV) death (rate ratio, RR, 0.82; 95% CI 0.66 to 1.02; p=0.07). A COVID-19 sensitivity analysis, censoring data at 1 year of follow-up showed a greater magnitude of treatment effect (RR 0.66; 95% CI 0.48 to 0.91; p=0.011). Purpose Patient-level data from IRONMAN were used to evaluate the effectiveness and cost-utility of FDI compared to usual care for patients with a current or recent HHF, or raised plasma natriuretic peptide concentrations, from a UK National Health Service (NHS) perspective. Methods A cost-utility analysis (CUA) was conducted covering the first year after randomization. Numbers-needed-to-treat (NNTs) were calculated for the primary endpoint censored at 1 year. In the CUA model, patient survival and rates of (re)hospitalization due to HF, other CV events, infections, respiratory conditions, and other non-CV events were modeled based directly on data from the IRONMAN RCT. UK-specific costs were obtained from the national schedule of NHS costs. Quality of life was estimated based on EQ-5D-5L data collected from patients included in the IRONMAN RCT. Results were undiscounted and reported as absolute and incremental costs in 2023 pounds sterling, and quality-adjusted life expectancy in quality-adjusted life years (QALYs). A willingness-to-pay threshold of £20,000 per QALY was adopted to allow calculation of a net monetary benefit (NMB), a summary measure of the overall value of FDI in monetary terms, capturing changes in both cost and QALY outcomes. Results The NNT analysis showed that 9 patients would need to be treated with FDI to avoid one composite primary endpoint event (CV death and HHF) over 1 year. Relative to usual care, FDI was associated with an improvement of 0.01 QALYs per patient over 1 year (0.58 versus 0.57 QALYs). Total average costs per-patient were £1,672 for FDI, versus £1,975 for usual care, leading to a saving of £302 per patient with FDI. The cost of iron procurement was more than offset by reductions in costs of (re)hospitalizations (Figure). FDI was therefore dominant over usual care, yielding an NMB of £483 over 1 year. Conclusions This short-term, within-trial CUA suggests that FDI both improves QALYs and reduces healthcare expenditure versus usual care when administered to patients with HF and iron deficiency in the UK. Iron repletion with FDI may be a prudent allocation of healthcare resources in this patient population.Breakdown of costs