Diastolic Dysfunction Research Articles

Development of machine learning models for prediction of left ventricular systolic dysfunction in patients with isolated left ventricular dilation

Abstract Background/Introduction Isolated left ventricular dilation (ILVD), in the absence of concomitant LV systolic dysfunction, is a risk factor for new reduction in LV ejection fraction (LVEF) and adverse clinical outcomes. We assessed the performance of different machine learning (ML) models in predicting new reduction in LVEF in patients with ILVD. Methods A retrospective analysis of de-identified patient records in the Tempus Database with at least two transthoracic echocardiograms (TTE) conducted between January 2019 and December 2022 were retrospectively analyzed, with the follow up period ending in January 2023. Inclusion/exclusion criteria are shown in Figure 1A. Briefly, patients with ILVD were defined based on echocardiographic parameters as those with LVEF > 50% and LV end diastolic volume indexed (LVEDVi) > 62 mL/m2 for females and > 75 mL/m2 for males, without prior LVEF < 50% and/or grade 2/3 diastolic dysfunction. The endpoint was LVEF < 40% on future (≥90 days) TTE. Five hard voting ML models and one soft voting ensemble model were trained with data parsed from TTE reports (Figure 1B). Feature importance (SHAP) was calculated, and receiver operating characteristic (ROC) and Kaplan Meier curves evaluated the final model (Figure 1C-E). Results A total of 2,962 patients met the inclusion criteria. The median time from index to last TTE was 578 (IQR = 500) days. LVEF < 40% on follow up TTE was noted in 6% of patients (177 patients, median 478 days to endpoint, IQR = 535 days). Of the six models developed, the ensemble model had the highest ROC area under the curve (0.791, Figure 1D), precision (0.163), F1-score (0.266), and specificity (0.773). The ensemble model also had the lowest predicted prevalence (25.5%), although this was higher than the observed prevalence in the test set (5.7%). Patients predicted to develop LVEF < 40% had a 8.2x higher risk of developing LVEF < 40% within five years of index (p<0.001, Figure 1E). Feature importance showed that male gender, higher heart rate, lower LVEF at index TTE, higher LVEDVi, and lower tricuspid annular plane systolic excursion had the highest mean absolute impact on the model’s output probability (Figure 1C). Conclusion Using only data parsed from the index TTE, ensembling a model for the prediction of developing LVEF < 40% in patients with ILVD and without a history of LV diastolic or systolic dysfunction performed the best. Additional analyses including clinical variables such as comorbidities, symptoms, and medications may improve the model’s performance.

Trimethylamine N-oxide as a Novel Biomarker for Left Ventricular Diastolic Dysfunction and Functional Remodeling in ST-Elevation Myocardial Infarction Patients

Abstract Background Over the last three decades, the mortality from ST-elevation myocardial infarction (STEMI) has halved. However, the incidence of heart failure or persistent angina remains high after STEMI, and the post-STEMI left ventricular (LV) systolic and diastolic function remains unpredictable. Thus, there is an unmet need to identify patients at risk of LV diastolic dysfunction or adverse remodeling. Purpose This study aims to investigate the potential of Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite associated with heart failure, and atherosclerosis, as a biomarker for adverse LV remodeling and diastolic dysfunction following STEMI. Methods In this prospective, observational cohort study, 210 STEMI patients with multivessel coronary artery disease (CAD) were enrolled after primary PCI. At 3 months follow-up, all patients underwent complete revascularization with FFR-guided PCI. Plasma TMAO, C-reactive protein (CRP), and brain natriuretic peptide (BNP) levels at 3 months follow-up and peak troponin level at primary PCI were collected. Echocardiographies were performed within 24 hours of STEMI and at 12-month follow-ups. Diastolic dysfunction was defined according to the ASE 2016 guidelines.(1) Functional LV remodeling (FLVR) was categorized into 4 categories according to Chimed et al.(2) Receiver operating characteristic (ROC) curve analysis, including the Delong test and Youden index, was performed to compare the biomarkers' diagnostic value and determine the optimal cutoffs for predicting diastolic dysfunction and FLVR, respectively. Results Of the 210 patients enrolled, 85 (40.48%) were female, with a median age of 65 years [interquartile range (IQR): 58.00, 76.00] and a median body mass index (BMI) of 27.39 kg/m² (IQR: [24.56, 30.69]). The area under the ROC curve for predicting post-PCI LV diastolic dysfunction ≥ grade II was 0.72 (95% CI 0.63–0.81; p<0.001) for TMAO (Figure 1). The optimal TMAO cutoff value of 3.80 yielded a sensitivity of 0.75 (95% CI 0.63–0.86) and a specificity of 0.82 (95% CI 0.76–0.88). For FLVR grade 3 or 4, the area under the ROC curve was 0.62 (95% CI 0.50–0.74) and 0.72 (95% CI 0.62 -0.83) for TMAO and BNP, respectively (Figure 2), but the AUC was not significantly different (p= 0.191). In multivariable logistic regression analysis, TMAO was independently associated with FLVR grade 3 or 4 (OR 1.18, 95% CI 1.00-1.38, p = 0.046) and diastolic dysfunction ≥grade 2 (OR 1.30, 95% CI 1.12-1.50, p < 0.001). Conclusion The novel parameter of TMAO is a useful predictor for LV diastolic dysfunction after STEMI. TMAO is independently associated with an increased risk of LV diastolic dysfunction and worse FLVR. These results suggest that monitoring plasma TMAO levels could be an effective and cost-efficient strategy for monitoring patients with an elevated risk of LV diastolic dysfunction or adverse LV remodeling.Figure 1Figure 2

Development and validation of a predicting model for risk of rehospitalization within 30 days in heart failure patients with preserved ejection fraction

Abstract Objective This study aimed to develop and validate a predicting model for risk of rehospitalization within 30 days post discharge in patients diagnosed with Heart Failure with Preserved Ejection Fraction (HFpEF). Methods Clinical data of 9555 HFpEF patients registered in the heart failure registry from 2014 to 2022 at our hospital were analyzed. A total of 8160 patients (from 2014-2021) were designated as the training set, and 1395 patients (from 2022) as the validation set. A predictive model was established based on risk factors associated with 30-day rehospitalization due to heart failure identified by the Least Absolute Shrinkage and Selection Operator (LASSO) regression and logistic regression analysis. The model's stability was ensured through Bootstrap internal validation and Temporal validation external validation. Results LASSO and logistic regression analyses identified eight risk factors associated with increased risk of 30-day rehospitalization, including New York Heart Association (NYHA) classification, albumin, c-reactive protein, N-terminal pro b-type natriuretic peptide (NT-proBNP) divided by 100, anemia, pleural effusion, atrial fibrillation, and pulmonary hypertension. The established predictive model demonstrated good discriminative ability in the internal validation with an Area Under the Curve (AUC) value of 0.714, and a 95% confidence interval (CI) of 0.693-0.736 after 500 Bootstrap replicates. In the Temporal validation external validation, the model exhibited robust stability with an AUC value of 0.740 and a 95% CI of 0.693-0.781. When compared to analogous models from prior studies, present model showcased superior predictive accuracy in that both Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) values were positive and within their respective 95% confidence intervals (P-values <0.05). Conclusion This study successfully developed and validated a predictive model for 30-day rehospitalization due to heart failure in patients diagnosed with HFpEF. This model might allow the timely identification of high-risk HFpEF patients for 30-day rehospitalization due to heart failure and optimizes the patient management accordingly.

Chronotropic incompetence as a critical predictor for cardiovascular outcomes in heart failure with preserved ejection function

Abstract Background Chronotropic incompetence (CI), linked with exercise intolerance, is a prevalent feature of heart failure with preserved ejection fraction (HFpEF). Our study aimed to explore the impact of CI on cardiovascular outcomes in HFpEF patients. Methods From November 2019 to December 2022, we enrolled 359 subjects who underwent invasive cardiopulmonary exercise testing (iCPET) due to heart failure symptoms. After excluding individuals without HFpEF (those with resting pulmonary capillary wedge pressure [PCWP] < 15mmHg or exercise PCWP < 25mmHg), we identified 113 patients for long-term follow-up. Our assessment of cardiovascular outcomes encompassed hospitalization for heart failure (HHF) and cardiovascular death. We employed Cox regression analysis to evaluate the associations between exercise hemodynamic parameters and outcomes. Results Among the cohort, 85 (75.2%) subjects with CI were older (71 vs. 66 years) and more frequently women (61 vs. 28%) compared to those without CI. At peak exercise, patients with CI exhibited significantly reduced left atrial booster strain, impaired right ventricle-arterial coupling, decreased systemic vascular resistance, cardiac output (CO), stroke volume, VO2, respiratory exchange ratio, and minute ventilation/carbon dioxide production (VE/VCO2) slope. A significant increase in PCWP (36 ± 10 vs. 26 ± 11mmHg, p=0.012) was noted in patients with CI. Over a median follow-up of 22.6 months, 20 (17.7%) subjects experienced cardiovascular events. Multivariate Cox proportional analyses revealed that CI (Hazard ratio [HR] 1.725, 95% confidence intervals [CI] 1.212-2.413) and an elevated PCWP/CO slope (HR 1.829, 95% CI 1.331-2.382) were predictive of outcomes. Conclusions Patients with CI demonstrated heightened filling pressure, a steeper VE-VCO2 slope, and reduced VO2 compared to those without CI. These factors likely contribute to adverse cardiovascular outcomes in HFpEF patients with CI.

What does routinely-collected electronic health record data tell us about the use of heart failure medication among older people in Wales? Making progress but could do better

Abstract Background European Society of Cardiology 2021 guidelines recommend 4 pillars of treatment to reduce mortality for those with heart failure (HF) and reduced ejection fraction (HFrEF): pillar 1) angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), pillar 2) beta-blocker (BB), pillar 3) mineralocorticoid receptor antagonist (MRA), pillar 4) sodium-glucose co-transporter 2 inhibitor (SGLT2i). When there is heart failure with preserved ejection fraction (HFpEF), guidelines recommend diuretics to alleviate congestion and treatment of risk factors such as hypertension and diabetes. Prior to 2021, United Kingdom guidelines did not include SGLT2i. Purpose To examine how HF treatment is recorded in routinely-collected electronic health record (EHR) data for older people in Wales, and to explore how that has changed since 2015. Methods We conducted a retrospective, population-level, observational study using linked anonymised EHR data in Wales (2015-22). 737,230 individuals were aged 65y+ in the study period (21.5% of population in 2022). Of these, 65,010 had a code for heart failure in their primary or secondary care records. We excluded 13,990 individuals with fewer than 12 months data pre- or post-diagnosis. We looked forward, from HF diagnosis, for codes associated with specific medications. Results The final cohort comprised 51,020 individuals aged 65y and over with a diagnosis of heart failure between 2015-2022. Incidence and prevalence of heart failure increased across the study period (1.4-1.5% and 8.5-9.1% respectively). Preceding cardiovascular diagnoses included hypertension (69.5%), atrial fibrillation (36.7%), myocardial infarction (30.5%), coronary artery disease (25.7%), and valve disease (17.7%). Diabetes (41.7%), chronic kidney disease (30.9%) and cancer (26.4%) were the most common comorbidities. The subtype of HF (HFrEF or HFpEF) was only evident in 5,850. Treatments recorded most often were loop diuretics, ACE-I, and BB (Table 1). SGLT2i codes increased in 2020/2021(Figure 1). At 10-12 months post diagnosis, the proportion with simultaneous pillar combinations was; 27.4% 1 + 2, 12.5% 1, 2 + 3, and only 2% 1, 2, 3 + 4. Conclusions In Wales, there is a need to improve the coding of HF subtype in primary care records. We suggest interpreting data with the assumption that approximately half of the cohort are likely to have HFrEF. While the cohort proportion on ACE-I or beta-blockers may be appropriate, the proportion with more than 1 simultaneous pillar of treatment recorded appears low. The use of SGLT2i in codes is increasing. These results are important in evaluating health service delivery and in establishing baseline data from which to monitor improvements.

A novel risk score incorporating frailty or congestion status predicted mortality in patients with heart failure with preserved ejection fraction.

Abstract Introduction In patients with heart failure (HF), frailty or congestion is strongly associated with clinical outcomes. However, existing risk prediction models for HF prognosis do not incorporate these important clinical factors. The estimated plasma volume status (ePVS) is an easy-to-calculate index to estimate plasma volume. which is associated with the prognosis in HF patients. Purpose This study intends to construct an inclusive risk prediction model for all-cause mortality in patients with HF with preserved ejection fraction (HFpEF), incorporating evaluations of frailty and congestion alongside traditional risk factors. Methods We analyzed data from 1212 patients (81±9 years, 55% female) registered in the PURSUIT-HFpEF (Prospective, Multicenter, Observational Study of Patients with Heart Failure with Preserved Ejection Fraction) study, a multicenter registry of patients hospitalized for acute decompensated HFpEF. We evaluated clinical factors including Clinical Frailty Scale (CFS) and blood test results collected before discharge. We calculated ePVS at discharge using the Duarte formula as ePVS (mL/g)=100×(1-hematocrit)/hemoglobin (g/dL). Patients were followed for median of 713 days (IQR 369-1088 days) to observe all-cause death. Patients were randomly assigned to the derivation and validation cohorts (2:1 ratio). Using the Bayesian Information Criterion (BIC), a stepwise model selection was executed on 51 clinical parameters, including CFS and ePVS, to identify independent predictors of mortality. A risk model for mortality was constructed based on these predictors and their coefficients. The accuracy of the risk score was validated using time-dependent ROC curves both in the derivation cohort (n=801) and in the validation cohort (n=411). Results During the follow-up period, all-cause death was observed in 315 patients (25.9%). Age, sex, CFS, NT-proBNP and ePVS were selected as independent predictors of all-cause death. The score shown in the Table was applied to each factor, and the sum of the scores was calculated as the risk score. The AUC of the risk score for predicting 1-year mortality in the derivation cohort was 0.79 (95% CI 0.74, 0.85). The optimal cut-off value of 6 provided a sensitivity and specificity of 74.9% and 74.4%, respectively. The AUC for 1-year mortality in the validation cohort was 0.70 (95% CI 0.63, 0.77). Conclusions The novel risk prediction model incorporating CFS and ePVS effectively predicted mortality in HFpEF. This model could be a valuable tool for risk stratification.Table

Prognostic value of hemodynamically significant secondary tricuspid regurgitation in patients hospitalised for heart failure with preserved ejection fraction

Abstract Introduction Heart Failure with preserved ejection fraction (HFpEF) is a significant clinical concern, characterized by a rising prevalence and substantial morbidity. Despite the frequent presence of secondary tricuspid regurgitation (TR) in this population, its prognostic implications remain unknown. Purpose The aim of this study is to assess the rate of the composite of mortality and heart failure readmissions by considering the presence of hemodynamically significant secondary TR in patients hospitalised for HFpEF. Methods Prospective observational cohort study. Patients admitted for acute HFpEF (ejection fraction > 50%) between September 2019 to December 2022 were included. Patients with primary TR, pacemaker, moderate-severe left valve disease, end-stage renal failure (creatinine clearance < 30 ml/min/BSA) and recent myocardial infarction were excluded. TR was considered significant if rated as moderate or higher, following established semi-quantitative and quantitative criteria in current guidelines. Patients were followed-up for one year to assess the incidence of the composite primary outcome of death and heart failure readmission. Results A total of 110 patients were included. Median age was 85 [78-89] years, 64% were female. The mean left ventricle ejection fraction was 57% (+/-5%). Significant TR was observed in 44.5% (n=49) of cases. Patients with significant TR had higher NT-ProBnp values (4555 [2620-7025] pg/mL vs 2400 [1300-5494] pg/mL; P = 0.01), and worse echocardiographic parameters of right heart size and function compared to those without significant TR (TABLE). The incidence of the composite outcome was higher in patients with significant TR compared to patients without significant TR (P = 0.01, LogRank test) (FIGURE). In a Cox regression multivariate analysis including age and sex, significant TR was independently associated with the incidence of the primary outcome (HR 1.86; CI 1.10 - 3.13; P = 0.006). Conclusion In patients hospitalised for HFpEF, significant TR was independently associated with a higher incidence of death and heart failure readmission at one year-follow-up. Further research is needed in this group, particularly to explore novel risk stratification and therapeutic approaches.Kaplan-Meier curveTable

SGLT2 inhibitor, a new bullet in heart failure management

The global health landscape is confronted with substantial challenges stemming from diabetes mellitus and heart failure (HF). The escalating incidence of diabetes mellitus (DM), in correlation with HF, underscores the imperative necessity for efficacious strategies in the realm of prevention and management. The most recent advancements in therapeutic approaches, specifically Sodium-glucose transporter 2 inhibitors (SGLT2i), present a promising prospect for enhancing outcomes and addressing the existing gaps in HF management. This paper aims to elucidate the significance of SGLT2i in the therapeutic management of both reduced and preserved heart failure, with or without the presence of DM. SGLT2i are new heart failure drugs. In trials, SGLT2i improved diastolic dysfunction, reduced oxidative stress, inflammation, fibrosis, and myofilament rigidity. The first SGLT2 inhibitor studies, EMPA-REG OUTCOME, DECLARE-TIMI 58, and CANVAS, showed that Empagliflozin and Canagliflozin reduced HF mortality and rehospitalization in type 2 diabetes mellitus (T2DM) patients. Dapagliflozin reduces HF hospitalizations without impacting T2DM mortality. Canagliflozin avoided creatinine rises, kidney disease deaths, and cardiovascular deaths in the CREDENCE Study. SGLT2i improve health in heart failure with preserved ejection fraction (HFpEF). SGLT2i improved health status statistically in the PRESERVED-HF and EMPEROR-Preserved investigations. SGLT2i became known as a promising therapeutic choice in the treatment of HF. The substantial evidence from prominent large-scale clinical trials has substantiated the cardiovascular and renal protective effects of SGLT2i. Furthermore, the benefits of these medications are relevant for individuals who have been diagnosed with heart failure with reduced ejection fraction (HFrEF), as well as those who are experiencing heart failure with preserved ejection fraction (HFpEF). Keyword: diabetes mellitus, heart failure, management, SGLT2 inhibitor

Prognostic impact of left atrial reverse remodeling in patients with ADHF-HFpEF regardless of atrial fibrillation -PURSUIT-HFpEF Registry-

Abstract Background Left atrial (LA) dilatation is associated with increased mortality in patients with cardiovascular disease including heart failure (HF) and LA reverse remodeling (LARR) was reported to be associated with favorable outcomes in patients with HF. However, it remains to be clarified whether LARR could have prognostic value in patients with HF with preserved ejection fraction (HFpEF). Purpose The purpose of this study is to elucidate whether LARR is associated with clinical outcome in patients with HFpEF in relation to the presence of atrial fibrillation (AF). Methods We prospectively studied 492 patients with acute decompensated heart failure with preserved ejection fraction (ADHF-HFpEF) without the poor outcome during the first year postdischarge. Echocardiography was performed just before discharge and at 1 year after discharge. LARR was defined as the reduction of 15% or more in left atrial end-systolic volume (LAV). The primary outcome was rehospitalization for worsening heart failure. Results All study patients were divided into 2 groups according to the presence of AF at discharge (AF group, n=182 and non-AF group, n=310). During a mean follow-up period of 1.4±1.2 years, 78 patients were rehospitalized for worsening heart failure (37 patients in AF group and 41 in non-AF group). ΔLAV, the degree of reduction in LAV during the first year postdischarge, was significantly independently associated with primary outcome after multivariable adjustment both in AF group (p=0.033, HR 0.992 [0.984-0.999]) and non-AF group (p=0.021, HR 0.986 [0.974-0.998]). Kaplan-Meier analysis revealed that patients with LARR had significantly lower risk for primary outcome than those without LARR not only in the whole study patients (8% vs 20%, p=0.001) but also both in AF group (9% vs 24% p=0.013) and in non-AF group (8% vs 16% p=0.043). Among clinical characteristics during the index hospitalization, the presence of AF and prior HF hospitalization were significantly independently associated with LARR at multivariate Cox logistic regression analysis (p=0.006, OR 0.554 [0.364-0.843] and p=0.007, OR 0.491 [0.292-0.826], respectively). Conclusion(s) The left atrial reverse remodeling could have the prognostic impact in patients with ADHF-HFpEF regardless of the presence of atrial fibrillation.Kaplan-Meier curves in AF and non-AF

Latent class analysis reveals a novel phenotype of heart failure that spans the left ventricular ejection fraction range

Abstract Background It is increasingly evident that heart failure (HF) represents a heterogenous syndrome rather than a single clinical entity. The elusiveness of effective therapies for heart failure with preserved ejection fraction (HFpEF) has led to a consensus that our current, unidimensional construct of HF using only left ventricular ejection fraction (LVEF) does not adequately capture the multiplicity of the disease states. The ability to harmonize echocardiographic data from multiple sources has enabled use of unsupervised cluster-based analysis to identify multidimensional cardiac structural phenotypes. Purpose To identify cardiac structural phenotypes of HF across the LVEF spectrum. Methods We harmonized echocardiographic data from eight randomized clinical HF trials (ESCAPE, EXACT-HF, FIGHT, I-PRESERVE, NEAT-HFpEF, RELAX, STICH and TOPCAT), which included both HFrEF and HFpEF populations (total n=4223 echocardiograms). These studies collectively spanned the years 2000 through 2015 and represent a balanced LVEF distribution. Latent class analysis (LCA) was performed iteratively to identify predominant structural phenotypes using LVEF, RV function, LV end diastolic volume, LV mass index, eccentricity, mitral valve deceleration time, and lateral E/e’ ratio. Results LCA identified 4 echocardiographic phenotypes. Three phenotypes skewed toward either high or low EF, but one phenotype demonstrated a relatively even distribution of patients with HFrEF, heart failure with mildly reduced ejection fraction (HFmrEF) and HFpEF (36.0%, 21.4% and 42.7%, respectively). Patients in this phenotype had preserved RV function and left ventricular hypertrophy (97%), of which 56.8% had concentric and 43.2% eccentric LVH. E/e’ was normal in 63% of subjects. A vast majority (91%) of patients had recent-onset HF (diagnosed within the past year). There were no remarkable distinguishing comorbidities. Notable differences in biomarker profile included higher levels of troponin I, cyclic GMP and lower levels of neurohormones (aldosterone, endothelin-1, dopamine, and norepinephrine) than the other phenotypes. Conclusions This is the first cluster-based analysis to identify a quantitative structural HF phenotype of HF that is not distinguished by LVEF. While the underlying pathophysiology is unclear, most patients have recent onset HF and biomarker profiles with relatively low neurohormone activity. These features may reflect a distinct pathophysiology that could indicate a specific, targeted intervention.

The prothrombotic state in patients with type 2 diabetes mellitus and ischemic heart failure: an association with endothelial dysfunction

Abstract Background Heart failure (HF) is associated with a substantial prothrombotic state and an increased risk of thromboembolism, regardless of the presence of atrial fibrillation (AF). Although oral anticoagulation in HF with known AF is recommended, there is no conclusive evidence supporting clinical benefits of chronic anticoagulation in HF subjects without AF. Other factors enhancing prothrombotic state, often concomitant with HF, are type 2 diabetes mellitus (T2D) and coronary artery disease (CAD). T2D as well as CAD are independently associated with a hypercoaguability due to multiple mechanisms including endothelial dysfunction and oxidative stress. Dysfunction of endothelium was observed in patients with HF, however a little is known about its influence on prothrombotic state in a very high risk HF population. Purpose This study aimed to investigate whether the prothrombotic state in patients with T2D, CAD, and HF, depends on the left ventricular ejection fraction (LVEF) or endothelial function. Methods We assessed 54 patients with stable chronic HF, CAD, and T2D. Based on the echocardiography examination 28 of them were those with HF with reduced ejection fraction (HFrEF) and 26 of them were classified as HF with preserved ejection fraction (HFpEF) according to current guidelines. Fibrin clot density reflected by clot permeability (Ks) and thrombin generation were evaluated. Endothelial function was determined in flow-mediated (FMD) and nitroglycerin-mediated dilatation (NMD) tests of the brachial artery. Results Subjects in both groups were comparable in terms of cardiovascular risk factors except for lower glomerular filtration rate (GFR) by 18.1%. HFrEF patients had lower Ks by 20.3%, along with higher endogenous thrombin potential (ETP) by 18.9% and maximum thrombin level (Peak) by 24.1% as compared with HFpEF. While there were no differences in FMD and NMD between subjects, we found negative correlations of NMD with ETP and Peak (r=-0.448, P=0.001; r=-0.304, P=0.034, respectively). Moreover, the proportion of NMD and FMD along with GFR and LVEF were also significantly associated with both thrombogram parameters (<0.01 for all). By the multivariate analysis of the whole population, NMD, LVEF, low-density lipoprotein and GFR were independent predictors of ETP (R2=0.530, P<0.001) while NMD, LVEF, and GFR predicted Peak levels (R2=0.327, P=0.002). Conclusion We showed for the first time that patients with ischemic etiology of HFrEF and T2D presented altered fibrin clot properties and enhanced thrombin generation compared to HFpEF subjects. It might be hypothesized that endothelial dysfunction induced by T2D could intensify hypercoagulability in patients with HF.Figurę 1

Differences in clinical characteristics, angina, and quality of life among patients with microvascular vs vasospastic angina and no obstructive coronary artery disease (ANOCA)

Abstract Background In patients with angina and no obstructive coronary disease (ANOCA), the underlying pathophysiology includes microvascular angina (endothelial-dependent and independent coronary microvascular dysfunction (CMD)) and vasospastic angina (microvascular spasm and epicardial spasm) diagnosed with invasive coronary functional angiography (CFA). However, whether there are differences in demographics, clinical characteristics, and outcomes by underlying diagnosis is unknown. We hypothesize that microvascular angina patients will be older and have more cardiovascular risk factors and worse outcomes than the vasospastic angina group. Objective To explore the differences in demographics, risk factors, and outcomes in ANOCA patients with microvascular and vasospastic angina. Methods A prospective registry-based cohort study of consecutive CFA was performed in 156 ANOCA patients between 2020 and 2023 using the Doppler-tipped guide wire method. Patients were classified into microvascular angina, vasospastic angina, and mixed disease. Microvascular angina was defined as endothelial-independent CMD (coronary flow reserve [CFR] < 2.5 in response to adenosine) and/or endothelial-independent CMD (coronary blood flow [CBF] < 50% or no change in vessel diameter in response to 54 mcg intracoronary acetylcholine). Vasospastic angina as microvascular (<90% constriction) and epicardial spasm (>90% constriction) to 108 mcg intracoronary acetylcholine. The mixed disease group included microvascular and vasospastic angina. Validated questionnaires evaluated angina (SAQ-7), functional capacity (DASI), dyspnea severity (UCSD SOB), and perceived stress (PSS) were obtained from patients at office visits prior to undergoing CFA. Results Among 156 ANOCA patients, 114 had microvascular angina, 10 had vasospastic angina, and 32 had mixed disease. The average age was 58.5 (SD 11.2) years. Demographics and prevalence of risk factors, such as hypertension, hyperlipidemia, or diabetes, showed no significant differences among the microvascular, vasospastic, or mixed disease groups. The prevalence of heart failure with preserved ejection fraction (HFpEF) was high across the groups, and outcomes did not differ significantly among them. The SAQ-7 score average ranged from 16.9 to 40.3, consistent with moderate to severe angina, and the DASI score ranged from 32.2 to 34.9, consistent with moderate functional capacity. Dyspnea severity ranged from 30 to 41, consistent with low to moderate severity, and perceived stress ranged from 11.5 to 13, consistent with low to moderate stress among all participants. Conclusion In patients with ANOCA undergoing invasive CFA, demographics, cardiovascular risk factors, and outcomes were similar regardless of underlying diagnosis. We demonstrate a high prevalence of risk factors and HFpEF and evidence of moderate to severe symptoms and functional capacity in ANOCA patients across all diagnoses.Abbreviation explanation for table 1

Prevalence of transthyretin amyloid cardiomyopathy in patients hospitalised for heart failure with preserved ejection fraction in an LATAM center

Abstract Introduction Transthyretin Amyloid cardiomyopathy (ATTR-CM) usually presents as heart failure with preserved ejection fraction (HFpEF). Its diagnosis has a significant clinical impact, as specific treatment is currently available. Purpose To assess the prevalence of ATTR-CM in patients hospitalised for HFpEF and increased septal thickness in our institution of general community hospital in Latin America (LATAM). Methods Cross-sectional study. Patients hospitalised for HFpEF (>50%) and septal thickness ≥ 12 mm during the period from 8/2019 to 1/2023 were prospectively included. Patients with pacemaker, significant left valve disease and end-stage renal failure (creatinine clearance < 30 ml/min/BSA) were excluded. A pyrophosphate bone scintigraphy (PYP) was planned to be performed in order to assess ATTR-CM. The prevalence of ATTR-CM and its 95% confidence interval were calculated. Results A PYP was performed in 59/82 patients hospitalised for HFpEF. Median age was 85 [IQR 78-88] years, and 54% were women. At admission, 61% (n=36) had atrial fibrillation and the median NT Pro-Bnp was 3536 [1700-7748] pg/mL. The mean left ventricle ejection fraction was 57% (+/- 5%). The prevalence of ATTR-CM diagnosed by PYP was 19% (95% CI 9.7-30.1, n=11). There were no significant clinical differences between patients who performed a PYP and did not. Patients with ATTR-CM had lower blood pressure and higher septal thickness, NT Pro-Bnp and troponin levels compared to patients without ATTR-CM (TABLE). Conclusion In patients admitted for HFpEF and increased septal thickness, the diagnosis of ATTR-CM was relatively common (one of five had ATTR-CM) in our region (LATAM). We believe that systemic assessment with PYP should be performed in patients hospitalised with HFpEF and increased wall thickness.

Albuminuria is associated with progression of diastolic dysfunction in patients at risk for cardiovascular disease

Abstract Background The number of the patients with heart failure with preserved ejection fraction (HFpEF) is increasing as society ages, which indicates that the number of pre-HFpEF patients is increasing even more. To combat this sociomedical burden, it is critical to establish cost-effective and simple biomarkers to identify the high-risk population at early phase of the disease. Recent studies demonstrated the association between albuminuria and incident heart failure, but the prognostic impact of albuminuria on diastolic dysfunction, an early phenotype of HFpEF, has not been elucidated. Purpose To examine the impact of albuminuria on the diastolic function over time in the patients with cardiovascular risks. Methods One hundred and fifty-eight patients with at least one cardiovascular risk factor without history of heart failure were followed up for 5 years. Echocardiogram was conducted at baseline, year 3, and year 5. Diastolic dysfunction was defined as E/e’ >14. Albuminuria was defined as urine albumin-to-creatinine ratio (UACR) 30 ≧mg/gCre. The patients with ejection fraction <40% and those had diastolic dysfunction at baseline were excluded from the study. The relationship between albuminuria at baseline and diastolic function at year 3 and 5 were investigated. Results Among 158 subjects, 27 showed albuminuria at baseline and the prevalence of hypertension, dyslipidemia, and diabetes was not significantly different between patients with and without albuminuria. The baseline E/e’ tended to be higher in patients with albuminuria, although the difference was not statistically significant (Fig1: E/e’ = 10.0±2.4 vs. 9.4±2.2, p = 0.08) . However, the patients with albuminuria showed a steeper increase in E/e’ than those without albuminuria, and the significant difference was observed at year 3, that was even greater at year 5 (Fig1: E/e’ = 11.1±2.8 vs 10.0±2.6, p = 0.04 in year 3, E/e’ = 12.5±4.1 vs 10.3±2.9, p = 0.002 in year 5, respectively). Furthermore, log UACR at baseline showed significant correlation with E/e’ at year 5 (p = 0.02, r = 0.21) and normo-, micro-, and macroalbuminuria (UACR<30, 30-300, and >300mg/gCre, respectively) at baseline showed elevated E/e’ at year 5 in this order ( p = 0.01 for UACR<30 vs. 30-300mg/gCre, and p = 0.04 for UACR<30 vs. >300mg/gCre, reapectively ). The prevalence of incident diastolic dysfunction increased greater in patients with albuminuria throughout the follow-up period and the difference reached statistical significance at year 5 (Fig2: 18.5% vs. 9.2%, p = 0.28 for year 3, and 25.9% vs. 8.4%, p = 0.009 for year 5, respectively). Conclusion In the patients with cardiovascular risk factors, albuminuria was associated with development and progression of diastolic dysfunction over subsequent 5 years. Future prospective study is warranted to investigate the effectiveness of albuminuria-directed care to prevent development of HFpEF.

Impact of microvascular resistance reserve on post-STEMI cardiac remodelling and diastolic function

Abstract Background Coronary microvascular dysfunction (CMD) is a common sequelae of ST-segment elevation myocardial infarction (STEMI), preventing adequate recovery of left ventricular (LV) perfusion. The interferences of con-commitment epicardial stenosis or hyperemic hemodynamic alterations limit traditional physiologic metrics. The microvascular resistance reserve (MRR) was developed to overcome these shortcomings. Purpose We aim to investigate the association between post-STEMI MRR, and the ensuing left ventricle (LV) diastolic dysfunction, and functional remodeling. Methods In this prospective, observational study, we enrolled STEMI patients with multivessel disease who successfully underwent primary percutaneous coronary intervention (PCI). At three months post-PCI, all patients received complete revascularization followed by coronary physiology assessment using the bolus thermodilution method to measure the fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR). MRR was calculated using the formula: MRR = (CFR/FFR) × (Pa rest/Pa hyper), where Pa rest and Pa hyper represent resting and hyperemic aortic pressure, respectively(1). CMD was defined as an MRR < 3.0 based on Boerhout et al(2). Diastolic dysfunction was defined according to the ASE 2016 guidelines. Functional LV remodelling (FLVR) was categorized according to Chimed et al(3). The relationship between CMD and the stages of FLVR and diastolic dysfunction was scrutinized over a 12-month follow-up period. Results We enrolled 210 patients, of whom 125 (59.5%) were men with a median age of 65 (IQR: 58–76). At the 3-month follow-up, the MRR was 3.46 (IQR 3.00, 3.92), with 56 (26.7%) patients having CMD (MRR<3.0). MRR is significantly correlated with the change of LVEF between primary PCI and 12 months (r=0.48, p<0.001, Fig1A). CMD patients have lower LVEF at 12 months (50.00% vs. 40.00%; p < 0.001) and demonstrated significantly less recovery in LV systolic function (-10.00% vs. 8.00%; p < 0.001, Fig 1B, 1C). CMD patients had a higher prevalence of grade 2 or 3 LV diastolic dysfunction (65.38% vs. 3.95%; p < 0.001, Fig 2A) and a higher incidence of advanced FLVR (Groups 3 and 4) compared to those without CMD (30.77% vs. vs. 10.53%; p < 0.001, Fig 2B). In multivariable logistic regression analysis, MRR was independently associated with LV diastolic dysfunction (0.17, 95%CI 0.08-0.33, p<0.001). Conclusions The novel parameter MRR is significantly related to LVEF recovery in STEMI patients and is an independent predictor for advanced LV diastolic dysfunction and FLVR. CMD patients, as diagnosed with MRR, showed a higher prevalence of advanced FLVR and diastolic dysfunction. These results suggest that MRR is a useful parameter for the identification and management of CMD in STEMI patients.

Daily Subcutaneous injections of Relaxin is a therapy for heart failure with preserved ejection fraction

Abstract Background and Significance: Relaxin (RLX), a hormone of pregnancy has engendered a great deal of excitement as a therapy for cardiovascular diseases. Clinical trials treated patients with acute decompensated Heart Failure (HF) with RLX (i.v. 30µg/kg/day-2 days) and reported a 37% decrease in mortality during a 6-months follow up. This led the FDA to declare RLX a ‘break-through’ therapy. However, a larger trial failed to meet the sought-after end points. Here, we propose that periodic subQ RLX pulses are more effective. We measured the pharmacokinetics of serum RLX following subQ injections of RLX in Sprague Dawley rats. Further, we treated rats with confirmed HFpEF with daily subQ RLX (2-weeks) to reverse the diastolic dysfunction (DD), arrhythmia and fibrotic profile. Methods Sprague-Dawley (250 g, n=20, either sex) received 2-subQ injections 12 hrs apart of RLX (from Relaxera) or the vehicle. Serial blood samples were drawn following each injection to measure [RLX]. ZSF1 rats (9-weeks old, either sex) were placed on a high fat diet (HFD) and serial echos tracked the DD. Once severe DD was established (25-35 weeks of HFD), rats received daily subQ injections of RLX (100µg/kg) or vehicle. After 2-weeks, hearts were perfused to optically map action potentials and Ca2+ transients, and analyze the arrhythmia profile. IF and Westerns were used to measure changes in fibrosis (collagen 1), Nav1.5, connexin 43, Wnt1 and β-catenin. Results After an injection, RLX reached a peak in ~60 min, fell to 50% in 5-6 hours. Injections of 0, 30, 100 or 500 µg/kg yielded peak levels of 0, 11.26±3.52, 58.33±16.10, and 209.42±29.04 ng/ml and residual levels after 24-hrs of 0, 4.9, 45.1 and 156 pg/ml, respectively. The 30µg/kg injections had no effect and 100 µg/kg increased Nav1.5 (25%), Cx43 (30%) and β-catenin (90%). The 500 µg/kg injections increased Nav1.5 and Cx43 but upregulated β-catenin, only slightly. In ZSF1 HFpEF rats that received the vehicle (n=12), a premature stimulus (at 30 ms) elicited arrhythmia in 67% of the hearts. RLX injections reversed DD, suppressed sustained atrial and ventricular arrhythmias (n=0/12) but not self-terminating arrhythmias, lasting < 10sec. RLX improved the conduction velocity (CV), particularly at fast rates (100ms) from 0.74 to 0.9 m/s (p<0.001, n=12). RLX significantly increased Cx43 expression, Nav1.5 and β-catenin at intercalated disks. RLX reduced collagen deposition in HFpEF rats, to normal levels and increased Wnt1 compared to control HFpEF rats. Conclusions The ZSF1 diabetic rat on a HFD recapitulates human HFpEF, high blood pressure, fibrosis, DD, AF and VF. SubQ RLX injections reversed DD i.e. enlarged Left Atrium, E/e’ ratio, fibrosis, and the arrhythmia vulnerability by increasing CV, Cx43, and Nav1.5. Daily subQ RLX injections were highly effective as a therapy for HFpEF.Echo parameterHFpEF + RLX

Autonomous cortisol secretion in patients with primary aldosteronism is associated with left ventricular hypertrophy and diastolic dysfunction

Abstract Background and Aims: Autonomous cortisol secretion (ACS) constitutes a significant portion of patients diagnosed with primary aldosteronism (PA) and is potentially linked to adverse cardiovascular outcomes. This study aimed to explore the impact of ACS on cardiac remodeling and diastolic dysfunction in PA patients. Methods We prospectively enrolled 567 PA patients from March 2000 to March 2023. ACS was defined as a cortisol level >1.8 μg/dL after a 1 mg dexamethasone suppression test (DST). Clinical, biochemical, and echocardiographic data were collected at baseline and during one-year follow-up after targeted treatments including adrenalectomy and mineralocorticoid receptor antagonist administration. Results In this prospective cohort, 21.5% of PA patients had concurrent ACS. PA patients with ACS were older and had a higher prevalence of diabetes. They also exhibited significantly higher left ventricular mass index (LVMI) and worse diastolic function (E/e'). Baseline post-1 mg DST cortisol levels positively correlated with baseline LVMI and E/e' in restricted cubic spline analysis. Multivariable linear regression analysis showed that ACS presence was significantly associated with higher LVMI and worse E/e' after adjusting for significant variables. Among patients who underwent adrenalectomy, both those with and without ACS showed significant improvements in LVMI and E/e'. Patients who received mineralocorticoid receptor antagonist treatment also showed significant improvement in E/e', irrespective of ACS presence. However, significant LVMI improvement was observed only in PA patients without ACS who received mineralocorticoid receptor antagonist treatment. Conclusions The presence of ACS in PA patients was associated with worse left ventricular hypertrophy and diastolic dysfunction. Adrenalectomy and mineralocorticoid receptor antagonist treatment partially reversed cardiac remodeling in PA patients with ACS.

Diastolic dysfunction and survival in patients with preserved or mildly reduced left ventricular ejection fraction

Abstract Background Left ventricular ejection fraction (LVEF) is relatively indiscriminate for prognosis in patients with preserved or mildly reduced LVEF (>40%) following myocardial infarction (MI). Aims This study sought to determine the value of guideline-based assessment of diastolic dysfunction (DD) in predicting all-cause and cardiac mortality in patients with a first-ever MI and LVEF>40%. Methods A retrospective single centre study involving 2234 patients with a first-ever MI (STEMI or NSTEMI) with LVEF>40% was performed. Clinical, angiographic, and echocardiographic data were obtained from prospectively maintained institutional databases. Outcomes data were obtained from the state-wide registry. Echocardiography was performed early post-admission for all patients. Significant diastolic dysfunction (DD) was defined as grade 2+3 diastolic dysfunction according to current American Society of Echocardiography/ European Association of Cardiovascular Imaging guidelines. Results The mean age of patients was 61.4±12.3 years, 70.7% were males, and 12.1% had 3-vessel disease. The mean LVEF was 55.8±7.2% and 9.1% had significant DD. At a median follow up of 4.5 years, there were 219 deaths (46 cardiac deaths). On Cox proportional hazards multivariable analyses incorporating significant clinical, angiographic, and echocardiographic variables, significant DD was an independent predictor of both all-cause (HR 2.01,95%CI 1.37-2.94, p<0.001) and cardiac (HR 3.97,95%CI 1.98-7.99, p<0.001) mortality. Conclusions Significant DD is an independent predictor of all-cause and cardiac mortality following MI in patients with preserved or mildly reduced LVEF and thus effectively re-stratifies prognosis in a subgroup where the LVEF is relatively indiscriminate for survival. The benefit of further investigation and/or treatment in this subgroup needs further study.

The BET inhibitor Apabetalone protects against heart failure with preserved ejection fraction by suppressing myocardial inflammation

Abstract Background Posttranslational histone modifications, play a major role in cardiac hypertrophy and dysfunction. Apabetalone (APA), a selective inhibitor of bromodomain and extraterminal containing protein family (BET) proteins, prevents bromodomain-containing protein 4 (BRD4) interactions with chromatin thus modulating transcriptional programs in different organs. Purpose We sought to investigate whether APA could be beneficial in cardiometabolic heart failure with preserved ejection fraction (cHFpEF). Methods Mice were subjected to high fat diet feeding and L-NAME treatment for 15 weeks to induce cHFpEF. Histology, mouse echocardiography (Vevo3100) and Treadmill exhaustion test were performed. Unbiased gene expression profiling by PCR array and proteomics analysis (Olink) was employed in left ventricular (LV) myocardial specimens from HFpEF mice and control animals. Cultured cardiomyocytes (CMs) treated with palmitic acid (PA) were used as an in vitro model of metabolic stress. cHFpEF mice were chronically treated with the BET inhibitor APA (150mg/kg/day) or vehicle (DMSO). In order to translate our findings to the human setting, passive stiffness of skinned CMs collected from cHFpEF patients was assessed before and after APA treatment. Results HFpEF mice displayed LV hypertrophy, diastolic dysfunction, myocardial fibrosis, lung congestion and impaired exercise tolerance as compared to controls. Interestingly, diastolic dysfunction - assessed by E/A ratio and isovolumic relaxation time (IVRT) - and lung congestion were significantly reduced in HFpEF mice treated with APA, while exercise tolerance was improved. Transcriptomic analysis in PA-treated CMs and LV mouse specimens from cHFpEF mice showed a profound deregulation of genes controlling inflammation, namely IL-6, TNF-alpha, and IL-1beta. ChIP assays showed BRD4 occupancy on the promoter of several inflammatory genes, including IL6. Treatment with APA suppressed most of inflammatory genes, with a pronounced effect on IL6 expression. Moreover, APA reduced circulating levels of several inflammatory chemokines. The beneficial effects of APA were explained by modulation of IL-6/CaMKII/STAT3 pathway both in cHFpEF hearts and PA-treated CMs. In skinned CMs from cHFpEF patients, both APA and IL6 blockade were able to attenuate passive stiffness. Conclusions Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in patients with cHFpEF.

Cardiac structure and function in patients with chronic obstructive pulmonary disease

Abstract Background Chronic obstructive pulmonary disease (COPD) is common and strongly associated with cardiovascular disease, but the pathophysiology has not been fully elucidated. Purpose We aimed to investigate cardiac structure and function in patients with COPD compared to a matched general population. Methods In a prospective cohort study, 796 patients with COPD were included and matched 1:2 on age and sex with controls from a general population study. All participants underwent an examination program including echocardiography. Standardized linear regression coefficients were used to compare cardiac structure and function in patients with COPD vs. controls. Impaired left ventricular (LV) function was defined as a left ventricular ejection fraction (LVEF) <50%, or global longitudinal strain (GLS) <16% (numerical). Impaired right ventricular (RV) function was defined as tricuspid annular plane systolic excursion (TAPSE) <1.7 cm. Diastolic dysfunction was defined as having at least two of the following parameters: E/e’ >14, septal e’ velocity <7cm/s, or lateral e’ velocity <10 cm/s, left atrial volume index (LAVi) >34 mL/m2, or tricuspid regurgitation velocity (TRV) >2.8 m/s. Logistic regression was used to assess associations between having COPD and systolic and diastolic dysfunction. Results Mean age was 70.2 ± 8.3 years and 52% were females. COPD patients had a mean forced expiratory volume in 1 second (FEV1) of 49.4 ± 18.8% predicted. At baseline, 43% of the patients with COPD had hypertension and 10% had diabetes (DM). Additionally, 57% with COPD had cardiovascular disease at baseline, including 12% with ischemic heart disease (IHD), 15% with atrial fibrillation (AF), 6% with heart failure, and 5% with a previous ischemic stroke. Patients with COPD had impaired measures of cardiac structure and function including a lower GLS (COPD vs. controls: 16.3 vs. 19.2%), lower TAPSE (2.3 vs. 2.6 cm), larger LAVi (29.0 vs. 24.7 mL/m2), and higher TRV (2.7 vs. 2.3 m/s), p for all associations <0.001. (See figure). Patients with COPD had a significantly higher prevalence of impaired LV systolic function (OR for GLS <16%: 8.18, 95% CI(6.04; 11.1), p <0.001), impaired RV systolic function (OR for TAPSE <1.7 cm: 2.77, 95% CI(1.63; 4.69), p <0.001), and LV diastolic dysfunction (OR for diastolic dysfunction grade I or higher: 4.00, 95% CI(3.12; 5.13), p <0.001) after adjustment for age, sex, hypertension, smoking, DM, IHD, AF, and lower density lipoprotein. (See figure). Conclusion Patients with COPD had significantly impaired LV and RV systolic function as well as impaired diastolic function compared with individuals from the general population. These findings underscore the importance of recognizing and addressing cardiovascular comorbidities in COPD.