Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1.

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.

Diabetes mellitus does not alter mortality or hospitalisation risk in patients with newly diagnosed heart failure with preserved ejection fraction: Time to rethink pathophysiological models of disease progression.

INTRODUCTION: Type 2 diabetes is a common and adverse prognostic co-morbidity for patients with heart failure with reduced ejection fraction (HFrEF). The effect of diabetes on long-term outcomes for heart failure with preserved ejection fraction (HFpEF) is less established. METHODS: Prospective cohort study of patients referred to a regional HF clinic with newly diagnosed with HFrEF and HFpEF according to the 2016 European Society of Cardiology guidelines. The association between diabetes, all-cause mortality and hospitalisation was quantified using Kaplan-Meier or Cox regression analysis. RESULTS: Between 1st May 2012 and 1st May 2013, of 960 unselected consecutive patients referred with suspected HF, 464 and 314 patients met the criteria for HFpEF and HFrEF respectively. Within HFpEF and HFrEF groups, patients with diabetes were more frequently male and in both groups patients with diabetes were more likely to be treated with ß-adrenoceptor antagonists and angiotensin converting enzyme inhibitors. After adjustment for age, sex, medical therapy and co-morbidities, diabetes was associated with increased mortality in individuals with HFrEF (HR 1.46 95% CI: 1.05-2.02; p = .023), but not in those with HFpEF (HR 1.26 95% CI 0.92-1.72; p = .146). CONCLUSION: In unselected patients with newly diagnosed HF, diabetes is not an adverse prognostic marker in patients with HFpEF, but is in HFrEF.

Impact of cardiac rehabilitation on ventricular-arterial coupling and left ventricular function in patients with acute myocardial infarction.

To maintain efficient myocardial function, optimal coordination between ventricular contraction and the arterial system is required. Exercise-based cardiac rehabilitation (CR) has been demonstrated to improve left ventricular (LV) function. This study aimed to investigate the impact of CR on ventricular-arterial coupling (VAC) and its components, as well as their associations with changes in LV function in patients with acute myocardial infarction (AMI) and preserved or mildly reduced ejection fraction (EF). Effective arterial elastance (EA) and index (EAI) were calculated from the stroke volume and brachial systolic blood pressure. Effective LV end-systolic elastance (ELV) and index (ELVI) were obtained using the single-beat method. The characteristic impedance (Zc) of the aortic root was calculated after Fourier transformation of both aortic pressure and flow waveforms. Pulse wave separation analysis was performed to obtain the reflection magnitude (RM). An exercise-based, outpatient cardiac rehabilitation (CR) program was administered for up to 6 months. Twenty-nine patients were studied. However, eight patients declined to participate in the CR program and were subsequently classified as the non-CR group. At baseline, E' velocity showed significant associations with EAI (beta -0.393; P = 0.027) and VAC (beta -0.375; P = 0.037). There were also significant associations of LV global longitudinal strain (LV GLS) with EAI (beta 0.467; P = 0.011). Follow-up studies after a minimum of 6 months demonstrated a significant increase in E' velocity (P = 0.035), improved EF (P = 0.010), and LV GLS (P = 0.001), and a decreased EAI (P = 0.025) only in the CR group. Changes in E' velocity were significantly associated with changes in EAI (beta -0.424; P = 0.033). Increased aortic afterload and VA mismatch were associated with a negative impact on both LV diastolic and systolic function. The outpatient CR program effectively decreased aortic afterload and improved LV diastolic and systolic dysfunction in patients with AMI and preserved or mildly reduced EF.

Impact of Rapid Up-Titration of Guideline-Directed Medical Therapies on Quality of Life: Insights From the STRONG-HF Trial.

BACKGROUND: This analysis provides details on baseline and changes in quality of life (QoL) and its components as measured by EQ-5D-5L questionnaire, as well as association with objective outcomes, applying high-intensity heart failure (HF) care in patients with acute HF. METHODS: In STRONG-HF trial (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies) patients with acute HF were randomized just before discharge to either usual care or a high-intensity care strategy of guideline-directed medical therapy up-titration. Patients ranked their state of health on the EQ-5D visual analog scale score ranging from 0 (the worst imaginable health) to 100 (the best imaginable health) at baseline and at 90 days follow-up. RESULTS: In 1072 patients with acute HF with available assessment of QoL (539/533 patients assigned high-intensity care/usual care) the mean baseline EQ-visual analog scale score was 59.2 (SD, 15.1) with no difference between the treatment groups. Patients with lower baseline EQ-visual analog scale (meaning worse QoL) were more likely to be women, self-reported Black and non-European (P<0.001). The strongest independent predictors of a greater improvement in QoL were younger age (P<0.001), no HF hospitalization in the previous year (P<0.001), lower NYHA class before hospital admission (P<0.001) and high-intensity care treatment (mean difference, 4.2 [95% CI, 2.5-5.8]; P<0.001). No statistically significant heterogeneity in the benefits of high-intensity care was seen across patient subgroups of different ages, with left ventricular ejection fraction above or below 40%, NT-proBNP (N-terminal pro-B-type natriuretic peptide) and systolic blood pressure above or below the median value. The treatment effect on the primary end point did not vary significantly across baseline EQ-visual analog scale (Pinteraction=0.87). CONCLUSIONS: Early up-titration of guideline-directed medical therapy significantly improves all dimensions of QoL in patients with HF and improves prognosis regardless of baseline self-assessed health status. The likelihood of achieving optimal doses of HF medications does not depend on baseline QoL. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03412201.

Correlates of Plasma NT-proBNP/Cyclic GMP Ratio in Heart Failure With Preserved Ejection Fraction: An Analysis of the RELAX Trial.

BACKGROUND: Phosphodiesterases degrade cyclic GMP (cGMP), the second messenger that mediates the cardioprotective effects of natriuretic peptides. High natriuretic peptide/cGMP ratio may reflect, in part, phosphodiesterase activity. Correlates of natriuretic peptide/cGMP in patients with heart failure with preserved ejection fraction are not well understood. Among patients with heart failure with preserved ejection fraction in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) trial, we examined (1) cross-sectional correlates of circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide)/cGMP ratio, (2) whether selective phosphodiesterase-5 inhibition by sildenafil changed the ratio, and (3) whether the effect of sildenafil on 24-week outcomes varied by baseline ratio. METHODS AND RESULTS: In 212 subjects, NT-proBNP/cGMP ratio was calculated at randomization and 24 weeks. Correlates of the ratio and its change were examined in multivariable proportional odds models. Whether baseline ratio modified the sildenafil effect on outcomes was examined by interaction terms. Higher NT-proBNP/cGMP ratio was associated with greater left ventricular mass and troponin, the presence of atrial fibrillation, and lower estimated glomerular filtration rate and peak oxygen consumption. Compared with placebo, sildenafil did not alter the ratio from baseline to 24 weeks (P=0.17). The effect of sildenafil on 24-week change in peak oxygen consumption, left ventricular mass, or clinical composite outcome was not modified by baseline NT-proBNP/cGMP ratio (P-interaction >0.30 for all). CONCLUSIONS: Among patients with heart failure with preserved ejection fraction, higher NT-proBNP/cGMP ratio associated with an adverse cardiorenal phenotype, which was not improved by selective phosphodiesterase-5 inhibition. Other phosphodiesterases may be greater contributors than phosphodiesterase-5 to the adverse phenotype associated with a high natriuretic peptide/cGMP ratio in HFpEF. REGISTRATION INFORMATION: clinicaltrials.gov. Identifier: NCT00763867.

A real-world experience of a prescribing policy for SGLT2-inhibitors in HFrEF in a Malaysian public tertiary cardiac centre.

A prescribing policy for SGLT2-inhibitors was implemented in a local public tertiary cardiology centre in Sabah to improve access for heart failure (HF) patients. The study evaluated 169 HF patients with reduced ejection fraction (HFrEF) who met the policy criteria. After starting SGLT2- inhibitors, a significant proportion of patients experienced decreased NTproBNP levels, indicating a positive response. HF hospitalisation rates within 1 year were lower compared to the previous year. No adverse events were reported, suggesting that the treatment is safe. Findings demonstrates the benefits of implementing prescribing policies to enhance treatment accessibility and generate valuable real-world data at the local healthcare level..

Leucine Supplementation Prevents the Development of Skeletal Muscle Dysfunction in a Rat Model of HFpEF.

Heart failure with preserved ejection fraction (HFpEF) is associated with exercise intolerance due to alterations in the skeletal muscle (SKM). Leucine supplementation is known to alter the anabolic/catabolic balance and to improve mitochondrial function. Thus, we investigated the effect of leucine supplementation in both a primary and a secondary prevention approach on SKM function and factors modulating muscle function in an established HFpEF rat model. Female ZSF1 obese rats were randomized to an untreated, a primary prevention, and a secondary prevention group. For primary prevention, leucine supplementation was started before the onset of HFpEF (8 weeks of age) and for secondary prevention, leucine supplementation was started after the onset of HFpEF (20 weeks of age). SKM function was assessed at an age of 32 weeks, and SKM tissue was collected for the assessment of mitochondrial function and histological and molecular analyses. Leucine supplementation prevented the development of SKM dysfunction whereas it could not reverse it. In the primary prevention group, mitochondrial function improved and higher expressions of mitofilin, Mfn-2, Fis1, and miCK were evident in SKM. The expression of UCP3 was reduced whereas the mitochondrial content and markers for catabolism (MuRF1, MAFBx), muscle cross-sectional area, and SKM mass did not change. Our data show that leucine supplementation prevented the development of skeletal muscle dysfunction in a rat model of HFpEF, which may be mediated by improving mitochondrial function through modulating energy transfer.

Heart rate score in remote monitoring: An additional tool for predicting outcomes in heart failure with reduced ejection fraction.

BACKGROUND: Heart rate score (HRS) ≥ 70% has been associated with arrhythmic events and mortality but these studies were not specific for heart failure (HF) patients. We hypothesized that HRS ≥ 70% obtained from remote monitoring (RM) is associated with HF hospitalizations and arrhythmic events in HF with reduced ejection fraction (HFrEF). METHODS: HRS was calculated from RM in patients with HFrEF and ICD or CRT-D. Two groups were defined: HRS ≥ 70% (G1, n = 55) and HRS < 70% (G2, n = 48) RESULTS: A total of 103 patients were included (64.4 ± 13.04 years, 69.9% male, mean left ventricular ejection fraction (LVEF) 33.62 ± 11.97% and FUP 61.7 ± 38.87 months). The device was CRT-D in 59.2% and ICD in 40.8% and the majority (90.3%) had the device implanted in primary prevention. G1 patients were more frequently male (p = .017) and had more coronary disease (p = .035). HRS ≥70% was an independent predictor for unplanned HF hospitalizations (OR: 1.905 (95% CI: 1.328-3.649), p < .001)). The indication for device implantation (primary vs. secondary prevention), type of device, NYHA class, age, gender and LVEF were not independent predictors of the outcome. VF (4.9 ± 20.0 G1 vs. 1.1 ± 5.47 G2, p = .046) and VT episodes were more prevalent in G1 (3.1 ± 8.93 G1 vs. 0.3 ± 1.59 G2, p = .026), as well as appropriate device shocks (4.3 ± 12.06 G1 vs. 0.3 ± 1.49 G2, p = .023). There was no difference in inappropriate shocks or mortality outcomes between groups. CONCLUSION: HRS ≥70% obtained from RM was an independent predictor of HF hospitalizations and was associated with arrhythmic events with VT and VF episodes and appropriate device shocks in HFrEF patients.

Response predictors to cardiac resynchronization therapy in chronic heart failure: a 10-year-cardiovascular center experience.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been established as an effective therapy for heart failure with reduced ejection fraction. Randomized clinical trials have shown its impact on mortality and HF hospitalizations, as well as improvement of symptoms and quality of life. OBJECTIVES: Finding clinical, electrocardiographic, and echocardiographic variables that may predict the response to cardiac resynchronization therapy (CRT). METHODS: We performed a single-center, observational, analytic, and retrospective study that included 102 patients with heart failure (HF) diagnosis who underwent CRT according to guideline-directed therapy from January 2010 to April 2020 in a third-level center. CRT response was defined as an improvement of New York Heart Association functional class in at least 1 category associated with a recovery of ≥ 5% in the left ventricular ejection fraction (LVEF). RESULTS: Our study population was 102 patients of which 61 (59.8%) were men. The mean age at HF diagnosis was 54 ± 18.7 years. Ischemic heart disease was the etiology in 37 (36.3%) cases. Fifty-one (50%) patients were classified as responders. Responders had wider QRS, and lower LVEF and right ventricular fractional area change at baseline. After CRT, responders had a greater reduction of QRS duration, and improvement in LVEF, global longitudinal strain, and echocardiographic dyssynchrony parameters. Multivariate regression analysis showed that left bundle branch block (LBBB), left ventricular end-diastolic volume (LVEDV), tricuspid annular plane systolic excursion (TAPSE), and baseline difference of pre-ejection periods were predictors of a positive response to CRT in this population. CONCLUSIONS: LBBB, TAPSE, LVEDV, and pre-ejection time difference are independent variables that can predict adequate response to CRT.

ANTECEDENTES: La terapia de resincronización cardíaca (TRC) se ha establecido como una terapia efectiva para la insuficiencia cardíaca con fracción de eyección reducida. Ensayos clínicos aleatorizados han demostrado su impacto en la mortalidad y hospitalizaciones por insuficiencia cardíaca, así como la mejora de los síntomas y la calidad de vida. OBJETIVOS: Determinar las variables clínicas, electrocardiográficas y ecocardiográficas que puedan predecir la respuesta a la terapia de resincronización cardíaca (TRC). MÉTODO: Estudio unicéntrico, observacional, analítico, retrospectivo, que incluyó 102 pacientes con diagnóstico de IC sometidos a TRC y terapia dirigida por guías, de enero de 2010 a abril de 2020, en un centro de tercer nivel. La respuesta a TRC fue definida como mejoría de la clase funcional de la New York Heart Association en al menos 1 categoría, asociado con una recuperación ≥ 5% en la fracción de expulsión del ventrículo izquierdo (FEVI). RESULTADOS: Incluimos a 102 pacientes, 61 (59.8%) fueron hombres. El promedio de edad al diagnóstico de IC fue 54 ± 18.7 años. La cardiopatía isquémica fue la etiología en 37 (36.3%) pacientes. 51 (50%) pacientes, fueron clasificados como respondedores. Los respondedores presentaron QRS amplio, menor FEVI y menor fracción de acortamiento del ventrículo derecho al inicio del estudio. Después de la TRC, los respondedores tuvieron una mayor reducción en la duración del QRS, mejoría en la FEVI, strain longitudinal global y parámetros de disincronía ecocardiográfica. El análisis de regresión multivariado mostró que el bloqueo de rama izquierdo (BRI), el volumen telediastólico del ventrículo izquierdo (VTDVI) la excursión sistólica del plano anular tricuspídeo (TAPSE) y la diferencia basal del período expulsivo fueron predictores de respuesta positiva a TRC. CONCLUSIONES: BRI, TAPSE, VTDVI y la diferencia basal de períodos preexpulsivos son variables independientes que predicen respuesta adecuada a TRC.

Extracellular vesicles in heart failure.

Physiologically, extracellular vesicles (EVs) have been implicated as crucial mediators of immune response, cell homeostasis, angiogenesis, cell differentiation and growth, and tissue repair. In heart failure (HF) they may act as regulators of cardiac remodeling, microvascular inflammation, micro environmental changes, tissue fibrosis, atherosclerosis, neovascularization of plaques, endothelial dysfunction, thrombosis, and reciprocal heart-remote organ interaction. The chapter summaries the nomenclature, isolation, detection of EVs, their biologic role and function physiologically as well as in the pathogenesis of HF. Current challenges to the utilization of EVs as diagnostic and predictive biomarkers in HF are also discussed.

Cardiac biopsies reveal differences in transcriptomics between left and right ventricle in patients with or without diagnostic signs of heart failure.

New or mild heart failure (HF) is mainly caused by left ventricular dysfunction. We hypothesised that gene expression differ between the left (LV) and right ventricle (RV) and secondly by type of LV dysfunction. We compared gene expression through myocardial biopsies from LV and RV of patients undergoing elective coronary bypass surgery (CABG). Patients were categorised based on LV ejection fraction (EF), diastolic function and NT-proBNP into pEF (preserved; LVEF ≥ 45%), rEF (reduced; LVEF < 45%) or normal LV function. Principal component analysis of gene expression displayed two clusters corresponding to LV and RV. Up-regulated genes in LV included natriuretic peptides NPPA and NPPB, transcription factors/coactivators STAT4 and VGLL2, ion channel related HCN2 and LRRC38 associated with cardiac muscle contraction, cytoskeleton, and cellular component movement. Patients with pEF phenotype versus normal differed in gene expression predominantly in LV, supporting that diastolic dysfunction and structural changes reflect early LV disease in pEF. DKK2 was overexpressed in LV of HFpEF phenotype, potentially leading to lower expression levels of ß-catenin, α-SMA (smooth muscle actin), and enhanced apoptosis, and could be a possible factor in the development of HFpEF. CXCL14 was down-regulated in both pEF and rEF, and may play a role to promote development of HF.

Torsemide Versus Furosemide After Discharge in Patients Hospitalized With Heart Failure Across the Spectrum of Ejection Fraction: Findings From TRANSFORM-HF.

BACKGROUND: The TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) found no significant difference in all-cause mortality or hospitalization among patients randomized to a strategy of torsemide versus furosemide following a heart failure (HF) hospitalization. However, outcomes and responses to some therapies differ by left ventricular ejection fraction (LVEF). Thus, we sought to explore the effect of torsemide versus furosemide by baseline LVEF and to assess outcomes across LVEF groups. METHODS: We compared baseline patient characteristics and randomized treatment effects for various end points in TRANSFORM-HF stratified by LVEF: HF with reduced LVEF, ≤40% versus HF with mildly reduced LVEF, 41% to 49% versus HF with preserved LVEF, ≥50%. We also evaluated associations between LVEF and clinical outcomes. Study end points were all-cause mortality or hospitalization at 30 days and 12 months, total hospitalizations at 12 months, and change from baseline in Kansas City Cardiomyopathy Questionnaire clinical summary score. RESULTS: Overall, 2635 patients (median 64 years, 36% female, 34% Black) had LVEF data. Compared with HF with reduced LVEF, patients with HF with mildly reduced LVEF and HF with preserved LVEF had a higher prevalence of comorbidities. After adjusting for covariates, there was no significant difference in risk of clinical outcomes across the LVEF groups (adjusted hazard ratio for 12-month all-cause mortality, 0.91 [95% CI, 0.59-1.39] for HF with mildly reduced LVEF versus HF with reduced LVEF and 0.91 [95% CI, 0.70-1.17] for HF with preserved LVEF versus HF with reduced LVEF; P=0.73). In addition, there was no significant difference between torsemide and furosemide (1) for mortality and hospitalization outcomes, irrespective of LVEF group and (2) in changes in Kansas City Cardiomyopathy Questionnaire clinical summary score in any LVEF subgroup. CONCLUSIONS: Despite baseline demographic and clinical differences between LVEF cohorts in TRANSFORM-HF, there were no significant differences in the clinical end points with torsemide versus furosemide across the LVEF spectrum. There was a substantial risk for all-cause mortality and subsequent hospitalization independent of baseline LVEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03296813.

Easy method to determine fluid responsiveness in septic shock patients: end-tidal CO2 - a prospective observational study.

BACKGROUND: In critically ill patients, especially those with septic shock, fluid management can be a challenging aspect of clinical care. One of the primary steps in treating patients with hemodynamic instability is optimizing intravascular volume. The Passive Leg Raising (PLR) maneuver is a reliable test for assessing fluid responsiveness, as demonstrated by numerous studies and meta-analyses. However, its use requires the measurement of cardiac output, which is often complex and may necessitate clinician experience and specialized equipment. End-Tidal Carbon Dioxide (ETCO2) measurement is relatively easy and is generally stable under steady metabolic conditions. It depends on the body's CO2 production, diffusion of CO2 from the lungs into the bloodstream, and cardiac output. If the other two parameters (metabolic conditions and minute ventilation) are constant, ETCO2 can provide information about cardiac output. The aim of the present study is to investigate the sensitivity of ETCO2 measurement in demonstrating fluid responsiveness. METHODS: All patients diagnosed with septic shock and meeting the inclusion criteria were subjected to a passive leg raising test, and cardiac outputs were measured by echocardiography. An increase in cardiac output of 15% or more was considered indicative of the fluid responder group, while patients with an increase below 15% or no increase were classified as the non-responder group. Patients' intensive care unit admission diagnoses, initial laboratory parameters, tidal volume, minute volume before and after the PLR maneuver, mean and systolic blood pressure, heart rate, Pulse Pressure Variation (PPV) values, and ETCO2 values were recorded. RESULTS: Before and after the ETCO2 test, there was no statistically significant difference between the two groups. However, the change in ETCO2 (ΔETCO2) was significantly higher in the responder group. In the non-responder group, ΔETCO2 was 2.57% (0.81), whereas it was 5.71% (2.83) in the responder group (p<0.001). Receiver Operating Characteristic (ROC) analysis was performed for ΔETCO2, baseline Stroke Volume Variation (SVV), ΔSVV, baseline Heart Rate (HR), ΔHR, baseline PPV, and ΔPPV to predict fluid responsiveness. ΔETCO2 predicted fluid responsiveness with a sensitivity of 85% and a specificity of 86% when it was 4% or higher. When ΔETCO2 was 5% or higher, it predicted fluid responsiveness with a specificity of 99.3% and a sensitivity of 75.5%, with an Area Under the Curve (AUC) of 0.89 (95% confidence interval, 0.828-0.961). CONCLUSION: This study demonstrates that in septic patients, ETCO2 during the PLR test can indicate fluid responsiveness with high sensitivity and specificity and can be used as an alternative to cardiac output measurement.

ß-Blocker Withdrawal and Functional Capacity Improvement in Patients With Heart Failure With Preserved Ejection Fraction.

Importance: Increasing the patient's heart rate (HR) has emerged as a therapeutic option in patients with heart failure with preserved ejection fraction (HFpEF). However, the evidence is conflicting, and the profile of patients who benefit most from this strategy remains unclear. Objective: To assess the association of ß-blocker treatment withdrawal with changes in the percentage of predicted peak oxygen consumption (VO2) across indexed left ventricular diastolic (iLVEDV) and indexed left ventricular systolic volumes (iLVESV), and left ventricular ejection fraction (LVEF) in patients with HFpEF and chronotropic incompetence. Design, Setting, and Participants: This post hoc analysis was conducted using data from the investigator-blinded multicenter, randomized, and crossover clinical trial, PRESERVE-HR, that took place from October 1, 2018, through December 31, 2020, to investigate the short-term effects (2 weeks) of ß-blocker withdrawal on peak oxygen consumption (peak VO2). Patients with stable HFpEF (New York Heart Association functional class II to III) receiving treatment with ß-blocker and chronotropic incompetence were included. Intervention: Participants in the PRESERVE-HR trial were randomized to withdraw vs continue with ß-blocker treatment. After 2 weeks, they were crossed over to receive the opposite intervention. This crossover randomized clinical trial examined the short-term effect of ß-blocker withdrawal on peak VO2. Main Outcomes and Measures: The primary outcome was to evaluate the association between ß-blocker withdrawal and short-term changes in percentage of peak VO2 across iLVEDV, iLVESV, and LVEF in patients with HFpEF and chronotropic incompetence treated with ß-blocker. Results: A total of 52 patients (mean age, 73 [SD, 13] years; 60% female) were randomized. The mean resting HR, peak HR, peak VO2, and percentage of peak VO2 were 65 (SD, 9) beats per minute (bpm), 97 (SD, 15) bpm, 12.4 (SD, 2.9) mL/kg per minute, and 72.4% (SD, 17.7%), respectively. The medians (minimum-maximum) of iLVEDV, iLVESV, and LVEF were 44 mL/m2 (IQR, 19-82), 15 mL/m2 (IQR, 7-32), and 64% (IQR, 52%-78%), respectively. After stopping ß-blocker treatment, the median increase in peak HR was plus 30 bpm (95% CI, 25-35; P < .001). ß-Blocker cessation was differentially associated with change of percentage of peak VO2 across the continuum of iLVESV (P for interaction = .02), indicating a greater benefit in those with lower iLVESV. Conclusions and Relevance: In this study, results showed that in patients with HFpEF and chronotropic incompetence receiving treatment with ß-blocker, lower iLVESV may identify those with a greater short-term improvement in maximal functional capacity after stopping ß-blocker treatment. Further studies are warranted for further investigation. Trial Registration: ClinicalTrials.gov (NCT03871803).

Validation of a noninvasive cardiac output monitor in maternal cardiac disease: comparison of NICOM and transthoracic echocardiogram.

BACKGROUND: The physiological changes to the cardiovascular system during pregnancy are considerable and are more pronounced in those with cardiac disease. In the general population, noninvasive hemodynamic monitoring is a valid alternative to pulmonary artery catheterization, which poses risk in the pregnant population. There is limited data on noninvasive cardiac output monitoring in pregnancy as an alternative to pulmonary artery catheterization. OBJECTIVE: We sought to compare transthoracic echocardiography with a noninvasive cardiac output monitor (NICOM, Cheetah Medical) in pregnant patients with and without cardiac disease. STUDY DESIGN: This was a prospective, open-label validation study that compared 2-dimensional transthoracic echocardiography with NICOM estimations of cardiac output in each trimester of pregnancy and the postpartum period. Participants with and without cardiac disease with a singleton gestation were included. NICOM estimations of cardiac output were derived from thoracic bioreactance and compared with 2-dimensional transthoracic echocardiography for both precision and accuracy. A mean percentage difference of ±30% between the 2 devices was considered acceptable agreement between the 2 measurement techniques. RESULTS: A total of 58 subjects were enrolled; 36 did not have cardiac disease and 22 had cardiac disease. Heart rate measurements between the 2 devices were strongly correlated in both groups, whereas stroke volume and cardiac output measurements showed weak correlation. When comparing the techniques, the NICOM device overestimated cardiac output in the control group in all trimesters and the postpartum period (mean percentage differences were 50.3%, 52.7%, 48.1%, and 51.0% in the first, second, and third trimesters and the postpartum period, respectively). In the group with cardiac disease, the mean percentage differences were 31.9%, 29.7%, 19.6%, and 35.2% for the respective timepoints. CONCLUSION: The NICOM device consistently overestimated cardiac output when compared with 2-dimensional transthoracic echocardiography at all timepoints in the control group and in the first trimester and postpartum period for the cardiovascular disease group. The physiological changes of pregnancy, specifically the mean chest circumference and total body water, may alter the accuracy of the cardiac output measurement by the NICOM device as they are currently estimated. Although NICOM has been validated for use in the critical care setting, there is insufficient data to support its use in pregnancy.

Heart failure with preserved ejection fraction: everything the clinician needs to know.

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognised and diagnosed in clinical practice, a trend driven by an ageing population and a rise in contributing comorbidities, such as obesity and diabetes. Representing at least half of all heart failure cases, HFpEF is recognised as a complex clinical syndrome. Its diagnosis and management are challenging due to its diverse pathophysiology, varied epidemiological patterns, and evolving diagnostic and treatment approaches. This Seminar synthesises the latest insights on HFpEF, integrating findings from recent clinical trials, epidemiological research, and the latest guideline recommendations. We delve into the definition, pathogenesis, epidemiology, diagnostic criteria, and management strategies (non-pharmacological and pharmacological) for HFpEF. We highlight ongoing clinical trials and future developments in the field. Specifically, this Seminar offers practical guidance tailored for primary care practitioners, generalists, and cardiologists who do not specialise in heart failure, simplifying the complexities in the diagnosis and management of HFpEF. We provide practical, evidence-based recommendations, emphasising the importance of addressing comorbidities and integrating the latest pharmacological treatments, such as SGLT2 inhibitors.

Association of Beta-Blocker Use With Exercise Capacity in Participants With Heart Failure With Preserved Ejection Fraction: A Post Hoc Analysis of the RELAX Trial.

Patients with heart failure with preserved ejection fraction (HFpEF) often receive ß-blocker (BB) therapy for management of co-morbidities. However, the association of BB therapy with exercise capacity and health-related quality of life (HRQL) in HFpEF is not well-studied. In this post hoc analysis of the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF (RELAX) trial, which included patients with chronic stable HFpEF with peak exercise capacity assessment at baseline and at 12 and 24 weeks of follow-up, we evaluated the association of BB use with the measures of exercise capacity (peak exercise oxygen uptake), anaerobic threshold, and HRQL (Minnesota living with heart failure questionnaire). Separate linear mixed-effect models were constructed for each outcome with adjustment for treatment arm, demographics, medical history, left ventricular ejection fraction, and duration of heart failure. Of the 216 study participants (median age 69 years, 48.2% women), 76% reported BB use at baseline. Participants with (vs without) BB therapy were older (70 vs 63.5 years, p = 0.001) and had a higher prevalence of ischemic heart disease (44% vs 23%, p = 0.01). In the adjusted linear mixed model, BB use over time was not associated with peak exercise oxygen uptake (ß 95% confidence interval [CI] 0.2 (-0.31 to 0.7), p = 0.5) and 6-minute walk distance (ß 95% CI 14.69 [-14.25 to 43.63], p = 0.3). However, BB use was associated with a higher anaerobic threshold (ß 95% CI 0.32 (0.02 to 0.62), p = 0.036) and better HRQL (lower quality of life as assessed by Minnesota living with heart failure questionnaire score) (ß 95% CI -6.68 [-10.96 to -2.4], p = 0.002). Future trials are needed to better evaluate the effects of BB on exercise capacity in patients with chronic stable HFpEF.

One size does not fit all: Perioperative management of patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is recognized as an important risk factor for perioperative complications. However, anesthesia management of HFpEF patients remains a considerable challenge without clear guidance. HFpEF is heterogeneous in its pathophysiological processes, diverse clinical presentations, adverse remodeling of cardiovascular and other organs, and clinical outcomes. It is difficult to manage the disease with one fixed approach because of this. This review phenotypes HFpEF patients by combining their clinical features and anesthesia care issues. Five phenotypes of HFpEF patients are identified: A, O, P, C, and Y. The clinical features, anesthesia implications, and anesthesia management for each phenotype are highlighted and discussed. Such an approach to HFpEF patients in the operating room could deliver safe, high-quality perioperative care.