Serial direct sodium removal in patients with heart failure and diuretic resistance.

AIMS: Loop diuretics may exacerbate cardiorenal syndrome (CRS) in heart failure (HF). Direct sodium removal (DSR) using the peritoneal membrane, in conjunction with complete diuretic withdrawal, may improve CRS and diuretic resistance. METHODS AND RESULTS: Patients with HF requiring high-dose loop diuretics were enrolled in two prospective, single-arm studies: RED DESERT (n = 8 euvolaemic patients), and SAHARA (n = 10 hypervolaemic patients). Loop diuretics were withdrawn, and serial DSR was utilized to achieve and maintain euvolaemia. At baseline, participants required a median 240 mg (interquartile range [IQR] 200-400) oral furosemide equivalents/day, which was withdrawn in all participants during DSR (median time of DSR 4 weeks [IQR 4-6]). Diuretic response (queried by formal 40 mg intravenous furosemide challenge and 6 h urine sodium quantification) increased substantially from baseline (81 ± 37 mmol) to end of DSR (223 ± 71 mmol, p < 0.001). Median time to re-initiate diuretics was 87 days, and the median re-initiation dose was 8% (IQR 6-10%) of baseline. At 1 year, diuretic dose remained substantially below baseline (30 [IQR 7.5-40] mg furosemide equivalents/day). Multiple dimensions of kidney function such as filtration, uraemic toxin excretion, kidney injury, and electrolyte handling improved (p < 0.05 for all). HF-related biomarkers including N-terminal pro-B-type natriuretic peptide, carbohydrate antigen-125, soluble ST2, interleukin-6, and growth differentiation factor-15 (p < 0.003 for all) also improved. CONCLUSIONS: In patients with HF and diuretic resistance, serial DSR therapy with loop diuretic withdrawal was feasible and associated with substantial and persistent improvement in diuretic resistance and several cardiorenal parameters. If replicated in randomized controlled studies, DSR may represent a novel therapy for diuretic resistance and CRS. CLINICAL TRIAL REGISTRATION: RED DESERT (NCT04116034), SAHARA (NCT04882358).

Asymptomatic Aortic Stenosis: From Risk Stratification to Treatment.

Our understanding of the natural history of aortic stenosis has significantly increased over the last decade. There have been considerable advances in the diagnosis and risk stratification of patients with aortic stenosis and in surgical and anesthetic techniques. In addition, transcatheter aortic valve replacement has established itself as a viable alternative to surgical management. Inevitably, these developments have raised questions regarding the merits of waiting for symptom onset in asymptomatic patients with severe aortic stenosis before offering treatment. Recent observational and randomized trial data suggest that early intervention in asymptomatic patients with severe aortic stenosis and normal left ventricular function may confer a prognostic advantage to a watchful waiting strategy. In this review, we highlight advances in the management and risk stratification of patients with asymptomatic severe aortic stenosis with particular consideration of recent findings supporting early valvular intervention.

International evaluation of an artificial intelligence-powered electrocardiogram model detecting acute coronary occlusion myocardial infarction.

Aims: A majority of acute coronary syndromes (ACS) present without typical ST elevation. One-third of non-ST-elevation myocardial infarction (NSTEMI) patients have an acutely occluded culprit coronary artery [occlusion myocardial infarction (OMI)], leading to poor outcomes due to delayed identification and invasive management. In this study, we sought to develop a versatile artificial intelligence (AI) model detecting acute OMI on single-standard 12-lead electrocardiograms (ECGs) and compare its performance with existing state-of-the-art diagnostic criteria. Methods and results: An AI model was developed using 18 616 ECGs from 10 543 patients with suspected ACS from an international database with clinically validated outcomes. The model was evaluated in an international cohort and compared with STEMI criteria and ECG experts in detecting OMI. The primary outcome of OMI was an acutely occluded or flow-limiting culprit artery requiring emergent revascularization. In the overall test set of 3254 ECGs from 2222 patients (age 62 ± 14 years, 67% males, 21.6% OMI), the AI model achieved an area under the curve of 0.938 [95% confidence interval (CI): 0.924-0.951] in identifying the primary OMI outcome, with superior performance [accuracy 90.9% (95% CI: 89.7-92.0), sensitivity 80.6% (95% CI: 76.8-84.0), and specificity 93.7 (95% CI: 92.6-94.8)] compared with STEMI criteria [accuracy 83.6% (95% CI: 82.1-85.1), sensitivity 32.5% (95% CI: 28.4-36.6), and specificity 97.7% (95% CI: 97.0-98.3)] and with similar performance compared with ECG experts [accuracy 90.8% (95% CI: 89.5-91.9), sensitivity 73.0% (95% CI: 68.7-77.0), and specificity 95.7% (95% CI: 94.7-96.6)]. Conclusion: The present novel ECG AI model demonstrates superior accuracy to detect acute OMI when compared with STEMI criteria. This suggests its potential to improve ACS triage, ensuring appropriate and timely referral for immediate revascularization.

Myocardial sodium-glucose cotransporter 2 expression and cardiac remodelling in patients with severe aortic stenosis: The BIO-AS study.

AIM: Cardiac remodelling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. Our study aimed to evaluate the expression of sodium-glucose cotransporter 2 (SGLT2) gene and protein in patients with severe AS stratified in high gradient (HG) and low flow-low gradient (LF-LG) AS and its association with cardiac functional impairments. METHODS AND RESULTS: Gene expression and protein levels of main biomarkers of cardiac fibrosis (galectin-3, sST2, serpin-4, procollagen type I amino-terminal peptide, procollagen type I carboxy-terminal propeptide, collagen, transforming growth factor [TGF]-ß), inflammation (growth differentiation factor-15, interleukin-6, nuclear factor-κB [NF-κB]), oxidative stress (superoxide dismutase 1 [SOD1] and 2 [SOD2]), and cardiac metabolism (sodium-hydrogen exchanger, peroxisome proliferator-activated receptor [PPAR]-α, PPAR-γ, glucose transporter 1 [GLUT1] and 4 [GLUT4]) were evaluated in blood samples and heart biopsies of 45 patients with AS. Our study showed SGLT2 gene and protein hyper-expression in patients with LF-LG AS, compared to controls and HG AS (p < 0.05). These differences remained significant even after adjusting for age, gender, body mass index, history of diabetes mellitus, arterial hypertension, and coronary artery disease. SGLT2 gene expression was positively correlated with: (i) TGF-ß (r = 0.72, p < 0.001) and collagen (r = 0.73, p < 0.001) as markers of fibrosis; (ii) NF-κB (r = 0.36, p < 0.01) and myocardial interleukin-6 (r = 0.68, p < 0.001) as markers of inflammation: (iii) SOD2 (r = -0.38, p < 0.006) as a marker of oxidative stress; (iv) GLUT4 (r = 0.33, p < 0.02) and PPAR-α (r = 0.36, p < 0.01) as markers of cardiac metabolism. CONCLUSION: In patients with LF-LG AS, SGLT2 gene and protein were hyper-expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress.

Twelve-month follow-up results from the SIRONA 2 clinical trial.

AIMS: In the SIRONA 2 trial, the safety and efficacy of pulmonary artery (PA) pressure (PAP)-guided heart failure (HF) management using a novel PAP sensor were assessed at 30 and 90 days, respectively, and both endpoints were met. The current study examines the prespecified secondary endpoints of safety and accuracy of the PA sensor along with HF hospitalizations and mortality, HF symptoms, functional capacity, quality of life, and patient compliance through 12 months. METHODS AND RESULTS: SIRONA 2 is a prospective, multi-centre, open-label, single-arm trial evaluating the Cordella™ PA Sensor System in 70 patients with New York Heart Association (NYHA) functional class III HF with a prior HF hospitalization and/or increase of N-terminal pro-brain natriuretic peptide within 12 months of enrolment. Sensor accuracy was assessed and compared with measurements obtained by standard right heart catheterization (RHC). Safety was defined as freedom from prespecified adverse events associated with use of the Cordella PA Sensor System and was assessed in all patients who entered the cath lab for PA sensor implant. HF hospitalizations and mortality, HF symptoms, functional capacity, quality of life, and patient compliance were also assessed. At 12 months, there was good agreement between the Cordella PA Sensor System and RHC, with the average difference for mean PAP being 2.9 ± 7.3 mmHg. The device safety profile was excellent with 98.4% freedom from device/system-related complications. There were no pressure sensor failures. HF hospitalizations and mortality were low with a rate of 0.33 event per patient year. Symptoms as assessed by NYHA (P < 0.0001) and functional capacity as measured by 6 min walk test (P = 0.02) were significantly improved. Patients' adherence to daily transmissions of PAP and vital signs measurements was 95%. CONCLUSIONS: Long-term follow-up of the SIRONA 2 trial supports the safety and accuracy of the Cordella PA Sensor System in enabling comprehensive HF management in NYHA class III HF patients.

Cell Therapy Improves Quality-of-Life in Heart Failure: Outcomes From a Phase III Clinical Trial.

Patients with heart failure experience limitations in daily activity and poor quality-of-life. Prospective surveillance of health-related quality-of-life supplemented traditional death and hospitalization outcomes in the multinational, randomized, double-blinded CHART-1 clinical trial that assessed cardiopoiesis-guided cell therapy in ischemic heart failure patients with reduced left ventricular ejection fraction. The Minnesota Living with Heart Failure Questionnaire (MLHFQ), a Food and Drug Administration qualified instrument for evaluating therapeutic effectiveness, was applied through the 1-year follow-up. Cell treated (n = 109) and sham procedure (n = 140) cohorts reported improved MLHFQ scores comparable between the 2 study arms (mean treatment difference with baseline adjustment -3.2 points, P = .107). Superiority of cell treatment over sham in betterment of the MLHFQ score was demonstrated in patients with pre-existing advanced left ventricular enlargement (baseline-adjusted mean treatment difference -6.4 points, P = .009). In this highly responsive subpopulation, benefit on the MLHFQ score paralleled reduction in death and hospitalization post-cell therapy (adjusted Mann-Whitney odds 1.43, 95% CI, 1.01-2.01; P = .039). The potential of cell therapy in addressing the quality-of-life dimension of heart failure requires further evaluation for disease relief.

Bleeding and thrombotic risk of different antiplatelet regimens posttranscatheter edge-to-edge mitral valve repair in patients with an indication for oral anticoagulation: Results from an all-comers national registry.

BACKGROUND: Evidence-based recommendations for antithrombotic treatment in patients who have an indication for oral anticoagulation (OAC) after transcatheter edge-to-edge mitral valve repair (TEER) are lacking. AIMS: To compare bleeding and thrombotic risk for different antithrombotic regimens post-TEER with MitraClip in an unselected population with the need for OACs. METHODS: Bleeding and thrombotic complications (stroke and myocardial infarction) up to 3 months after TEER with mitraclip were evaluated in 322 consecutive pts with an indication for OACs. These endpoints were defined by the Mitral Valve Academic Research Consortium criteria and were compared between two antithrombotic regimens: single antithrombotic therapy with OAC (single ATT) and double/triple ATT with a combination of OAC and aspirin and/or clopidogrel (combined ATT). RESULTS: Collectively, 108 (34%) patients received single ATT, 203 (63%) received double ATT and 11 (3%) received triple ATT. Bleeding events occurred in 67 patients (20.9%), with access site related events being the most frequent cause (37%). Bleeding complications were observed more frequently in the combined ATT group than in the single ATT group: 24% versus 14% [p = 0.03, adjusted RR: 0.55 (0.3-0.98)]. Within the combined group, the bleeding risk was 23% in the double ATT and 45% in the triple ATT group. Thrombotic complications occurred in only three patients (0.9%), and all belonged to the combined ATT group. CONCLUSIONS: In patients with an indication for OACs, withholding of antiplatelet therapy post-TEER with Mitraclip was associated with a 45% reduction in bleeding and without a signal of increased thrombotic risk.

Coronary Microvascular Dysfunction in Patients With Heart Failure: Characterization of Patterns in HFrEF Versus HFpEF.

BACKGROUND: Coronary microvascular dysfunction (CMD) is involved in heart failure (HF) onset and progression, independently of HF phenotype and obstructive coronary artery disease. Invasive assessment of CMD might provide insights into phenotyping and prognosis of patients with HF. We aimed to assess absolute coronary flow, absolute microvascular resistance, myocardial perfusion, coronary flow reserve, and microvascular resistance reserve in patients with HF with preserved ejection fraction and HF with reduced ejection fraction (HFrEF). METHODS: Single-center, prospective study of 56 consecutive patients with de novo HF with nonobstructive coronary artery disease divided into HF with preserved ejection fraction (n=21) and HFrEF (n=35). CMD was invasively assessed by continuous intracoronary thermodilution and defined as coronary flow reserve <2.5. Left ventricular and left anterior descending artery-related myocardial mass was quantified by echocardiography and coronary computed tomography angiography. Myocardial perfusion (mL/min per g) was calculated as the ratio between absolute coronary flow and left anterior descending artery-related mass. RESULTS: Patients with HFrEF showed a higher left ventricular and left anterior descending artery-related myocardial mass compared with HF with preserved ejection fraction (P<0.010). Overall, 52% of the study population had CMD, with a similar prevalence between the 2 groups. In HFrEF, CMD was characterized by lower absolute microvascular resistance and higher absolute coronary flow at rest (functional CMD; P=0.002). CMD was an independent predictor of a lower rate of left ventricular reverse remodeling at follow-up. In patients with HF with preserved ejection fraction, CMD was mainly due to higher absolute microvascular resistance and lower absolute coronary flow during hyperemia (structural CMD; P≤0.030). CONCLUSIONS: Continuous intracoronary thermodilution allows the definition and characterization of patterns with distinct CMD in patients with HF and could identify patients with HFrEF with a higher rate of left ventricular reverse remodeling at follow-up.

Validation of an automated artificial intelligence system for 12­lead ECG interpretation.

BACKGROUND: The electrocardiogram (ECG) is one of the most accessible and comprehensive diagnostic tools used to assess cardiac patients at the first point of contact. Despite advances in computerized interpretation of the electrocardiogram (CIE), its accuracy remains inferior to physicians. This study evaluated the diagnostic performance of an artificial intelligence (AI)-powered ECG system and compared its performance to current state-of-the-art CIE. METHODS: An AI-powered system consisting of 6 deep neural networks (DNN) was trained on standard 12­lead ECGs to detect 20 essential diagnostic patterns (grouped into 6 categories: rhythm, acute coronary syndrome (ACS), conduction abnormalities, ectopy, chamber enlargement and axis). An independent test set of ECGs with diagnostic consensus of two expert cardiologists was used as a reference standard. AI system performance was compared to current state-of-the-art CIE. The key metrics used to compare performances were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1 score. RESULTS: A total of 932,711 standard 12­lead ECGs from 173,949 patients were used for AI system development. The independent test set pooled 11,932 annotated ECG labels. In all 6 diagnostic categories, the DNNs achieved high F1 scores: Rhythm 0.957, ACS 0.925, Conduction abnormalities 0.893, Ectopy 0.966, Chamber enlargement 0.972, and Axis 0.897. The diagnostic performance of DNNs surpassed state-of-the-art CIE for the 13 out of 20 essential diagnostic patterns and was non-inferior for the remaining individual diagnoses. CONCLUSIONS: Our results demonstrate the AI-powered ECG model's ability to accurately identify electrocardiographic abnormalities from the 12­lead ECG, highlighting its potential as a clinical tool for healthcare professionals.

Continuous vs Bolus Thermodilution to Assess Microvascular Resistance Reserve.

BACKGROUND: Coronary flow reserve (CFR) and microvascular resistance reserve (MRR) can, in principle, be derived by any method assessing coronary flow. OBJECTIVES: The aim of this study was to compare CFR and MRR as derived by continuous (CFRcont and MRRcont) and bolus thermodilution (CFRbolus and MRRbolus). METHODS: A total of 175 patients with chest pain and nonobstructive coronary artery disease were studied. Bolus and continuous thermodilution measurements were performed in the left anterior descending coronary artery. MRR was calculated as the ratio of CFR to fractional flow reserve and corrected for changes in systemic pressure. In 102 patients, bolus and continuous thermodilution measurements were performed in duplicate to assess test-retest reliability. RESULTS: Mean CFRbolus was higher than CFRcont (3.47 ± 1.42 and 2.67 ± 0.81 [P < 0.001], mean difference 0.80, upper limit of agreement 3.92, lower limit of agreement -2.32). Mean MRRbolus was also higher than MRRcont (4.40 ± 1.99 and 3.22 ± 1.02 [P < 0.001], mean difference 1.2, upper limit of agreement 5.08, lower limit of agreement -2.71). The correlation between CFR and MRR values obtained using both methods was significant but weak (CFR, r = 0.28 [95% CI: 0.14-0.41]; MRR, r = 0.26 [95% CI: 0.16-0.39]; P < 0.001 for both). The precision of both CFR and MRR was higher when assessed using continuous thermodilution compared with bolus thermodilution (repeatability coefficients of 0.89 and 2.79 for CFRcont and CFRbolus, respectively, and 1.01 and 3.05 for MRRcont and MRRbolus, respectively). CONCLUSIONS: Compared with bolus thermodilution, continuous thermodilution yields lower values of CFR and MRR accompanied by an almost 3-fold reduction of the variability in the measured results.

Comprehensive invasive evaluation of coronary microcirculation in patients with Takotsubo syndrome.

BACKGROUND AND AIMS: The etiology and pathophysiology of Takotsubo syndrome (TTS) remain a matter of debate. In murine models of coronary microvascular dysfunction (CMD), abnormalities in myocardial perfusion led to the development of TTS. Importantly, TTS was reversible when normal perfusion was restored. However, in clinical practice, the assessment of coronary microcirculation in patients with TTS has primarily relied on non-invasive or indirect, angiography-derived methods. METHODS AND RESULTS: For the first time, we performed invasive microcirculatory assessment, by both validated techniques currently available in the catheterization laboratory, namely intracoronary bolus and continuous thermodilution, in patients with TTS, upon hospital admission and at short term follow-up. Our findings demonstrate that CMD was consistently present in all patients upon hospital admission, as assessed by both techniques. At a median follow-up of 3 months, after the recovery of left ventricular ejection fraction, two third of patients no longer exhibited CMD. CONCLUSIONS: These findings support the hypothesis that an acute and transient worsening in coronary microvascular function plays a pivotal role in the pathophysiology of TTS.

Association of Mild-to-Moderate Aortic Regurgitation With Outcomes in Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: To assess aortic regurgitation (AR) prevalence, its hemodynamic effect, and long-term prognostic implications in patients admitted with de novo or worsened heart failure with preserved ejection fraction (HFpEF). METHODS: Consecutive patients hospitalized with de novo or worsened HFpEF between 2014 and 2020 were enrolled. Patients with more than moderate aortic and/or mitral valve disease were excluded. Based on the presence and degree of AR, patients were divided into those without AR, those with mild, and those with moderate AR. Data on cardiovascular death, heart failure (HF) rehospitalization, and their composite (major adverse cardiovascular events) were collected. RESULTS: The final study population consisted of 458 HFpEF patients: 156 (34.1%) with mild-AR, 153 (33.4%) with moderate-AR, and the remaining 149 (32.5%) with no AR. Mild-to-moderate AR patients were older, with larger left atrium-left ventricle (LV) volumes, greater LV mass index, higher filling pressure, and prevalence of diastolic dysfunction compared with the no-AR group (all P<.05). During 5-year follow-up, 113 patients died of cardiovascular causes, 124 patients were rehospitalized for HF, whereas 196 experienced the composite endpoint. Mild-to-moderate AR was identified as an independent predictor of all-cause death (HR, 1.62; 95% CI, 1.14 to 1.58; P=.04) and major adverse cardiovascular event occurrence (HR, 1.48; 95% CI, 1.05 to 2.09; P=.02). A total of 126 (35.5%) of 355 patients showed progression of AR at follow-up echocardiography. CONCLUSION: Mild-to-moderate AR is common among patients hospitalized for HFpEF. It is associated with adverse LV remodeling and worse long-term outcomes. These findings warrant further prospective studies addressing the importance of AR in prognostic stratification and exploring therapeutic strategies to mitigate its hemodynamic effect on HF.

Detection of transthyretin amyloid cardiomyopathy by automated data extraction from electronic health records.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive and fatal cardiomyopathy, is frequently misdiagnosed or entails diagnostic delays, hindering patients from timely treatment. This study aimed to generate a systematic framework based on data from electronic health records (EHRs) to assess patients with ATTR-CM in a real-world population of heart failure (HF) patients. Predictive factors or combinations of predictive factors related to ATTR-CM in a European population were also assessed. METHODS AND RESULTS: Retrospective unstructured and semi-structured data from EHRs of patients from OLV Hospital Aalst, Belgium (2012-20), were processed using natural language processing (NLP) to generate an Observational Medical Outcomes Partnership Common Data Model database. NLP model performance was assessed on a random subset of EHRs by comparing algorithm outputs to a physician-generated standard (using precision, recall, and their harmonic mean, or F1-score). Of the 3127 HF patients, 103 potentially had ATTR-CM (age 78 ± 9 years; male 55%; ejection fraction of 48% ± 16). The mean diagnostic delay between HF and ATTR-CM diagnosis was 1.8 years. Besides HF and cardiomyopathy-related phenotypes, the strongest cardiac predictor was atrial fibrillation (AF; 72% in ATTR-CM vs. 60% in non-ATTR-CM, P = 0.02), whereas the strongest non-cardiac predictor was carpal tunnel syndrome (21% in ATTR-CM vs. 3% in non-ATTR-CM, P < 0.001). The strongest combination predictor was AF, joint disorders, and HF with preserved ejection fraction (29% in ATTR-CM vs. 18% in non-ATTR-CM: odds ratio = 2.03, 95% confidence interval = 1.28-3.22). CONCLUSIONS: Not only well-known variables associated with ATTR-CM but also unique combinations of cardiac and non-cardiac phenotypes are able to predict ATTR-CM in a real-world HF population, aiding in early identification of ATTR-CM patients.

Asymptomatic Severe and Moderate Aortic Stenosis: Time for Appraisal of Treatment Indications.

Over the last decades, we have witnessed considerable improvements in diagnostics and risk stratification of patients with significant aortic stenosis (AS), paralleled by advances in operative and anesthetic techniques. In addition, accumulating evidence points to the potential benefit of early valve replacement in such patients prior to the onset of symptoms. In parallel, interventional randomized trials have proven the benefit of transcatheter aortic valve replacement in comparison to a surgical approach to valve replacement over a broad risk spectrum in symptomatic patients with AS. This article reviews contemporary management approaches and scrutinizes open questions regarding timing and mode of intervention in asymptomatic patients with severe AS. We also discuss the challenges surrounding the management of symptomatic patients with moderate AS as well as emerging dilemmas related to the concept of a life-long treatment strategy for patients with AS.

Innovative Device-Based Strategies for Managing Acute Decompensated Heart Failure.

Acute decompensated heart failure (ADHF) is a major cause of hospitalizations in older adults, leading to high mortality, morbidity, and healthcare costs. To address the persistent poor outcomes in ADHF, novel device-based approaches targeting specific pathophysiological mechanisms are urgently needed. The recently introduced DRI2P2S classification categorizes these innovative therapies based on their mechanisms. Devices include dilators (increasing venous capacitance), removers (directly removing sodium and water), inotropes (enhancing left ventricular contractility), interstitials (accelerating lymph removal), pushers (increasing renal arterial pressure), pullers (decreasing renal venous pressure), and selective drippers (selective intrarenal drug infusion). Some are tailored for chronic HF, while others focus on the acute setting. Most devices are in early development, necessitating further research to understand mechanisms, assess clinical effectiveness, and ensure safety before routine use in ADHF management. Exploring these innovative device-based strategies may lead to improved outcomes and revolutionize HF treatment in the future.

State-of-the-Art: Noninvasive Assessment of Left Ventricular Function Through Myocardial Work.

The assessment of myocardial work (MW) using noninvasive pressure-strain loop analysis is a novel echocardiographic method that provides a more precise assessment of cardiac performance by considering the left ventricular loading condition. By integrating various MW components such as index, efficiency, and constructive and wasted work, an extensive analysis of left ventricular mechanics and energetics can be achieved. This approach offers a more comprehensive assessment of global cardiac function and performance, surpassing conventional surrogate indices. In this review, we aim to summarize the existing knowledge on MW and its distinctive characteristics in various cardiac pathologies.