BACKGROUND:Secondary or functional mitral regurgitation (FMR) of atrial origin is prevalent in heart failure with preserved ejection fraction (HFpEF) and portends a worse clinical course. Unlike ventricular FMR, it lacks evidence-based treatment and is often overlooked. Sacubitril-valsartan may provide benefit in this HFpEF phenotype. OBJECTIVE:To assess the impact of sacubitril-valsartan on exercise hemodynamics in patients with HFpEF and atrial FMR. METHODS:This multicenter, prospective, randomized, open-label trial with blinded endpoint assessment enrolls patients with stable HFpEF and at least moderate FMR documented within 1 year prior to enrollment. Participants are randomly assigned to sacubitril-valsartan plus standard medical therapy or to standard therapy alone, consisting of a mineralocorticoid receptor antagonist and a sodium-glucose cotransporter-2 inhibitor. Cardiopulmonary exercise testing with echocardiography is performed at baseline and after 6 months, with interval 24-hour home blood pressure monitoring to ensure blood pressure control in both arms. The primary endpoint is the change in exercise-induced pulmonary hypertension, assessed by the change in the mean pulmonary arterial pressure to cardiac output slope. This slope reflects total pulmonary resistance driven by both pre- and postcapillary factors, capturing key HFpEF features, including myocardial properties, vascular remodeling and the overall impact of (dynamic) atrial FMR. Secondary endpoints include changes in FMR severity, peak oxygen consumption, natriuretic peptide levels, left atrial size and function, and patient-reported outcomes. Prespecified adverse events include hypotension, renal failure, hyperkalemia, and angioedema. CONCLUSION:The PRAISE-MR (Sacubitril-Valsartan in Heart Failure with Preserved Ejection Fraction and Secondary Mitral Valve Regurgitation) trial will evaluate whether sacubitril-valsartan, an angiotensin receptor neprilysin inhibitor, is beneficial in patients with HFpEF and atrial FMR.

More than 64 million people worldwide have heart failure (HF), and these numbers are expected to rise. Acute HF (AHF) is the leading cause of hospitalization in patients over 65 years old and is linked to high mortality and readmission rates. AHF may also be a frequent complication in patients hospitalized for other medical reasons as well as after cardiac or non-cardiac surgery. These three entities are summarized as secondary AHF. As secondary AHF has been largely overlooked by medical research and education, little is known about its pathophysiology, phenotypes, diagnosis, management, and prognosis. Secondary AHF occurring after non-cardiac surgery warrants particular attention due to its very high mortality rates of up to 44% within 1 year and is therefore the focus of this review. The scope of this document is to summarize the available evidence regarding the pathophysiology, prevention, diagnosis, treatment, and prognosis of AHF after non-cardiac surgery. Key to prevention is understanding and addressing the pathophysiology of AHF after non-cardiac surgery, which involves close monitoring of fluid status to avoid volume overload and/or hypovolemia, avoiding hypo- and/or hypertension, treating pain and anaemia to prevent tachycardia, and avoiding electrolyte disturbances to prevent arrhythmias. Cardiac biomarkers, such as cardiac troponins and natriuretic peptides, serve as important diagnostic tools and enhance risk stratification in the perioperative setting. A low threshold to perform echocardiography in this population is suggested. Vigilant post-operative care is essential for the early recognition and treatment of AHF after non-cardiac surgery, which could help improve outcomes for patients.

In patients with heart failure, neurohumoral activation leads to increased renal sodium avidity across the entire renal tubules, resulting in a positive sodium and water balance, leading to decompensated heart failure requiring intravenous diuretics. As the dose of diuretic therapy required to achieve euvolaemia is difficult to estimate due to considerable intra- and interindividual differences, the European Society of Cardiology recommends assessment of the diuretic response within hours either via evaluation of the urinary sodium concentration or via urinary volume after initial diuretic administration. All diuretic agents enhance sodium excretion to a different extent depending on their side of action across the renal tubules, and renal adaptation mechanisms due to neurohumoral stimulation. Impaired sodium excretion, even in the presence of fluid loss, is associated with worse clinical outcomes. Therefore, assessing urinary sodium excretion is considered a good and direct marker of the diuretic efficacy. Such natriuresis-guided protocols have been tested prospectively by the Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure and the Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure study, both demonstrating increased natriuresis and diuresis. Moreover, the Readily Available Urinary Sodium Analysis in Patients with Acute Decompensated Heart Failure study has demonstrated that a nurse-led natriuresis-guided protocol is feasible through the use of a point-of-care urinary sodium sensor, allowing an immediately readable urinary sodium result, enabling fast changes in diuretic therapy. This review summaries the rationale, current evidence and gaps supporting the role of urinary sodium concentration in patients with acute decompensated heart failure.

AIMS:Loop diuretics alleviate symptoms in heart failure (HF), but despite recommendations for dynamic dosing, implementation in practice remains challenging. The EASY-STOP trial investigated whether ambulatory urinary sodium monitoring using a point-of-care sensor could guide diuretic down-titration. METHODS AND RESULTS:This prospective, single-centre study enrolled 50 euvolaemic HF patients on stable guideline-directed medical therapy for ≥3 months and receiving maintenance loop diuretic (≥20 mg furosemide equivalent daily). After a 1-week baseline phase of daily self-measured first-void and post-diuretic urinary sodium assessment, loop diuretics were gradually reduced by 50% and discontinued when ≤20 mg furosemide equivalents. Urinary monitoring continued for another 3 weeks. Successful down-titration was defined as remaining congestion-free (no rise in New York Heart Association class ≥I, oedema, pleural effusion, ascites, rise in right ventricular systolic pressure ≥10 mmHg, or worsening diastolic dysfunction ≥1 grade). Investigators and patients were blinded for urinary sodium analysis during the study. Patients were 75 (68-79) years old, had left ventricular ejection fraction 46 (± 11)%, estimated glomerular filtration rate 47 (35-65) ml/min and N-terminal pro-B-type natriuretic peptide 899 (326-2558) ng/L. Among the 50 patients, 62 diuretic down-titrations were performed, of which 34 (55%) were successful. Baseline urinary sodium before loop diuretic down-titration was similar between groups. However, patients who successfully achieved down-titration exhibited a significant increase in first-void urinary sodium following down-titration (53-74 mmol/L, p < 0.001), whereas those requiring reinitiation showed no significant change (56-58 mmol/L, p = 0.331). A 10 mmol/L increase predicted successful down-titration with 79.4% sensitivity and 78.6% specificity (area under the curve = 0.851). CONCLUSIONS:Point-of-care urinary sodium monitoring may represent a non-invasive and personalized approach to diuretic titration in HF management. Further trials are warranted to validate its clinical utility and long-term benefits.

In heart failure, sodium retention generally occurs out of proportion to water retention and may occur disproportionate to chloride retention, requiring excretion of other cations (i.e. potassium, magnesium, and hydrogen). Renal homeostatic mechanisms keep chloride levels in balance, making it the primary regulator of intravascular tonicity. Excess total body sodium stores and potassium depletion increase the vulnerability to dehydration, especially in the intracellular compartment. With decompensation, extracellular volume expansion with sodium and chloride overload occurs, further enhancing potassium losses. While diuretics are vital to treat fluid overload, they derange important electrolyte and water balances. Diuretic therapies in heart failure produce disproportionate electrolyte-free water excretion, further exacerbate potassium depletion, and cause chloride losses disproportionate to natriuresis. This can be mitigated by allowing liberal electrolyte-free water intake, providing aggressive potassium and chloride supplementation, and using upfront proximal diuretics to preserve the chloride balance.

The mean pulmonary artery pressure corrected for cardiac output (mPAP/CO), measured using exercise echocardiography and calculated as the mPAP/CO slope, has improved risk stratification in various populations. However, the prognostic value and reproducibility of simpler methods remain uncertain. To evaluate whether the methodology employed to calculate the non-invasive mPAP/CO relationship affects prognostic accuracy and measurement consistency. This secondary analysis of a multicenter cohort study included patients with unexplained dyspnea who underwent exercise echocardiography. The mPAP was derived from the colloid-enhanced peak tricuspid regurgitation velocity using the Chemla formula. CO was calculated by multiplying heart rate by stroke volume, determined from the velocity time integral of the left ventricular outflow tract. The mPAP and CO were measured at rest, intermediate, and peak effort. The mPAP/CO relationship was calculated using six methods: (1) 3-point linear regression, (2) 2-point slope (rest to peak), (3) 2-point slope (rest to intermediate), (4) single-point mPAP/CO at rest, (5) single-point mPAP/CO at intermediate effort and (6) single-point mPAP/CO at peak effort. The primary outcome was a composite of all-cause mortality or heart failure hospitalization. Prognostic performance was evaluated using Receiver Operating Characteristic (ROC) curves, with area under the curve (AUC) comparisons conducted using the DeLong test to assess differences between calculation methods. Reproducibility was assessed by three independent observers using intraclass correlation coefficients (ICC) with 95% confidence intervals. Among 2538 exercise echocardiograms (January 2016-March 2023), 2278 were analyzed (age 62±15 years, 53% women) The patients' characteristics are shown in Figure 1. Over a median follow-up of 19 (11-36) months, the overall event rate was 6.0%. Single-value at peak effort (AUC: 0.715) performed better than 3-point slope, 2-point slope (rest to peak), and single-value at rest (p<0.05 for comparisons), with no difference with single-value at intermediate effort (Figure 2A). ICC for single values demonstrated good reproducibility (ICC between 0.841 – 0.873), while ICC for multipoint methods was poor to moderate (ICC between 0.394-0.556) (Figure 2B). For risk stratification in unexplained dyspnea, single-point mPAP/CO ratios at peak and intermediate effort show at least similar prognostic value to more complex multipoint methods. Due to significantly better reproducibility, they are attractive and reliable alternatives to the currently used multipoint mPAP/CO slope in clinical and research practice.

BACKGROUND:Patients with unexplained dyspnea and an elevated mean pulmonary artery pressure (mPAP)/cardiac output (CO) slope on invasive hemodynamic assessment during exercise have worse clinical outcomes. The aim of this study was to evaluate the incremental prognostic value of the noninvasive mPAP/CO slope in addition to heart failure with preserved ejection fraction (HFpEF) probability scores and diastolic stress testing in patients with unexplained dyspnea. METHODS:In a multicenter cohort study involving six Belgian dyspnea clinics, patients with unexplained dyspnea underwent exercise echocardiography for mPAP/CO slope assessment. Positive HFpEF scores were defined as HFA-PEFF (Heart Failure Association pretest probability echocardiography, functional testing, final diagnosis) score ≥ 5 and H2FPEF (heavy, hypertensive, atrial fibrillation, pulmonary hypertension, elder, filling pressure) score ≥ 6. The outcome evaluated was a composite of all-cause mortality or heart failure hospitalization. RESULTS:Among 2,452 patients (mean age, 63 ± 15 years; 53% women), mPAP/CO slope > 3.5 mm Hg · L-1 · min-1 best predicted adverse outcomes. The prognostic value of the mPAP/CO slope was greater in patients with negative HFpEF scores than in those with positive scores (interaction P = .02). The mPAP/CO slope remained independently prognostic after adjustment for N-terminal pro-B-type natriuretic peptide (hazard ratio [HR], 2.26; 95% CI, 1.33-3.82) and for HFpEF scores and diastolic stress testing (HR, 1.99; 95% CI, 1.37-2.88), whereas exercise tricuspid regurgitant velocity did not. Both HFpEF score-negative patients with slope > 3.5 mm Hg · L-1 · min-1 (HR, 2.99; 95% CI, 1.81-4.95) and HFpEF score-positive patients (HR, 6.29; 95% CI, 4.25-9.31) showed significantly higher risk compared with HFpEF score-negative patients with slope ≤ 3.5 mm Hg · L-1 · min-1. CONCLUSIONS:The mPAP/CO slope, unlike exercise tricuspid regurgitant velocity, adds prognostic value beyond natriuretic peptides, HFpEF scores, and diastolic stress testing, identifying high-risk patients with exercise-induced hemodynamic abnormalities who may benefit from invasive confirmation and closer follow-up.

Fluid restriction is frequently recommended to patients with chronic heart failure, but randomized clinical trials assessing the effects of fluid restriction remain scarce. In this multicenter open-label trial, outpatients with chronic heart failure were randomized to receiving advice for liberal fluid intake versus receiving advice for fluid restriction, up to 1,500 ml per day of fluid intake. The primary outcome of the trial was health status after 3 months, as assessed by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS). Secondary outcomes included thirst distress and safety events. Among 504 randomized patients (67.3% male), the KCCQ-OSS after 3 months was 74.0 in the liberal fluid intake group versus 72.2 in the fluid restriction group, with a mean difference after adjustment for baseline scores of 2.17 (95% confidence interval -0.06 to 4.39; P = 0.06), indicating that the primary outcome was not met. Thirst distress was higher in the fluid restriction group and no differences were observed for safety events between the two groups. These findings question the benefit of fluid restriction in chronic heart failure. ClinicalTrials.gov registration: NCT04551729 .

Acute right ventricular failure is a complex and rapidly progressive clinical syndrome, whereby the right ventricle fails to provide adequate left ventricular preload, dilates, and causes systemic venous congestion. Previous research in acute heart failure has primarily focused on the left ventricle. Yet, the need for a better understanding of right ventricular anatomy, physiology, and pathophysiology, as well as of the diagnosis and management of its acute failure is crucial. Diagnosis mandates a high degree of clinical suspicion, as the majority of signs and symptoms are nonspecific. An accurate and prompt identification of the underlying causes, including pulmonary embolism, right ventricular myocardial infarction, acute respiratory distress syndrome, post-cardiac surgery, and decompensated chronic pulmonary hypertension, is therefore essential. This review provides insights into right ventricular anatomy and functioning and discusses the pathophysiology of acute right ventricular failure, its differential aetiologies, clinical presentation, diagnosis, and treatment.