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In a randomized, placebo-controlled trial, patients with acute decompensated heart failure and volume overload who received intravenous acetazolamide plus a loop diuretic had a higher incidence of decongestion.

Heart failure with preserved ejection fraction (HFpEF) is under-recognized in clinical practice. Although a previously developed risk score, termed H 2 FPEF, can be used to estimate HFpEF probability, this score requires imaging data, which is often unavailable. Here we sought to develop an HFpEF screening model that is based exclusively on clinical variables and that can guide the need for echocardiography and further testing. In a derivation cohort ( n  = 414, 249 women), a clinical model using age, body mass index and history of atrial fibrillation (termed the HFpEF-ABA score) showed good discrimination (area under the curve (AUC) = 0.839 (95% confidence interval (CI) = 0.800–0.877), P  < 0.0001). The performance of the model was validated in an international, multicenter cohort ( n  = 736, 443 women; AUC = 0.813 (95% CI = 0.779–0.847), P  < 0.0001) and further validated in two additional cohorts: a cohort including patients with unexplained dyspnea ( n  = 228, 136 women; AUC = 0.840 (95% CI = 0.782–0.900), P  < 0.0001) and a cohort for which HF hospitalization was used instead of hemodynamics to establish an HFpEF diagnosis ( n  = 456, 272 women; AUC = 0.929 (95% CI = 0.909–0.948), P  < 0.0001). Model-based probabilities were also associated with increased risk of HF hospitalization or death among patients from the Mayo Clinic ( n  = 790) and a US national cohort across the Veteran Affairs health system ( n  = 3076, 110 women). Using the HFpEF-ABA score, rapid and efficient screening for risk of undiagnosed HFpEF can be performed in patients with dyspnea using only age, body mass index and history of atrial fibrillation. A risk score using only three clinical variables—age, body mass index and history of atrial fibrillation—predicts heart failure with preserved ejection fraction, an underdiagnosed condition, without the need for echocardiographic imaging.

Abdominal congestion may play an important role in the cardiorenal syndrome and has been demonstrated to drive disease progression. An animal model for abdominal congestion, without other culprit mechanisms that are often present in patients such as low cardiac output or chronic kidney disease, might be interesting to allow a better study of the pathophysiology of the cardiorenal syndrome. The objective of this study was to develop a clinically relevant and valid rat model with abdominal venous congestion and without pre-existing heart and/or kidney dysfunction. To do so, a permanent surgical constriction (20 Gauge) of the thoracic inferior vena cava (IVC) was applied in male Sprague Dawley rats (IVCc, n = 7), which were compared to sham-operated rats (SHAM, n = 6). Twelve weeks after surgery, abdominal venous pressure (mean: 13.8 vs 4.9 mmHg, p < 0.01), plasma creatinine (p < 0.05), plasma cystatin c (p < 0.01), urinary albumin (p < 0.05), glomerular surface area (p < 0.01) and width of Bowman's space (p < 0.05) of the IVCc group were significantly increased compared to the SHAM group for a comparable absolute body weight between groups (559 vs 530g, respectively, p = 0.73). Conventional cardiac echocardiographic and hemodynamic parameters did not differ significantly between both groups, indicating that cardiac function was not compromised by the surgery. In conclusion, we demonstrate that constriction of the thoracic IVC in adult rats is feasible and significantly increases the abdominal venous pressure to a clinically relevant level, thereby inducing abdominal venous congestion.

Carbamylation constitutes a posttranslational modification of proteins or amino acids and results from different pathways in vivo. First is the non-enzymatic reaction between isocyanic acid, a decomposition product of urea, and either the N-terminus or the ε-amino group of lysine residues. Isocyanic acid levels, while low in vivo, are in equilibrium with urea and are thus increased in chronic and end-stage renal diseases. An alternative pathway involves the leukocyte heme protein myeloperoxidase, which catalyzes the oxidation of thiocyanate in the presence of hydrogen peroxide, producing isocyanate at inflammation sites. Notably, plasma thiocyanate levels are increased in smokers, and leukocyte-driven protein carbamylation occurs both within human and animal atherosclerotic plaques, as well as on plasma proteins. Protein carbamylation is considered a hallmark of molecular aging and is implicated in many pathological conditions. Recently, it has been shown that carbamylated low-density lipoprotein (LDL) induces endothelial dysfunction via lectin-like-oxidized LDL receptor-1 activation and increased reactive oxygen species production, leading to endothelial nitric oxide synthase uncoupling. Moreover, carbamylated LDL harbors atherogenic activities, including both binding to macrophage scavenger receptors inducing cholesterol accumulation and foam-cell formation, as well as promoting vascular smooth muscle proliferation. In contrast, high-density lipoprotein loses its anti-apoptotic activity after carbamylation, contributing to endothelial cell death. In addition to involvement in atherogenesis, protein carbamylation levels have emerged as a particularly strong predictor of both prevalent and incident cardiovascular disease risk. Recent studies also suggest that protein carbamylation may serve as a potential therapeutic target for the prevention of atherosclerotic heart disease.

Opinion statement This review provides mechanistic insight in the pleiotropic effects of sodium-glucose transporter-2 (SGLT-2) inhibitors with particular interest to the pathophysiology of heart failure. The SGLT-2 inhibitor empagliflozin has recently demonstrated an unprecedented 38% reduction in cardiovascular mortality in patients with diabetes. Despite modest effects on long-term glycemic control, highly significant reductions in heart failure admissions and end-stage kidney disease were observed. SGLT-2 inhibitors are the latest approved class of glucose-lowering agents. By blocking sodium/glucose uptake in the proximal tubules of the nephron, they induce glycosuria. Treatment with SGLT-2 inhibitors in diabetes leads to a sustained ∼1% reduction in glycated hemoglobin levels, with favorable reductions in both arterial blood pressure (∼3–6 mmHg) and body weight (∼2–4 kg/m 2 ). However, those effects fail to explain fully the dramatic reduction in cardiovascular mortality, heart failure readmissions, and end-stage kidney disease. The unique pharmacological profile of SGLT-2 inhibitors puts them at the crossroads of important hemodynamic, neurohumoral, metabolic, and vascular endothelial pathways influencing cardiac and renal disease. SGLT-2 inhibitors decrease proximal tubular sodium and chloride reabsorption, leading to a reset of the tubuloglomerular feedback. This induces plasma volume contraction without activation of the sympathetic nerve system, decreases harmful glomerular hyper-filtration leading to better long-term renal preservation, and improves diuretic and natriuretic responses to other diuretic agents. Moreover, SGLT-2 inhibitors might improve the efficiency of myocardial energetics by offering β-hydroxybutyrate as an attractive fuel for oxidation and increase hematocrit improving oxygen transport. Finally, decreased vascular stiffness and improved endothelial function are observed with the use of SGLT-2 inhibitors in diabetes. Those multiple nonglycemic effects reinforce SGLT-2 inhibitors as the preferred glucose-lowering drug to treat diabetic patients with heart failure. In the future, they might even be considered in heart failure or chronic kidney disease patients without diabetes.

Cardiac resynchronization therapy (CRT) improves cardiac hemodynamics. Therefore, the maintenance dose of loop diuretic therapy might be reduced. Consecutive patients who underwent CRT (n = 648) were retrospectively evaluated. Loop diuretic dose was recorded at baseline before implantation and 6 months later with patients classified into 4 groups: (1) no loop diuretic, (2) down-titration, (3) unchanged dose, and (4) up-titration. Afterward total loop diuretic exposure was calculated. Renal function trajectories were evaluated as the difference between implantation and censoring serum creatinine (Cr) value. Clinical outcome was evaluated as the combined end point of heart failure readmissions and all-cause mortality. Independent predictors of successful loop diuretic down-titration were identified. Two hundred ninety-six patients (46%) received no loop diuretic at follow-up, 126 (19%) underwent down-titration, 137 (21%) remained on a stable dose, and 89 (14%) underwent up-titration. In comparison with the group that was free from loop diuretics (Cr = +0.06 mg/dl), renal function deteriorated faster during follow-up in patients on stable doses (Cr = +0.29 mg/dl; p = 0.045) and those underwent up-titration (Cr = +0.44 mg/dl; p = 0.009) but not in patients who were down-titrated (Cr = +0.13 mg/dl; p = 1.00). Patients receiving down-titration had a lower risk for the combined clinical end point (adjusted hazards ratio 0.43; confidence interval 0.22 to 0.83; p = 0.012). Factors associated with successful down-titration after 6 months of CRT included nonischemic cardiomyopathy, higher baseline dose of diuretics, higher ejection fraction at 6 weeks, and lower right ventricular systolic pressure at 6 weeks. In conclusion, after CRT, down-titration of loop diuretics is often feasible and associated with improved outcome and a slower rate of kidney function decline. Patients with nonischemic cardiomyopathy, treated with high doses of loop diuretics before implantation and beneficial left ventricular remodeling with CRT, are most likely to tolerate loop diuretic down-titration.

To the Editor: An accurate examination of the baseline characteristics of the patients in the Trial to Evaluate Cardiovascular Outcomes in Patients Treated with the Tricuspid Valve Repair System Pivotal (TRILUMINATE Pivotal) by Sorajja et al. (May 18 issue) 1 suggests a considerable overlap with heart failure with preserved ejection fraction, an extremely heterogeneous syndrome. The majority of patients had atrial fibrillation, hypertension, signs of congestion, atrial dilatation, variable degrees of right ventricular enlargement, and impaired cardiac output at rest. Deep phenotyping of patients who have heart failure with preserved ejection fraction might improve patient selection for interventions for tricuspid regurgitation. . . .

Background Cardiorenal syndrome poses significant diagnostic and therapeutic challenges. The Venous Excess Ultrasound (VExUS) grading system based on the combination of venous Doppler assessments has shown potential in predicting acute kidney injury and cardiovascular outcomes, but its relevance regarding the management of acutely decompensated heart failure (ADHF) remains to be fully understood. Methods In this prospective study, patients with ADHF and acute kidney injury (AKI) were enrolled from a medical intensive care unit over 20 months. The study involved echocardiography and VExUS grading at admission and 72 h later. Data collection included clinical parameters, diuretic dosages, urine output, and fluid balance. Statistical analyses focused on exploring the relationships between VExUS grades and its components, including the renal venous stasis index (RVSI), diuretic efficiency, and renal function improvement. Results The cohort of 43 patients showed varied VExUS grades at admission. Higher VExUS grades were significantly associated with lower diuretic efficiency. Specifically, the mean urine output per 40 mg of furosemide was 368 ± 213 mL, with patients having VExUS grade 2 or 3 exhibiting reduced diuretic efficiency compared to those with grade 0–1 (Grade 2 vs. Grade 0–1: 333 ± 214 mL vs. 507 ± 189 mL, p  = 0.02; Grade 3 vs. Grade 0–1: 270 ± 167 mL vs. 507 ± 189 mL, p  = 0.004). The relationship between VExUS grade and diuretic efficiency was independent of admission creatinine and prior use of loop-diuretics (β = -106 CI: -180; -32 p  = 0.006). Among the components of venous congestion assessment, the RVSI had the best ability to predict low diuretic efficiency (AUROC: 0.76 (0.60; 091) p  = 0.001). Improvement in VExUS grade at 72 h was correlated with significant renal function improvement (84.6% vs. 47.1% for improved vs. non-improved VExUS grades, p  = 0.03). Conclusion High VExUS and RVSI grades at admission are independently associated with reduced diuretic efficiency in ADHF patients with AKI. The findings emphasize the clinical value of venous congestion assessment in cardiorenal syndrome management including the selection of an initial diuretic dose.

Venous congestion is an important contributor to worsening renal function in heart failure and the cardiorenal syndrome. In patients, it is difficult to study the effects of isolated venous congestion on organ function. In this study, the consequences of isolated abdominal venous congestion on morphology and function of the kidneys, liver and heart were studied in a rat model. Twelve sham-operated (SHAM) male Sprague Dawley rats were compared to eleven inferior vena cava-constricted (IVCc) rats for twenty-one weeks. Abdominal venous pressure was significantly higher in the IVCc versus SHAM group (p < 0.0001). Indices of liver and kidney weight, function and morphology, inflammation as well as collagen deposition were significantly increased in the IVCc compared to SHAM group, (p < 0.05). Echocardiographic and hemodynamic parameters were largely unaffected by abdominal venous congestion. In this rat model of isolated abdominal venous congestion, retrogradely conducted glomerular hypertension without a concomitant change in glomerular filtration rate was observed. Adverse short-term hepatic morphological alterations were developed which explain the observed organ function dysfunction. Importantly, cardiac function remained comparable between both groups. This study provides relevant insight in the pathophysiology of abdominal congestion on organ function.