BACKGROUND AND AIMS:Spermidine, a polyamine abundant in plant-based and fermented foods, has been associated with reduced cardiovascular and all-cause mortality. However, whether dietary spermidine intake is reflected in circulating and skeletal muscle concentrations remains unclear, and tissue data are scarce. We therefore investigated the associations between dietary spermidine intake and spermidine concentrations in plasma and skeletal muscle in elderly patients with coronary artery disease. METHODS:We examined dietary spermidine and spermine intake using a food frequency questionnaire, and plasma and skeletal muscle concentrations by targeted LC-MS/MS. Associations between intake, plasma and skeletal muscle concentrations were assessed using multivariable linear regression models adjusted for age, sex, body mass index, educational level, total daily energy intake, serum creatinine, medical treatment and comorbidities. RESULTS:A total of 192 patients with coronary artery disease were included (age 72 years [68-76] and 80% male). Median dietary spermidine intake was 11.5 mg/day [9.5-14.3] (n = 184). Median spermidine concentrations were 21.0 ng/mL [16.2-27.1] in plasma (n = 188) and 7120 ng/g [6200-8500] in skeletal muscle (n = 101). Higher dietary spermidine intake was modestly associated with higher plasma spermidine concentrations, corresponding to an 18% higher plasma concentration per doubling of intake in the unadjusted model (p = 0.02). The association remained robust after adjustment for covariates (p < 0.05). Skeletal muscle spermidine concentrations were not associated with intake or plasma concentrations (p > 0.05). Skeletal muscle contained markedly higher polyamine concentrations than plasma, and skeletal muscle spermine exceeded spermidine 6.7-fold. Women exhibited higher energy-adjusted spermidine intake (p = 0.02) and higher skeletal muscle spermidine concentrations than men (p < 0.01). Participants with higher educational attainment had higher dietary spermidine intake and plasma spermidine concentrations (p < 0.05). CONCLUSIONS:These findings suggest that plasma spermidine reflects habitual dietary exposure to a limited extent, whereas skeletal muscle polyamine pools appear to be maintained by strong intracellular regulation. Potential sex-related differences in polyamine metabolism or tissue distribution warrant further investigation. Randomised controlled trials are required to establish causality and determine clinical relevance. TRIAL REGISTRATION:NCT06186102, registered at ClinicalTrials.gov on 7 December 2023 by the authors. TRIAL PROTOCOL:POLYCAD trial protocol, Trials, 2025.

CONTEXT:Alternate-day fasting (ADF) is a dietary regimen with prolonged fasting periods associated with metabolic and cardiovascular benefits. It remains unclear if ADF improves cardiac function and metabolism to explain these benefits. OBJECTIVE:This study aimed to investigate the effects of a 3-week ADF intervention on myocardial efficiency, perfusion, and substrate metabolism in overweight/obese individuals. METHODS:Sixteen participants with overweight (body mass index: 32 ± 1.9 kg/m2) completed this randomized crossover study comparing ADF with a standard diet. Dynamic cardiac positron emission tomography scans were performed using 5 tracers: [15O]water to assess myocardial blood flow and flow reserve (MFR), [11C]acetate to measure myocardial oxygen consumption (MVO2) and myocardial external efficiency (MEE), and [11C]β-hydroxybutyrate, [11C]palmitate, and [18F]fluorodeoxyglucose to assess metabolism of β-hydroxybutyrate (OHB), free fatty acid (FFA), and glucose, respectively. Blood samples were analyzed for OHB, FFA, glucose, lactate, and insulin. Blood pressure, heart rate, cardiac output, and left ventricular mass, ejection fraction, and volumes were assessed. RESULTS:ADF increased circulating ketones on fasting days (peak: 0.67 ± 0.09 mmol/L), which remained elevated on eating days (0.20 ± 0.03 mmol/L). However, myocardial substrate metabolism remained unaltered following ADF. Blood pressure and cardiac output significantly decreased after ADF (systolic/diastolic: 13/9 mmHg and 0.5 L/min, respectively; P < .001). MVO2 decreased by 10% (P = .01) and total left ventricular energy use by 19% (P < .01). Resting myocardial perfusion decreased by 9% (P < .05), and MFR increased by 34% (P < .01). CONCLUSION:A 3-week ADF regimen reduced blood pressure and MVO2, and improved MFR, suggesting ADF may provide a nonpharmacological strategy to improve cardiovascular health in individuals with overweight.

In patients with aortic valve stenosis (AS), the pathophysiological abnormalities involved in the transition to heart failure are unclear. As chronic heart failure progresses, the ratio between myocardial stroke work and oxygen consumption, that is, myocardial external efficiency (MEE), steadily deteriorates. However, in patients with AS, it is unknown whether changes in MEE are involved in disease progression. We investigated changes in MEE and whether MEE was associated with long-term prognosis in patients with AS. Ten healthy controls and 38 patients with moderate-to-severe AS and preserved left ventricular ejection fraction ≥ 50% were included in the study. To evaluate MEE, we used serial 11C-acetate positron emission tomography, cardiovascular magnetic resonance imaging, and echocardiography, with a median follow-up period of 2.8 yr. Furthermore, we conducted a long-term follow-up for a median of 5.2 yr to detect cardiac events and relate them to MEE. In patients with AS, MEE increased during follow-up from 25.2% [95% confidence interval (CI): 24.0-26.5%] to 29.5% (95% CI: 27.3-31.8%; P = 0.001) and was higher than healthy volunteers, 19.9% (18.1-21.8; P < 0.001). Patients who experienced a cardiac event during long-term follow-up (n = 24, 63%) had higher baseline MEE, 26.5% (95% CI: 24.6-28.4%), than event-free patients, 23.3% (95% CI: 22.2-24.3%; P = 0.004). In asymptomatic patients with AS, MEE increased over time and high baseline MEE predicted a poor prognosis. Thus, the myocardium displayed an inherent capacity to improve the coupling between oxidative metabolism and contractile function in response to pressure overload.NEW & NOTEWORTHY Patients with aortic valve stenosis can improve myocardial efficiency-delaying heart failure.

BACKGROUND AND AIMS:It is uncertain whether the effect of vericiguat varies across levels of background guideline-directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). METHODS:We conducted an exploratory analysis of VICTOR, which enrolled 6105 ambulatory patients with HFrEF without recent worsening. GDMT exposure was classified as basic adherence (on vs. off), indication-corrected adherence (accounting for eligibility and contraindications), and dose-corrected adherence (≥50% target dose). A GDMT intensity score was computed from class-specific dose levels. The primary endpoint was the composite of cardiovascular death or first HF hospitalization. Stratified Cox proportional hazards regression models estimated adjusted hazard ratios for vericiguat versus placebo within GDMT strata, with treatment-by-GDMT interaction test. RESULTS:Baseline contemporary GDMT use was high (any ARNI/ACE/ARB 93.9%, ARNI 56%, SGLT2i 59%, MRA 78%, beta-blocker 94%). Basic adherence: adjusted HRs for the primary endpoint were similar whether or not patients were on ACEi/ARB, ARNI, any RAS inhibitor, beta-blocker, or SGLT2i. Dose-corrected adherence: adjusted HRs favored vericiguat in ARNI target-dose users (0.73; 0.57-0.93) and in any RAS target-dose users (0.77; 0.64-0.93), with lower risk on vericiguat in patients not meeting MRA target dose (0.67; 0.48-0.95); interaction P-values were nominally significant. The GDMT intensity score showed no significant interaction with treatment. Patterns for cardiovascular death and all-cause death paralleled the primary endpoint. CONCLUSIONS:In ambulatory patients with HFrEF receiving contemporary GDMT, we did not find convincing evidence that the neutral effect of vericiguat on cardiovascular death or first HF hospitalization was modified by GDMT class, dose attainment, or overall intensity, in a cohort with very high background GDMT use and limited power for interaction testing. These exploratory, hypothesis-generating findings do not establish independent efficacy or pathway additivity for vericiguat and should not be used to guide clinical recommendations regarding GDMT sequencing.

Abstract Background Cardiogenic shock (CS) is characterized by impaired left ventricular (LV) mechanical performance and adverse remodeling. We evaluated whether transthoracic echocardiography (TTE)-derived modified cardiac efficiency (mCE), integrating stroke work and residual LV volume, is associated with short- and long-term mortality in CS and whether its prognostic value differs by shock etiology. Methods In this retrospective cohort study, consecutive adults admitted with CS to the cardiac intensive care unit at Mayo Clinic (2007-2018) were included if TTE was performed within 24 hours. mCE was calculated as (stroke volume × estimated LV end-systolic pressure) divided by LV end-systolic volume and categorized into quartiles. Primary outcome was in-hospital mortality; secondary outcome was 1-year mortality. Multivariable logistic and Cox models adjusted for illness severity, comorbidity burden, shock etiology, cardiac arrest, vasoactive therapy, and mechanical circulatory support. Results Among 667 patients, median mCE was 48 mmHg (IQR 32-74). In-hospital mortality was 28% and increased stepwise across decreasing mCE quartiles. The lowest quartile had a 2.5-fold higher adjusted odds of in-hospital death (OR 2.53; 95%CI: 1.49-4.37; P < 0.001). One-year mortality was 41%; the lowest quartile had a twofold higher adjusted hazard of death (HR 2.05; 95%CI: 1.45-2.89; P < 0.001). Associations were stronger in acute coronary syndrome-related CS (interaction P = 0.035 for in-hospital; P = 0.015 for 1-year). Within the lowest quartile, reduced systolic pressure further amplified mortality risk. Conclusions Early TTE-derived mCE was independently associated with short- and long-term mortality in CS, particularly in acute coronary syndrome-related CS, and captured the interaction between ventricular remodeling and mechanical performance underlying high-risk phenotypes.

INTRODUCTION:Evidence from randomized trials indicates beneficial effects of metformin treatment in heart failure with reduced ejection fraction (HFrEF), but mechanisms of action remain elusive. We investigated myocardial metformin distribution in vivo in HFrEF patients and explored its effects on cardiac fibrogenic progenitor cells from human HFrEF hearts in vitro. METHODS:We assessed myocardial metformin distribution and its dependency on myocardial viability in seven HFrEF patients (ejection fraction: 36 ± 8%; median age: 67 years) using 11C-metformin positron emission tomography (PET), 15O-H2O-PET, and exercise stress echocardiography. We characterized myocardial cellular composition by fluorescence-activated cell sorting and single-cell RNA sequencing (scRNA-seq) on mononuclear cells isolated from explanted left ventricles from four HFrEF patients and four control human hearts. A population of fibroadipogenic progenitor cells (FAPs) was identified and incubated after differentiation with metformin to test the effects on proliferation. RESULTS:Myocardial 11C-metformin kinetics were best described by reversible two-tissue-compartment kinetics. Global myocardial metformin net influx rate was 0.012 ± 0.007 ml ml-1 min-2, and the myocardium-to-blood ratio was 1.24 (95% confidence intervals: 1.03-1.44; P < .001) after 90 min. Regional myocardial metformin net influx correlated inversely with myocardial viability (r = -0.65, P = .04). By scRNA-seq, we identified cardiac FAPs expressing CD34 and PDGFRA, which transformed into extracellular matrix-forming myogenic cells upon activation. Incubation with metformin in clinically relevant doses (0.1 mM) inhibited FAP proliferation by 25%. CONCLUSION:Myocardial metformin uptake in HFrEF is marginal and confined to less viable and fibrotic regions. Cardiac FAPs are resident in human HFrEF myocardium and exhibit fibrogenic potential. Metformin inhibits FAP activation and proliferation at clinically relevant concentrations. These findings suggest that metformin may attenuate adverse left ventricular remodelling by targeting cardiac FAPs. CLINICAL TRIAL REGISTRATION:https://clinicaltrials.gov. Unique identifier: NCT03122769.

BACKGROUND:Women with heart failure with reduced ejection fraction (HFrEF) experience greater symptom burden than men, potentially due to skeletal muscle dysfunction. Skeletal muscle abnormalities are linked to systemic low-grade inflammation, a hallmark of HFrEF pathophysiology, and may be driven by altered inflammatory regulation of skeletal muscle homeostasis. In patients with HFrEF and age-matched controls, we investigated sex differences in skeletal muscle inflammation, muscle stem cells, fibro-adipogenic progenitor cells, and their associations with skeletal muscle mass and strength. METHODS:Participants underwent dual x-ray absorptiometry, cardiopulmonary exercise testing, and dynamometry. Vastus lateralis muscle biopsies were analyzed by flow cytometry to quantify immune cell populations, muscle stem cells, and fibro-adipogenic progenitor cells. Outcomes were log-transformed and analyzed using linear regression with sex-by-HFrEF interaction. Between-group differences were expressed as geometric mean ratios (GMRs). RESULTS:We included 86 patients with HFrEF and 41 age- and sex-matched healthy controls (mean age, 71±7 years; 32% women). Skeletal muscle immune cell composition differed by sex in HFrEF, with significant sex-by-HFrEF interactions for macrophage fraction (P=0.006), lymphocyte content (P=0.045), and lymphocyte fraction (P=0.039). In HFrEF, women showed an increased lymphocyte fraction (GMR, 1.27 [1.06-1.53]; P=0.014), whereas men had an increased macrophage content (GMR, 1.75 [1.16-2.64]; P=0.009). Macrophage content was associated with greater muscle mass and strength in women (mass, R=0.42, P=0.014; strength, R=0.42, P=0.013), but with reduced mass and strength in men (mass, R=-0.25, P=0.017; strength, R=-0.21, P=0.046). Muscle stem cells (GMR, 1.92 [0.99-3.74]; P=0.054) and fibro-adipogenic progenitor cells (GMR, 1.72 [1.03-2.85]; P=0.038) were reduced in HFrEF. CONCLUSIONS:Skeletal muscle immune cell alterations, particularly macrophage and lymphocyte imbalances, are associated with muscle dysfunction in HFrEF, exhibiting distinct sex-specific patterns. These findings demonstrate sex-specific skeletal muscle inflammation and dysfunction in HFrEF.

This study aims to investigate the effects of β-3-hydroxybutyrate (β-3-OHB) infusion on myocardial metabolic flexibility using hyperpolarized [2-13C]pyruvate magnetic resonance spectroscopy (MRS) in the pig heart. We hypothesized that β-3-OHB infusion will cause rapid, quantifiable alterations in tricarboxylic acid (TCA) cycle flux as measured non-invasively by 13C MRS and reflect myocardial work. Five female Danish landrace pigs underwent β-3-OHB infusion during a hyperinsulinemic euglycemic clamp (HEC). Cardiac metabolism and hemodynamics were monitored using hyperpolarized [2-13C]pyruvate MRS and cardiac MRI. β-3-OHB infusion during HEC resulted in significant increases in cardiac output over baseline (from 1.9 to 3.8 L/min, p = 0.0011) and heart rate (from 51 to 85 bpm, p = 0.0004). Metabolic analysis showed a shift towards increased lactate production and decreased levels of acetyl-carnitine and glutamate during β-3-OHB infusion. Following the termination of the infusion, a normalization of these metabolic markers was observed. These results demonstrate the profound metabolic adaptability of the myocardium to ketone body utilization. The infusion of Na-β-3-OHB significantly alters both the hemodynamics and metabolism of the porcine heart. The observed increase in cardiac output and metabolic shifts towards lactate production suggest that ketone bodies could potentially enhance cardiac function by providing an efficient-energy substrate that, if provided, is preferentially used. This study provides new insights into the metabolic flexibility of the heart and hints at the potential therapeutic benefits of ketone interventions in heart failure treatment.

Cardiogenic shock (CS) is characterized by reduced cardiac output (CO), reduced end-organ perfusion, and high mortality. Medical therapies have failed to improve survival. The ketone body 3-hydroxybutyrate (3-OHB) enhances cardiac function in heart failure and CS. We aimed to elucidate the cardiovascular and cardiometabolic effects of 3-OHB treatment during CS. In a randomized, assessor-blinded crossover design, we studied 16 female pigs (60 kg, 5 months of age). CS was induced by left main coronary artery microsphere injections. Predefined criteria for CS were a 30% reduction in CO or mixed venous saturation (SvO2). Intravenous 3-OHB infusion and a matching control solution were administered for 120 min in random order. Hemodynamic measurements were obtained by pulmonary artery catheterization and a left ventricular (LV) pressure-volume catheter. Myocardial mitochondrial function was assessed using high resolution respirometry. During CS, infusion with 3-OHB increased CO by 0.9 L/min (95%CI 0.4-1.3 L/min) compared with control infusion. SvO2 (P = 0.026) and heart rate (P < 0.001) increased. Stroke volume (P = 0.6) was not altered. LV contractile function as determined by LV end-systolic elastance improved during 3-OHB infusion compared with control infusion (P = 0.004). Systemic and pulmonary vascular resistance decreased, and diuresis increased. LV mitochondrial function was higher after 3-OHB infusion compared with control. We conclude that 3-OHB infusion enhances cardiac function by increasing contractility and reducing vascular resistance, while also preserving myocardial mitochondrial respiratory function in a large animal model of ischemic CS. These novel findings support the therapeutic potential of exogenous ketone supplementation in CS management.

BACKGROUND:Acute heart failure (AHF) is associated with high mortality rates, and contemporary medical treatments provide limited benefits in survival. Emerging evidence suggests that exogenous ketone bodies may have beneficial cardiovascular effects in patients with heart failure. The KETO-AHF (KETOne Supplements in Patients Hospitalized for Acute Heart Failure) trial is designed to assess the clinical benefits of initiating ketone supplementation with 1,3-butanediol compared with placebo in patients hospitalized for AHF with reduced ejection fraction. METHODS:KETO-AHF is a multicenter, randomized, double-blind, placebo-controlled trial investigating the effects of 1,3-butanediol (33 g 3 times daily) in patients hospitalized for AHF. Patients with symptoms and signs of AHF requiring intravenous loop diuretics and/or vasoactive treatment, elevated natriuretic peptides, and a left ventricular ejection fraction ≤ 35%, whether de novo or known heart failure, will be enrolled within 5 days of hospital admission. Participants will be randomized 1:1 to receive either 1,3-butanediol or placebo for a 30-day treatment period. The study aims to enroll 125 patients in each group. The primary endpoint is a hierarchical composite of all-cause mortality, heart failure rehospitalization, 6-minute walk test improvement, and reduction in NT-proBNP levels at 30 days. CONCLUSION:The KETO-AHF trial will provide insights into the effects of supplementation with the ketone body 1,3-butanediol in patients hospitalized for AHF.

BACKGROUND:Out-of-hospital cardiac arrest (OHCA) is associated with high mortality and poor neurological outcome, with significant metabolic changes upon return of spontaneous circulation (ROSC). This study aimed to investigate the association of metabolic derangements with outcomes in patients resuscitated from OHCA. METHODS:Blood samples from 156 consecutive unconscious OHCA patients in the Targeted Temperature Management trial were analyzed at hospital admission. Metabolic parameters including free fatty acids (FFAs), glucose, lactate, 3-hydroxybutyrate (3-OHB), and insulin were measured. Hierarchical clustering categorized patients based on metabolic response patterns. Thirty-day mortality and neurological outcomes were compared across these clusters. RESULTS:The median age was 62 years (IQR 54-68) and 87% were male. Hierarchical clustering identified three distinct metabolic profiles. Cluster A showed severe metabolic distress with elevated lactate, high insulin resistance, and modest FFA/3-OHB levels. Cluster B had low FFA/3-OHB levels while Cluster C showed high FFA/3-OHB levels; both were associated with lower lactate and insulin resistance compared with Cluster A. Cluster A was linked to greater cardiac arrest severity, including longer time to ROSC, increased defibrillations, and higher adrenaline use. Thirty-day mortality rates were: Cluster A, 68%; B, 33%; C, 21% (log-rank P < 0.001). Neurological deaths were lowest in Clusters C. Baseline FFA levels were independently associated with neurological death. CONCLUSION:This study identifies distinct metabolic profiles associated with neurological recovery after cardiac arrest, suggesting a potential link between metabolic states and outcomes that may reflect adaptive brain resilience. These findings highlight the need for further research to explore whether metabolic-targeted interventions could enhance recovery.

The acute pathophysiological changes after myocardial ischemia complicated by cardiogenic shock (CS) remain poorly defined, especially regarding compensatory mechanisms and myocardial mitochondrial function. We investigated immediate cardiovascular and mitochondrial effects in a porcine model of ischemic CS. CS was induced in 32 Danish Landrace pigs (60 kg) via repeated microembolization of the left coronary artery until a 30% reduction in cardiac output (CO) or mixed venous saturation. Monitoring included pulmonary artery and left ventricular pressure-volume catheters, with analysis of endomyocardial biopsies and arterial, mixed venous, and coronary sinus blood samples. CO deteriorated promptly due to decreased stroke volume. Contractility declined, and afterload increased, causing rapid ventriculo-arterial decoupling. Forward flow parameters were compromised prior to pressure-parameters. Diastolic function was impaired and mitochondrial damage was observed. CS rapidly impairs LV hemodynamic and mitochondrial function, highlighting the importance of monitoring forward flow and targeting mitochondrial function in treatment.

Coronary artery disease (CAD) remains a major cause of morbidity and mortality. Caloric restriction promotes cardiovascular health but is difficult to sustain. Spermidine, a naturally occurring polyamine and caloric-restriction mimetic, has been linked to improved longevity in epidemiological studies and shown to enhance autophagy, mitochondrial function, and cardiovascular ageing in preclinical models. This trial will investigate whether high-dose spermidine improves cardiac remodelling, exercise capacity, muscle mass, and systemic inflammation in elderly patients with CAD. This is a single-centre, randomised, double-blind, placebo-controlled, superiority trial at Aarhus University Hospital, Denmark. We have randomised 187 patients aged ≥ 65 years with CAD (prior coronary artery revascularisation or myocardial infarction ≥ 3 months prior to screening) and preserved left ventricular ejection fraction (> 40

Left (LAV) and right (RAV) atrial volumes are independent markers of cardiovascular risk in heart failure. Simultaneous assessment of myocardial blood flow (MBF) and atrial volumes might improve the clinical utility of cardiac PET. The aim of this study was to develop and validate an automated method for obtaining atrial volumes from dynamic myocardial perfusion PET scans without ECG-gating. The atria were segmented automatically using first-pass data from [15O]-water PET at rest, combining voxel-wise images of bolus area-under-curve and arrival time. Data of multiple patient cohorts were analyzed: retrospective method development in 36 subjects with systolic heart failure with prospective validation in 59 subjects with same-day echocardiograms (primary hypertrophic cardiomyopathy (n = 25), suspected or known cardiac amyloidosis (n = 25) and healthy controls (n = 9)). Test-retest repeatability of PET was assessed in clinical chest pain patients scanned twice on the same day (n = 15). Segmentation was successful in all scans (n=125). PET and echocardiography correlated for LAV in the development cohort (r=0.83, p<0.001) and in the validation cohort (LAV: r=0.83, RAV: r=0.77, both p<0.001). In alignment with echocardiography, PET identified statistically significant differences between healthy controls and subjects with hypertrophied hearts for LAV index: 26 (interquartile range: 24-29) versus 41 (32-51) ml/m2, p<0.001, and RAV index: 31 (25-43) versus 48 (38-61) ml/m2, p=0.003). Test-retest reproducibility was excellent for LAV (intraclass correlation coefficient ICC=0.96, repeatability coefficient RPC=8.6 ml/m2) and for RAV (ICC=0.96, RPC=11.6 ml/m2). Left and right atrial volumes can be extracted automatically, accurately and reproducibly using dynamic PET.

AIMS:Despite the high risk of rehospitalization for heart failure (HF) and death among patients admitted to the intensive cardiac care unit (ICCU), no accurate prediction score for these outcomes exists. We aimed to develop a risk score to predict unplanned HF hospitalization and death 1-year post-discharge in an unselected cohort of patients admitted to the ICCU. METHODS:Based on a national, multicentre study, we included all consecutive patients admitted to the ICCUs in 39 French centres from 7 to 22 April 2021. We randomly selected a training cohort of 21 centres (n = 1008) to develop the ICCU-HF score and a validation cohort of eight other centres (n = 463). The primary composite outcome was unplanned hospitalization for HF and cardiovascular death at 1-year follow-up after discharge. Using the score, patients were stratified into three risk groups to evaluate the prognostic value. RESULTS:Using a least absolute shrinkage and selection operator (LASSO) regression approach, we identified seven predictors: left ventricular ejection fraction, significant valvular disease grade 2+, Killip score >1, NT-proBNP, creatinine level, previous ventricular arrhythmia and use of inotropes during hospitalization. In 1471 patients (63 ± 15 years, 70% men), 99 (6.7%) experienced the primary outcome. The ICCU-HF score outperformed NT-proBNP, the strongest individual predictor (area under the curve [AUC] 0.77, 95% CI [0.71-0.83] vs. AUC 0.72, 95% CI [0.66-0.79], P = 0.008), demonstrating excellent performance with an AUC of 0.83 (95% CI: 0.77-0.89) to predict outcomes in the validation cohort. Compared with the low-risk group, the intermediate-risk and high-risk groups had significantly higher risks of the composite outcome (HR 4.09, 95% CI [2.23-7.50], P < 0.001 and 12.69, 95% CI [7.02-22.95], P < 0.001), proving strong risk stratification capability of the ICCU-HF score. CONCLUSIONS:The ICCU-HF score showed good performance in predicting the 1-year risk of unplanned HF hospitalization and death in a large cohort of unselected patients admitted to the ICCU, with excellent results in the validation cohort. This score effectively stratifies patients into risk groups, enhancing its utility in clinical decision-making.

Low-volume hypertonic solutions, such as half-molar lactate (LAC), may be a potential treatment used for fluid resuscitation. This study aimed to evaluate the underlying cardiovascular effects and mechanisms of LAC infusion compared to sodium-matched hypertonic sodium chloride (SAL). Eight healthy male participants were randomized in a controlled, single-blinded, crossover study. Each participant received a four-hour infusion of LAC and SAL in a randomized order. Assessor-blinded echocardiography and blood samples were performed. The primary endpoint was cardiac output (CO) measured by echocardiography. During LAC infusion, circulating lactate levels increased by 1.9 mmol/L (95 https://clinicaltrials.gov/ct2/show/NCT04710875 . Registered 1 December 2020.

Impaired cardiac ketone oxidative capacity is a possible disease mechanism in the development of diabetic cardiomyopathy. We examined whether the cardiovascular effects of ketone bodies are different in patients with type 1 diabetes (T1D) compared with healthy controls. Nine patients with T1D and eight age-matched healthy controls were randomized in a single-blind crossover design to receive a three-hour infusion of 3-hydroxybutyrate (3-OHB) or tonicity-matched saline in random order, separated by a one-hour washout period. Assessor-blinded echocardiographic evaluation of cardiovascular function was performed at baseline and following 150 minutes of each intervention. Circulating 3-OHB increased during 3-OHB infusion vs. placebo in healthy controls, with a similar increase in patients with T1D. In healthy controls, 3-OHB infusion increased cardiac output by 1.9±0.4 L/min but only by 0.5±0.1 L/min in patients with T1D. Stroke volume increased by 14±5 mL and left ventricular (LV) ejection fraction by 3±1 percentage points in healthy controls with no change in patients with T1D. During 3-OHB infusion in patients with T1D, LV global wasted work increased and LV global work efficiency decreased. In conclusion, patients with T1D displayed an abnormal cardiovascular response to 3-OHB infusion. Diabetic cardiomyopathy in patients may involve impaired cardiac ketone metabolism.

AIMS:Cardiogenic shock (CS) is a critical manifestation of severe cardiac dysfunction, necessitating precise evaluation of left ventricular (LV) function by transthoracic echocardiography. The prognostic value of global longitudinal strain (GLS) has not been examined in patients with CS. Therefore, we aimed to assess the prognostic significance of GLS in patients with CS. METHODS AND RESULTS:This was a retrospective study of patients with CS from 2007 to 2018 who had a transthoracic echocardiography performed within 24 h of admission. GLS was measured, and conventional parameters were obtained. LV dysfunction was categorized by GLS: > 9.7% (Quartile 1), 7.0% < GLS ≤ 9.7% (Quartile 2), 5.0% < GLS ≤ 7.0% (Quartile 3), and ≤5.0% (Quartile 4). Outcomes included in-hospital and 1-year all-cause mortality. Among 623 patients with CS with the median LVEF of 31% [inter-quartile range (IQR): 24-41%] and the median GLS of 7.0% (IQR: 5.0-9.7%), in-hospital mortality was 29%. Mortality increased across GLS quartiles: Quartile 1: 17%; Quartile 2: 22%; Quartile 3: 35%; and Quartile 4: 42%. GLS remained the only independent echocardiographic predictor of in-hospital mortality after adjusting for clinical covariates (adjusted odds ratio: 1.23 per 1% decrease, 95% confidence interval: 1.04-1.46, P = 0.015). GLS independently predicted 1-year all-cause mortality (P < 0.001). The prognostic value of GLS was superior in cases with acute coronary syndrome. A classification and regression tree analysis identified GLS as the most important echocardiographic variable for predicting in-hospital mortality. CONCLUSION:GLS independently predicted short- and long-term mortality in patients with CS, surpassing conventional echocardiographic parameters in prognostic value, supporting its potential role in risk stratification in this population.