Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2DM with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2DM and HFpEF remain unknown. METHODS: A total of 24 patients with T2DM and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. RESULTS: During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. CONCLUSIONS: In patients with T2DM and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2DM and HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.

Cardiovascular Effects of Increasing Positive End-Expiratory Pressure in A Model of Left Ventricular Cardiogenic Shock in Female Pigs.

BACKGROUND: Cardiogenic shock (CS) presents a medical challenge with limited treatment options. Positive end-expiratory pressure (PEEP) during mechanical ventilation has been linked with clinical benefits in patients with CS. We investigated if increasing PEEP levels could unload the left ventricle (LV) in CS in a large animal model of LV-CS. METHODS: LV-CS was induced in 26 female pigs (60 kg) by microsphere injections into the left main coronary artery. In one study protocol PEEP was increased (5, 10, and 15 cmH2O) and then reverted (15, 10, 5 cmH2O) in 3-minute intervals. In another protocol PEEP increments with higher granularity were conducted through 3-minute intervals (5, 8, 10, 13, and 15 cmH2O). Hemodynamic measurements were performed at all PEEP levels during the healthy state and LV-CS with LV pressure-volume loops. The primary endpoint was pressure-volume area (PVA). Secondary endpoints included other mechano-energetic parameters and estimates of LV preload and afterload. RESULTS: Cardiac output (CO) decreased significantly in LV-CS from 4.5±1.0 L/min to 3.1±0.9 L/min (P<0.001). Increasing PEEP resulted in lower PVA, demonstrating a 36±3% decrease in the healthy state (P<0.001) and 18±3% in LV-CS (P<0.001) at PEEP 15 cmH2O. These effects were highly reversible when PEEP was returned to 5 cmH2O. While mean arterial pressure declined with higher PEEP, CO remained preserved during LV-CS (P=0.339). Increasing PEEP caused reductions in key measures of LV preload and afterload during LV-CS. Right ventricular stroke work index was decreased with increased PEEP. Despite a minor increase in heart rate (HR) at PEEP levels of 15 cmH2O (71 bpm vs. 75 bpm, p<0.05), total mechanical power expenditure (PVA normalized to HR) decreased at higher PEEP. CONCLUSIONS: Applying higher PEEP levels reduced PVA, preserving CO while decreasing MAP. PEEP could be a viable LV unloading strategy if titrated optimally during LV-CS.

Enantiomer-Specific Cardiovascular Effects of the Ketone Body 3-Hydroxybutyrate.

BACKGROUND: The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3-OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D-3-OHB and L-3-OHB, remain undetermined. METHODS AND RESULTS: Three groups of 8 pigs each underwent a randomized, crossover study. The groups received 3-hour infusions of either D/L-3-OHB (racemic mixture), 100% L-3-OHB, 100% D-3-OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure-volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high-resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D-[11C]3-OHB and L-[11C]3-OHB positron emission tomography. All three 3-OHB infusions increased 3-OHB levels (P<0.001). D/L-3-OHB and L-3-OHB increased CO by 2.7 L/min (P<0.003). D-3-OHB increased CO nonsignificantly (P=0.2). Circulating 3-OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, D- and L-3-OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3-OHB extraction increased only during the D- and D/L-3-OHB infusions. D-[11C]3-OHB showed rapid cardiac uptake and metabolism, whereas L-[11C]3-OHB demonstrated much slower pharmacokinetics. CONCLUSIONS: 3-OHB increased CO by reducing afterload. L-3-OHB exerted a stronger hemodynamic response than D-3-OHB due to higher circulating 3-OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L-3-OHB as a potent cardiovascular agent with strong hemodynamic effects.

ALM/BMI: A Clinically Superior Index for Identifying Skeletal Muscle Dysfunction in Patients With Heart Failure.

BACKGROUND: Skeletal muscle wasting is critical in patients with heart failure (HF). Whereas prior studies have employed appendicular lean mass (ALM) normalized by height squared to identify low skeletal muscle mass, the potential of ALM normalized to body mass index (ALM/BMI) remains unexplored in patients with HF. In this study, we compared the use of 2 skeletal muscle mass indices in patients with HF to examine their sex-specific correlations with measures of physical capacity, quality of life, and daily physical activity. METHODS AND RESULTS: A total of 111 patients with HF underwent dual x-ray absorptiometry, physical capacity tests, and accelerometry and answered a quality-of-life questionnaire. ALM normalized by height squared and ALM/BMI indices disagreed in classifying low muscle mass (Cohen's κ, -0.008 [95% CI, -0.094 to 0.177]; P=0.93). ALM/BMI correlated well with 6-minute walking distance in women and men (R=0.67 and 0.49; P<0.001), with maximal oxygen uptake in women and men (R=0.41 and 0.48; P<0.05), and with maximal muscle strength in women and men (R=0.54 and 0.43; P<0.01). Inversely, ALM normalized by height squared did not correlate significantly with 6-minute walking distance or maximal oxygen uptake and correlated with maximal muscle strength only in men (R=0.43; P<0.001). Only ALM/BMI allowed for identification of a low-muscle-mass group characterized by poor quality of life (Minnesota Living With Heart Failure Questionnaire score of 33±21 versus 25±16; P=0.027) and less daily time spent in moderate to vigorous physical activity (8 [3-17] versus 15 [9-37] minutes; P<0.001). CONCLUSIONS: ALM/BMI was superior for identifying clinically significant muscle dysfunction in both female and male patients with HF.

Lactate infusion elevates cardiac output through increased heart rate and decreased vascular resistance: a randomised, blinded, crossover trial in a healthy porcine model.

BACKGROUND: Lactate is traditionally recognized as a by-product of anaerobic metabolism. However, lactate is a preferred oxidative substrate for stressed myocardium. Exogenous lactate infusion increases cardiac output (CO). The exact mechanism underlying this mechanism has yet to be elucidated. The aim of this study was to investigate the cardiovascular mechanisms underlying the acute haemodynamic effects of exogenous lactate infusion in an experimental model of human-sized pigs. METHODS: In this randomised, blinded crossover study in eight 60-kg-pigs, the pigs received infusions with one molar sodium lactate and a control infusion of tonicity matched hypertonic saline in random order. We measured CO and pulmonary pressures using a pulmonary artery catheter. A pressure-volume admittance catheter in the left ventricle was used to measure contractility, afterload, preload and work-related parameters. RESULTS: Lactate infusion increased circulating lactate levels by 9.9 mmol/L (95% confidence interval (CI) 9.1 to 11.0) and CO by 2.0 L/min (95% CI 1.2 to 2.7). Afterload decreased as arterial elastance fell by  -1.0 mmHg/ml (95% CI  -2.0 to  -0.1) and systemic vascular resistance decreased by  -548 dynes/s/cm5 (95% CI  -261 to  -835). Mixed venous saturation increased by 11 percentage points (95% CI 6 to 16), whereas ejection fraction increased by 16.0 percentage points (95% CI 1.1 to 32.0) and heart rate by 21 bpm (95% CI 8 to 33). No significant changes in contractility nor preload were observed. CONCLUSION: Lactate infusion increased cardiac output by increasing heart rate and lowering afterload. No differences were observed in left ventricular contractility or preload. Lactate holds potential as a treatment in situations with lowered CO and should be investigated in future clinical studies.

Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.

BACKGROUND: Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction. METHODS: In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents. RESULTS: We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1-0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, -2 mm Hg [95% CI, -4 to -1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mm Hg [95% CI, -5 to -1] ) and higher mean CO (0.5 L/min [95% CI, 0.1-0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, -98 ng/L [95% CI, -185 to -23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes. CONCLUSIONS: KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650.

Circulating 3-hydroxy butyrate predicts mortality in patients with chronic heart failure with reduced ejection fraction.

AIMS: In patients with chronic heart failure with reduced ejection fraction (HFrEF), myocardial ketone metabolism is increased and short-term treatment with the ketone body 3-hydroxy butyrate (3-OHB) has beneficial haemodynamic effects. In patients with HFrEF, we investigated whether the level of circulating 3-OHB predicted all-cause mortality and sought to identify correlations between patient characteristics and circulating 3-OHB levels. METHODS AND RESULTS: We conducted a cohort study in 218 patients with HFrEF. Plasma 3-OHB levels were measured using high-performance liquid chromatography tandem mass spectrometry. Data on all-cause mortality were obtained by reviewing the patients' medical records, which are linked to the national 'Central Person Registry' that registers the timing of all deaths in the country. Mean left ventricular ejection fraction was 35 ± 8.6%, mean age was 67 ± 10 years, 54% were New York Heart Association II, and 27% had type 2 diabetes mellitus. Median follow-up time was 7.3 (interquartile range 6.3-8.4) years. We observed large variations in 3-OHB levels between patients (median 59 µM, range: 14-694 µM). Patients with 3-OHB levels above the median displayed a markedly increased risk of death compared with those with low levels {hazard ratio [HR]: 2.1 [95% confidence interval (CI): 1.3-3.5], P = 0.003}. In a multivariate analysis, 3-OHB predicted mortality independently of known chronic heart failure risk factors [HR: 1.004 (95% CI: 1.001-1.007), P = 0.02] and with a similar statistical strength as N-terminal pro-brain natriuretic peptide (NT-proBNP) [HR: 1.0005 (95% CI: 1.000-1.001), P = 0.02]. For every 100 µmol increase in plasma 3-OHB, the hazard of death increased by 49%. The following factors significantly predicted 3-OHB levels in the univariate analysis: free fatty acids (FFAs) [ß: 238 (95% CI: 185-292), P < 0.0001], age [ß: 2.43 (95% CI: 1.14-3.72), P < 0.0001], plasma insulin {ß: -0.28 [95% CI: -0.54-(-0.02)], P = 0.036}, body mass index {ß: -3.15 [95% CI: -5.26-(-0.05)], P = 0.046}, diabetes [ß: 44.49 (95% CI: 14.84-74.14), P = 0.003], glycosylated haemoglobin [ß: 1.92 (95% CI: 0.24-3.59), P = 0.025], New York Heart Association class [ß: 26.86 (95% CI: 5.99-47.72), P = 0.012], and NT-proBNP [ß: 0.03 (95% CI: 0.01-0.04), P = 0.001]. In a multivariate analysis, only FFAs predicted 3-OHB levels [ß: 216 (95% CI: 165-268), P > 0.001]. CONCLUSIONS: In patients with HFrEF, circulating 3-OHB was a strong predictor of all-cause mortality independently of NT-proBNP. Circulating FFAs were the best predictor of 3-OHB levels.

Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasorelaxation and enhanced cardiac contractility.

The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output and myocardial perfusion without affecting blood pressure in humans, but the cardiovascular sites of action remain obscure. Here, we test the hypothesis in rats that 3-OHB acts directly on the heart to increase cardiac contractility and directly on blood vessels to lower systemic vascular resistance. We investigate effects of 3-OHB on (a) in vivo hemodynamics using echocardiography and invasive blood pressure measurements, (b) isolated perfused hearts in Langendorff systems, and (c) isolated arteries and veins in isometric myographs. We compare Na-3-OHB to equimolar NaCl added to physiological buffers or injection solutions. At plasma concentrations of 2-4 mM in vivo, 3-OHB increases cardiac output (by 28.3±7.8%), stroke volume (by 22.4±6.0%), left ventricular ejection fraction (by 13.3±4.6%), and arterial dP/dtmax (by 31.9±11.2%) and lowers systemic vascular resistance (by 30.6±11.2%) without substantially affecting heart rate or blood pressure. Applied to isolated perfused hearts at 3-10 mM, 3-OHB increases left ventricular developed pressure by up to 26.3±7.4 mmHg and coronary perfusion by up to 20.2±9.5%. Beginning at 1-3 mM, 3-OHB relaxes isolated coronary (EC50=12.4 mM), cerebral, femoral, mesenteric, and renal arteries as well as brachial, femoral, and mesenteric veins by up to 60% of pre-contraction within the pathophysiological concentration range. Of the two enantiomers that constitute racemic 3-OHB, D-3-OHB dominates endogenously; but tested separately, the enantiomers induce similar vasorelaxation. We conclude that increased cardiac contractility and generalized systemic vasorelaxation can explain the elevated cardiac output during 3-OHB administration. These actions strengthen the therapeutic rationale for 3-OHB in heart failure management.

Beneficial Effects of Ketone Ester in Patients With Cardiogenic Shock: A Randomized, Controlled, Double-Blind Trial.

BACKGROUND: Cardiogenic shock (CS) is a life-threatening condition with sparse treatment options. The ketone body 3-hydroxybutyrate has favorable hemodynamic effects in patients with stable chronic heart failure. Yet, the hemodynamic effects of exogenous ketone ester (KE) in patients with CS remain unknown. OBJECTIVES: The authors aimed to assess the hemodynamic effects of single-dose enteral treatment with KE in patients with CS. METHODS: In a double-blind, crossover study, 12 patients with CS were randomized to an enteral bolus of KE and isocaloric, isovolumic placebo containing maltodextrin. Patients were assessed with pulmonary artery catheterization, arterial blood samples, echocardiography, and near-infrared spectroscopy for 3 hours following each intervention separated by a 3-hour washout period. RESULTS: KE increased circulating 3-hydroxybutyrate (2.9 ± 0.3 mmol/L vs 0.2 ± 0.3 mmol/L, P < 0.001) and was associated with augmented cardiac output (area under the curve of relative change: 61 ± 22 L vs 1 ± 18 L, P = 0.044). Also, KE increased cardiac power output (0.07 W [95% CI: 0.01-0.14]; P = 0.037), mixed venous saturation (3 percentage points [95% CI: 1-5 percentage points]; P = 0.010), and forearm perfusion (3 percentage points [95% CI: 0-6 percentage points]; P = 0.026). Right (P = 0.048) and left (P = 0.017) ventricular filling pressures were reduced whereas heart rate and mean arterial and pulmonary arterial pressures remained similar. Left ventricular ejection fraction improved by 4 percentage points (95% CI: 2-6 percentage points; P = 0.005). Glucose levels decreased by 2.6 mmol/L (95% CI: -5.2 to 0.0; P = 0.047) whereas insulin levels remained unaltered. CONCLUSIONS: Treatment with KE improved cardiac output, biventricular function, tissue oxygenation, and glycemic control in patients with CS (Treatment With the Ketone Body 3-hydroxybutyrate in Patients With Cardiogenic Shock [KETO-SHOCK1]; NCT04642768).

Stimulation of the Hydroxycarboxylic Acid Receptor 2 With the Ketone Body 3-Hydroxybutyrate and Niacin in Patients With Chronic Heart Failure: Hemodynamic and Metabolic Effects.

Background The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) in patients with heart failure through unknown mechanisms. 3-OHB activates the hydroxycarboxylic acid receptor 2 (HCA2), which increases prostaglandins and suppresses circulating free fatty acids. We investigated whether the cardiovascular effects of 3-OHB involved HCA2 activation and if the potent HCA2-stimulator niacin may increase CO. Methods and Results Twelve patients with heart failure with reduced ejection fraction were included in a randomized crossover study and examined by right heart catheterization, echocardiography, and blood sampling on 2 separate days. On study day 1, patients received aspirin to block the HCA2 downstream cyclooxygenase enzyme, followed by 3-OHB and placebo infusions in random order. We compared the results with those of a previous study in which patients received no aspirin. On study day 2, patients received niacin and placebo. The primary end point was CO. 3-OHB increased CO (2.3 L/min, P<0.01), stroke volume (19 mL, P<0.01), heart rate (10 bpm, P<0.01), and mixed venous saturation (5%, P<0.01) with preceding aspirin. 3-OHB did not change prostaglandin levels, neither in the ketone/placebo group receiving aspirin nor the previous study cohort. Aspirin did not block 3-OHB-induced changes in CO (P=0.43). 3-OHB decreased free fatty acids by 58% (P=0.01). Niacin increased prostaglandin D2 levels by 330% (P<0.02) and reduced free fatty acids by 75% (P<0.01) but did not affect CO. Conclusions The acute increase in CO during 3-OHB infusion was not modified by aspirin, and niacin had no hemodynamic effects. These findings show that HCA2 receptor-mediated effects were not involved in the hemodynamic response to 3-OHB. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04703361.

Hemodynamic Effects of Ketone Bodies in Patients With Pulmonary Hypertension.

Background Pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) are debilitating diseases with a high mortality. Despite emerging treatments, pulmonary vascular resistance frequently remains elevated. However, the ketone body 3-hydroxybutyrate (3-OHB) may reduce pulmonary vascular resistance in these patients. Hence, the aim was to assess the hemodynamic effects of 3-OHB in patients with PAH or CTEPH. Methods and Results We enrolled patients with PAH (n=10) or CTEPH (n=10) and residual pulmonary hypertension. They received 3-OHB infusion and placebo (saline) for 2 hours in a randomized crossover study. Invasive hemodynamic and echocardiography measurements were performed. Furthermore, we investigated the effects of 3-OHB on the right ventricle of isolated hearts and isolated pulmonary arteries from Sprague-Dawley rats. Ketone body infusion increased circulating 3-OHB levels from 0.5±0.5 to 3.4±0.7 mmol/L (P<0.001). Cardiac output improved by 1.2±0.1 L/min (27±3%, P<0.001), and right ventricular annular systolic velocity increased by 1.4±0.4 cm/s (13±4%, P=0.002). Pulmonary vascular resistance decreased by 1.3±0.3 Wood units (18%±4%, P<0.001) with no significant difference in response between patients with PAH and CTEPH. In the rat studies, 3-OHB administration was associated with decreased pulmonary arterial tension compared with saline administration (maximal relative tension difference: 12±2%, P<0.001) and had no effect on right ventricular systolic pressures (P=0.63), whereas pressures rose at a slower pace (dP/dtmax, P=0.02). Conclusions In patients with PAH or CTEPH, ketone body infusion improves cardiac output and decreases pulmonary vascular resistance. Experimental rat studies support that ketone bodies relax pulmonary arteries. Long-term studies are warranted to assess the clinical role of hyperketonemia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04615754.

Prolonged Cardiogenic Shock Due to Hydrogen Sulfide Intoxication Requiring Long-Term Venoarterial Extracorporeal Membrane Support.

We describe a case of severe biventricular failure and cardiovascular collapse following exposure to the manure gas hydrogen sulfide. Initial tests indicated uncoupling of cellular bioenergetics in addition to myocardial damage. Cardiopulmonary support with venoarterial extracorporeal membrane oxygenation was initiated, and the patient could be successfully weaned from support after 28 days. (Level of Difficulty: Advanced.).

Detection of increased pyruvate dehydrogenase flux in the human heart during adenosine stress test using hyperpolarized [1-13C]pyruvate cardiovascular magnetic resonance imaging.

BACKGROUND: Hyperpolarized (HP) [1-13C]pyruvate cardiovascular magnetic resonance (CMR) imaging can visualize the uptake and intracellular conversion of [1-13C]pyruvate to either [1-13C]lactate or 13C-bicarbonate depending on the prevailing metabolic state. The aim of the present study was to combine an adenosine stress test with HP [1-13C]pyruvate CMR to detect cardiac metabolism in the healthy human heart at rest and during moderate stress. METHODS: A prospective descriptive study was performed between October 2019 and August 2020. Healthy human subjects underwent cine CMR and HP [1-13C]pyruvate CMR at rest and during adenosine stress. HP [1-13C]pyruvate CMR images were acquired at the mid-left-ventricle (LV) level. Semi-quantitative assessment of first-pass myocardial [1-13C]pyruvate perfusion and metabolism were assessed. Paired t-tests were used to compare mean values at rest and during stress. RESULTS: Six healthy subjects (two female), age 29 ± 7 years were studied and no adverse reactions occurred. Myocardial [1-13C]pyruvate perfusion was significantly increased during stress with a reduction in time-to-peak from 6.2 ± 2.8 to 2.7 ± 1.3 s, p = 0.02. This higher perfusion was accompanied by an overall increased myocardial uptake and metabolism. The conversion rate constant (kPL) for lactate increased from 11 ± 9 *10-3 to 20 ± 10 * 10-3 s-1, p = 0.04. The pyruvate oxidation rate (kPB) increased from 4 ± 4 *10-3 to 12 ± 7 *10-3 s-1, p = 0.008. This increase in carbohydrate metabolism was positively correlated with heart rate (R2 = 0.44, p = 0.02). CONCLUSIONS: Adenosine stress testing combined with HP [1-13C]pyruvate CMR is feasible and well-tolerated in healthy subjects. We observed an increased pyruvate oxidation during cardiac stress. The present study is an important step in the translation of HP [1-13C]pyruvate CMR into clinical cardiac imaging. Trial registration EUDRACT, 2018-003533-15. Registered 4th of December 2018, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003533-15.

Myocardial efficiency in patients with different aetiologies and stages of heart failure.

AIMS: Myocardial external efficiency (MEE) is the ratio of cardiac work in relation with energy expenditure. We studied MEE in patients with different aetiologies and stages of heart failure (HF) to discover the role and causes of deranged MEE. In addition, we explored the impact of patient characteristics such as sex, body mass index (BMI), and age on myocardial energetics. METHODS AND RESULTS: Cardiac energetic profiles were assessed with 11C-acetate positron emission tomography (PET) and left ventricular ejection fraction (LVEF) was acquired with echocardiography. MEE was studied in 121 participants: healthy controls (n = 20); HF patients with reduced (HFrEF; n = 25) and mildly reduced (HFmrEF; n = 23) LVEF; and patients with asymptomatic (AS-asymp; n = 38) and symptomatic (AS-symp; n = 15) aortic stenosis (AS). Reduced MEE coincided with symptoms of HF irrespective of aetiology and declined in tandem with deteriorating LVEF. Patients with AS-symp and HFmrEF had reduced MEE as compared with controls (22.2 ± 4.9%, P = 0.041 and 20.0 ± 4.2%, P < 0.001 vs. 26.1 ± 5.8% in controls) and a further decline was observed in patients with HFrEF (14.7 ± 6.3%, P < 0.001). Disproportionate left ventricular hypertrophy was a major cause of reduced MEE. Female sex (P < 0.001), a lower BMI (P = 0.001), and advanced age (P = 0.03) were associated with a lower MEE. CONCLUSION: MEE was reduced in patients with HFrEF, HFmrEF, and HF due to pressure overload and MEE may therefore constitute a treatment target in HF. Patients with LVH, advanced age, female sex, and low BMI had more pronounced reduction in MEE and personalized treatment within these patient subgroups could be relevant.

Remodeling after myocardial infarction and effects of heart failure treatment investigated by hyperpolarized [1-13 C]pyruvate magnetic resonance spectroscopy.

PURPOSE: Hyperpolarized [1-13 C]pyruvate MRS can measure cardiac metabolism in vivo. We investigated whether [1-13 C]pyruvate MRS could predict left ventricular remodeling following myocardial infarction (MI), long-term left ventricular effects of heart failure medication, and could identify responders to treatment. METHODS: Thirty-five rats were scanned with hyperpolarized [1-13 C]pyruvate MRS 3 days after MI or sham surgery. The animals were re-examined after 30 days of therapy with ß-blockers and ACE-inhibitors (active group, n = 12), placebo treatment (placebo group, n = 13) or no treatment (sham group, n = 10). Furthermore, heart tissue mitochondrial respiratory capacity was assessed by high-resolution respirometry. Metabolic results were compared between groups, over time and correlated to functional MR data at each time point. RESULTS: At 30 ± 0.5 days post MI, left ventricular ejection fraction (LVEF) differed between groups (sham, 77% ± 1%; placebo, 52% ± 3%; active, 63% ± 2%, P < .001). Cardiac metabolism, measured by both hyperpolarized [1-13 C]pyruvate MRS and respirometry, neither differed between groups nor between baseline and follow-up. Three days post MI, low bicarbonate + CO2 /pyruvate ratio was associated with low LVEF. At follow-up, in the active group, a poor recovery of LVEF was associated with high bicarbonate + CO2 /pyruvate ratio, as measured by hyperpolarized MRS. CONCLUSION: In a rat model of moderate heart failure, medical treatment improved function, but did not on average influence [1-13 C]pyruvate flux as measured by MRS; however, responders to heart failure medication had reduced capacity for carbohydrate metabolism.

A systematic approach to weaning from extracorporeal membrane oxygenation in patients with refractory cardiac failure.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is commonly used to provide haemodynamic support for patients with severe cardiac failure. However, timing ECMO weaning remains challenging. We aimed to examine if an integrative weaning approach based on predefined haemodynamic, respiratory and echocardiographic criteria is associated with successful weaning. METHODS: All patients weaned from ECMO between April 2017 and April 2019 at Aarhus University Hospital, Denmark, were consecutively enrolled. Predefined haemodynamic, respiratory and echocardiographic criteria were assessed before and during ECMO flow reduction. A weaning attempt was commenced in haemodynamic stable patients and patients remaining stable at minimal flow were weaned from ECMO. Comparisons were made between patients who met the criteria for weaning at first attempt and patients who did not meet these criteria. Patients completing a full weaning attempt with no further need for mechanical support within 24 h were defined as successfully weaned. RESULTS: A total of 38 patients were included in the study, of whom 26 (68%) patients met the criteria for weaning. Among these patients, 25 (96%) could be successfully weaned. Successfully weaned patients were younger and had less need for inotropic support and ECMO duration was shorter. Fulfilling the weaning criteria was associated with successful weaning and both favourable 30-d survival and survival to discharge. CONCLUSION: An integrative weaning approach based on haemodynamic, respiratory and echocardiographic criteria may strengthen the clinical decision process in predicting successful weaning in patients receiving ECMO for refractory cardiac failure.

Mitral valvulitis as a severe extra-articular manifestation of rheumatoid arthritis: a case report.

BACKGROUND: Extra-articular manifestations (EAMs) are common in patients with rheumatoid arthritis (RA). Cardiac EAMs are rare but may cause complete heart block and damage to the heart valves. CASE SUMMARY: We present the case of a middle-aged woman with long-standing RA and EAMs as the most prominent symptoms. The patient experienced complete atrioventricular heart block and developed nodular vegetations affecting the mitral valve, ultimately leading to severe mitral regurgitation and valve replacement. DISCUSSION: The diagnosis of cardiac EAMs in RA may be challenging for the clinicians. Symptoms and findings may mimic more common conditions such as malignancy and infectious endocarditis. A multidisciplinary approach is of paramount importance in order to make an early diagnosis and to provide optimal treatment to patients with RA and cardiac complications.

Prognostic impact of self-reported health on clinical outcomes in patients with heart failure.

AIMS: An in-depth understanding of the prognostic value of patient-reported outcomes (PRO) is essential to facilitate person-centred care in heart failure (HF). This study aimed to clarify the prognostic role of subjective mental and physical health status in patients with HF. METHODS AND RESULTS: Patients with HF were identified from the DenHeart Survey (n = 1499) and PRO data were obtained at hospital discharge, including the EuroQol five-dimensional questionnaire (EQ-5D), the HeartQoL, and the Hospital Anxiety and Depression Scale (HADS). Clinical baseline data were obtained from medical records and linked to nationwide registries with patient-level data on sociodemographics and healthcare contacts. Outcomes were all-cause and cardiovascular (CV) mortality, CV events, and HF hospitalization with 1- and 3-year follow-up. Analysing the PRO data on a continuous scale, a worse score in the following were associated with risk of all-cause and CV mortality after 1 year: the HeartQoL (adjusted hazard ratios (HRs) 1.91, 95% confidence interval (CI) 1.42-2.57 and 2.17, 95% CI 1.50-3.15, respectively), the EQ-5D (adjusted HRs 1.26, 95% CI 1.15-1.38 and 1.27, 95% CI 1.13-1.42, respectively), the HADS depression subscale (adjusted HRs 1.12, 95% CI 1.07-1.17 and 1.11, 95% CI 1.05-1.17, respectively), and the HADS anxiety subscale (adjusted HRs 1.08, 95% CI 1.03-1.13 and 1.09, 95% CI 1.04-1.15, respectively). Three-year results were overall in concordance with the 1-year results. A similar pattern was also observed for non-fatal outcomes. CONCLUSION: Health-related quality of life and symptoms of anxiety and depression at discharge were associated with all-cause and CV mortality at 1- and 3-year follow-up.

The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT).

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark. CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

Patient-reported outcomes and medication adherence in patients with heart failure.

AIMS: Patient-reported outcome measures (PROMs) may predict poor clinical outcome in patients with heart failure (HF). It remains unclear whether PROMs are associated with subsequent adherence to HF medication. We aimed to determine whether health-related quality of life, anxiety, and depression were associated with long-term medication adherence in these patients. METHODS AND RESULTS: A national cohort study of Danish patients with HF with 3-year follow-up (n = 1464). PROMs included the EuroQol five-dimensional, five-level questionnaire (EQ-5D-5L), the HeartQoL and the Hospital Anxiety and Depression Scale (HADS). Patient-reported outcomes (PRO) data were linked to demographic and clinical data at baseline, and data on all redeemed prescriptions for angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor neprilysin inhibitors (ACEI/ARB/ARNI), ß-blockers, and mineralocorticoid receptor antagonists during follow-up. Medication non-adherence was defined as <80% of proportion of days covered. In adjusted regression analyses, lower health-related quality of life (EQ-5D and HeartQoL) and symptoms of depression (HADS-D) at discharge were associated with non-adherence. After 3 years of follow-up, lower health-related quality of life (EQ-5D) was associated with non-adherence for ACEI/ARB/ARNI [adjusted OR 2.78, 95% confidence interval (CI): 1.19-6.49], ß-blockers (adjusted OR 2.35, 95% CI: 1.04-5.29), whereas HADS-D was associated with non-adherence for ACEI/ARB/ARNI (adjusted OR 1.07, 95% CI: 1.03-1.11) and ß-blockers (adjusted OR 1.06, 95% CI: 1.02-1.10). CONCLUSION: Lower health-related quality of life and symptoms of depression were associated with non-adherence across HF medications at 1 and 3 years of follow-up. Person-centred care using PROMs may carry a potential for identifying patients at increased risk of future medication non-adherence.