eMESH Struct. 2022-23

Study Overview
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Brief Summary
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A flexible energy metabolism matched with the contractile needs of the muscle is essential to a normal heart. Loss of metabolic flexibility and cardiac systolic efficiency coexist in Sepsis-induced Myocardial Dysfunction (SIMD), a phenomenon attributed to mitochondrial dysfunction and mishandling of energy substrates. Cardiac positron emission tomography (PET) could allow to quantify non invasively the selection of energy substrates by the hearts in sepsis and will be associated in parallel with functional status (ultrasound cardiography), injury biomarkers, apelinergic and metabolomic blood profiles. Comparisons will be performed between septic and acute on chronic heart failures, with or without systolic dysfunction.

Detailed Description
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Septic shock is both highly prevalent and morbid in the intensive care units. The mortality rate rises from 10-30% to 70-80% with sepsis-induced myocardial dysfunction (SIMD) occurence. SIMD is related to stress-induced cardiomyopathies and features bio-mechanistic components distinctive from chronic heart failure (CHF) traditionally attributed to a coronary disease. Dobutamine, a beta-adrenergic receptor agonist, is the inotrope drug actually recommended when cardiac index is too low, often in association with a mix of alpha-beta-adrenergic agonists like norepinephrine. In this context, dobutamine is marginally effective (1/3 responders), has potential deleterious impacts on function and viability of cardiomyocytes, and induces increased needs in cardiac energy metabolism. The healthy heart works almost exclusively on aerobic metabolism. While glucose is the essential fuel for brain and skeletal muscles, fatty acids through lipid oxidation are the main substrates for a normal resting heart (Randle cycle). This lipid oxidation is producing at least 70% of cardiac ATP, the balance is coming from glucose, with a marginal contribution from ketone bodies and lactate. The mitochondria is a cellular factory which produces more than 95% of body ATP. Mitochondria represent 30-40% of the cardiomyocyte total volume and consume oxygen to generate huge quantities of ATP/day by oxidative phosphorylation through 3 connective pathways: cytoplasmic glycolysis, Krebs cycle, and the mitochondrial electron transport chain inside the respiratory enzymes complex. Although a direct close relationship between myocardial metabolism homeostasis and function is not clearly established in normal condition, a compensatory equilibrium between fatty acid and glucose mitochondrial oxidations is a generally accepted concept. Indeed, the heart is omnivorous and can modulate fuel-substrates captation/utilization according to the physiological events (exercise, fast).That reprogramming capacity towards other various circumstances or pathological conditions is not guaranteed, with potential loss of metabolic flexibility. SIMD is highly prevalent in septic shock and is frequently indicative of a worsened outcome with increased mortality. Left ventricular systolic and diastolic dysfunctions are observed in 50% of acute sepsis within the first 48 hours after patient's admission. Animal experimental models can simulate human sepsis and SIMD by injecting endotoxin (LPS model) or feces in the abdominal cavity (cecal ligation puncture model), and with inflammatory cytokines, oxidative stress, nitric oxide and neutrophils as potential aggressors. Ventriculo-arterial and excitation-contraction decoupling are the hallmark of the contractile inefficiency observed in SIMD. Ca2+ handling (an ion molecule essential for heart function) in aberrant during sepsis and associated with impaired activation/phosphorylation and proteolytic cleavage increased of key regulators like heart troponin I. Resulting common cyto-histopathological damages are: myocardial apoptosis with focal necrosis, cardiac muscle edema, congestion, multiples inflammatory infiltrates, and mitochondrial structural insults with intra-myocardial accumulation of glycogen & lipids. The lathers could be a spillover effect of the cardiac metabolic shut-down consecutive to mitochondrial dysfunction. A decrease in fatty acid captation/oxidation has been documented in traditional CHF, not always offset by an enhanced use of glucose, but sometimes by an increased use of ketone bodies and lactates, and through an elevated myocardial proteolysis. This observation doesn't necessarily apply to sepsis and SIMD where cardiac energy metabolism is still a mystery. Systemic metabolic alterations in sepsis are complexe, with glycogenolysis and gluconeogenesis activations, insulinoresistance, and an increased lipolysis with enhanced fatty acid blood levels. In these conditions and in the heart, a drop of fatty acid oxidation is not necessarily compensated by an increased glucose use. Different denominations have been used to figure out these SIMD-induced metabolism disorders, the best being metabolic-bioenergetic shut-down and stunning. In fact, sepsis induces a metabolic hurricane in bloodstream, vital organs and mitochondria, resulting in a significant rise of the rest energy expenditure. Dhainaut et al were first to demonstrate in 1987 a shift in the selection of energy fuels by myocardial tissues in septic shock patients. Both fatty acid and glucose uses were diminished by 4 and 2 times, respectively. However, this study addressed to suboptimally fluid resuscitated patients, who were in early acute hyperdynamic shock (< 6 hours). In experimental mouse models challenged with LPS or cecal ligation puncture, and adequate fluid resuscitation, the cardiac microperfusion is altered (i.e. malperfusion), and mitochondrial oxidative metabolism diminished, with an increase of glucose myocardial uptake. The apelin system is a family of endogenous peptides hormones (the apelins), not related to catecholamines, but with strong cardiovascular properties. This functional impact correlates with the constitutive expression of apelins and their receptor APJ in heart and vessels. Cardiac effects of apelins are characterized by an enhanced contractile force (systolic function), without chronotropic but with a lusitropic effect and a dromo-modulation. Another one impact of the apelins is on the cardiac utilization of metabolic energy substrates. Apelins are facilitators-influencers glucose and fatty acid usage through recruitment of major specific carriers such as GLUT4 and FAT/CD36. Research investigations: Which energy source is privileged by cardiac mitochondria in acute septic shock with or without myocardial dysfunction vs non-septic CHF ? Is this tentative shift/move of energy substrate's use related to muscle dysfunction or only reactive to the systemic environment ? and is it specific of sepsis or common to any non-specific myocardial damage ? Is this shift related to a particular biophenotype of the apelinergic system which is involved in the cardiovascular homeostasis ? and/or a distinctive alteration of the cardiac injury biomarkers ? Is the systemic environmental metabolomic affected toward a trending way during acute septic shock ? Hypotheses: A myocardial positron emission tomography (PET) could allow to visualize and quantify non invasively energy supply selection of hearts in acute shock conditions related or not related to sepsis. Relationships can be found between PET profiles, sources of acute shock (sepsis vs non sepsis), functional data (ultrasound cardiography), cardiac injury specific biomarkers, apelinergic and metabolomic blood profiles. Objectives: 1) To show the analytical value of the cardiac captation kinetic of 3 energy tracers (palmitate for fatty acids, FDG for glucose and acetate fpr mitochondrial activity), 2) To correlate PET data with myocardial (dys)function observed by US cardiography, 3) To evaluate the patients blood metabolomic profile in terms of products accumulation derived from a failure of energy substrates oxidation, 4) To measure and compare myocardial injury/ remodelling biomarkers (troponins, NT-proBNP, galectin-3) and the systemic endogenous apelin biophenotype. Methods: 1) Prospective evaluative study of 4 groups of 8 patients in septic shock or in acute heart failure under hemodynamic support: i) a group with evidences of SIMD (US cardiography at the ICU ward in the first 48hrs: systolic ejection fraction < 45%), ii) a group in septic shock without evidence of SIMD, iii) a group with non-septic heart failure (systolic ejection fraction < 45% or cardiac insufficiency with reduced ejection fraction, iv) a group with non-septic (systolic ejection fraction < 50% or cardiac insufficiency with reduced ejection fraction.

Official Title
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Energy MEtabolism of Septic Heart.

Conditions
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Septic Shock, Chronic Heart Failure

Intervention / Treatment
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* Diagnostic Test: ultrasound cardiography
* Diagnostic Test: FDG PET scan
* Diagnostic Test: Palmitate PET scan
* Diagnostic Test: Acetate PET scan
* Diagnostic Test: Blood sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients hospitalized in intensive care unit and coronary unit of the Sherbrooke hospital/CHUS. Accepts healthy volunteers: 4 to 6 age- and sex-matched HV will be recruited and imaged at the end of the inclusion window for the assessment of cardiac energy tracer's uptake and as ref. controls. Exclusion Criteria: Pediatric patients Albumin allergy Moribund patients Patients too much unstable for the imaging procedure (clinical judgment) Unavailable tracers, staff, PET scan in a maximum delay of 72 hours

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Septic shock with SIMD: SIMD+<br>8 patients in septic shock (Sepsis-3-) with SIMD: ejection fraction (LVEF) < 45% in the first 48 hours of admission into the intensive care unit. No prior cardiac ultrasound or normal cardiac ultrasound values less than 2 years ago , or an ino-vasotropic infusion (milrinone, dobutamine, norepinephrine or epinephrine) required to obtain a LVEF ≥ 45%, or a drop of ≥ 20% compared to the LVEF value record ed less than 2 years ago. | Diagnostic Test: ultrasound cardiography<br>* Ultrasound to check heart functions and systolic ejection fraction.<br>Diagnostic Test: FDG PET scan<br>* FDG venous injection and positron emission tomography scan.<br>* Other names: FDG positron emission tomography;Diagnostic Test: Palmitate PET scan<br>* C11-Palmitate venous injection and positron emission tomography scan.<br>* Other names: Palmitate positron emission tomography;Diagnostic Test: Acetate PET scan<br>* C11-Acetate venous injection and positron emission tomography scan.<br>* Other names: Acetate positron emission tomography;Diagnostic Test: Blood sampling<br>* Collecting 20ml of venous blood.<br>* Other names: Collecting blood sample;|
| Septic shock without SIMD: SIMD-<br>8 patients in septic shock (Sepsis-3) without SIMD. Ejection fraction (LVEF) ≥ 45% with or without ino-vasotropic infusion (milrinone, dobutamine, norepinephrine or epinephrine), or similar to the LVEF recorded less than 2 years ago. | Diagnostic Test: ultrasound cardiography<br>* Ultrasound to check heart functions and systolic ejection fraction.<br>Diagnostic Test: FDG PET scan<br>* FDG venous injection and positron emission tomography scan.<br>* Other names: FDG positron emission tomography;Diagnostic Test: Palmitate PET scan<br>* C11-Palmitate venous injection and positron emission tomography scan.<br>* Other names: Palmitate positron emission tomography;Diagnostic Test: Acetate PET scan<br>* C11-Acetate venous injection and positron emission tomography scan.<br>* Other names: Acetate positron emission tomography;Diagnostic Test: Blood sampling<br>* Collecting 20ml of venous blood.<br>* Other names: Collecting blood sample;|
| Acute Heart Failure with reduced Ejection Fraction: HFrEF<br>8 patients with acutely reduced ejection fraction (LVEF) < 50%. with or without ino-vasotropic infusion (milrinone, dobutamine, norepinephrine or epinephrine) No prior cardiac ultrasound, or normal cardiac ultrasound values less than 2 years ago, or a drop of ≥ 20% compared to the LVEF recorded less than 2 years ago. No evidence of sepsis or septic shock. | Diagnostic Test: ultrasound cardiography<br>* Ultrasound to check heart functions and systolic ejection fraction.<br>Diagnostic Test: FDG PET scan<br>* FDG venous injection and positron emission tomography scan.<br>* Other names: FDG positron emission tomography;Diagnostic Test: Palmitate PET scan<br>* C11-Palmitate venous injection and positron emission tomography scan.<br>* Other names: Palmitate positron emission tomography;Diagnostic Test: Acetate PET scan<br>* C11-Acetate venous injection and positron emission tomography scan.<br>* Other names: Acetate positron emission tomography;Diagnostic Test: Blood sampling<br>* Collecting 20ml of venous blood.<br>* Other names: Collecting blood sample;|
| Acute Heart Failure with preserved Ejection Fraction: HFpEF<br>8 patients with acute heart failure and a preserved ejection fraction (ejection fraction (LVEF ≥ 50% or similar to normal cardiac ultrasound values recorded less than 2 years ago). No evidence of septic shock. | Diagnostic Test: ultrasound cardiography<br>* Ultrasound to check heart functions and systolic ejection fraction.<br>Diagnostic Test: FDG PET scan<br>* FDG venous injection and positron emission tomography scan.<br>* Other names: FDG positron emission tomography;Diagnostic Test: Palmitate PET scan<br>* C11-Palmitate venous injection and positron emission tomography scan.<br>* Other names: Palmitate positron emission tomography;Diagnostic Test: Acetate PET scan<br>* C11-Acetate venous injection and positron emission tomography scan.<br>* Other names: Acetate positron emission tomography;Diagnostic Test: Blood sampling<br>* Collecting 20ml of venous blood.<br>* Other names: Collecting blood sample;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FDG PET scan | Positron emission tomography with FDG radiotracer. It will report the glucose uptake by the heart. | 25 minutes | 
| Palmitate PET scan | Positron emission tomography with C11-palmitate radiotracer. It will report the fatty acid uptake by the heart. | 15 minutes | 
| Acetate PET scan | Positron emission tomography with C11-acetate radiotracer. It will report the acetate uptake by the heart. | 10 minutes | 
| Quantitative study of blood FDG:palmitate balance. | Measure of the blood FDG:palmitate balance by spectroscopy LC-MS and NMR. | 20 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure of myocardial injury biomarkers. | Measure of blood myocardial injury biomarkers by immuno-enzymatic methods (Troponin T, NT-pro BNP, Galectin 3 | 45 minutes | 
| Measure of apelinergics. | Measure of blood apelinergics (apelin-13 ,apelin-17, apelin-36 and ELABELA) by immuno-enzymatic methods. | 45 minutes | 
| Profiling of the systemic metabolomic. | Profiling of the systemic (blood) metabolomic by LC-MS and NMR. It will report metabolites in blood such as acetate, acetoacetate, acetone, 3-OH-butyrate, citrate, glutamate, lactate and pyruvate. | 45 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic shock, Heart dysfunction, Positron emission tomography, Energy substrates (glucose, fatty acid, acetate), Mitochondrial activity