Metagenomics and Integrative Systems Medicine of Cardiometabolic Diseases
Metagenomics and Integrative Systems Medicine of Cardiometabolic Diseases
Supported by state-of-the-art systems medicine competences including integrative
 computational and functional genomics, the overarching goal of the trial is to investigate
 the impact of qualitative and quantitative changes in the gut microbiota on the pathogenesis
 of cardiometabolic diseases (CMDs) and their associated co-morbidities. A major objective
 will be to translate the clinical and fundamental based discoveries into new diagnosis and
 preventive actions paving the way to novel modes of treatment in the successive stages of CMD
 progression.
Cardiovascular diseases represent a huge medico-economic issue that is supported by public
 health policy. It is linked not only to the high prevalence of these diseases but also the
 associated cost they encounter for. Therefore, it seems rather urgent to create and validate
 tools to predict evolution of this group of disease in order to better take care of patients
 before they enter the more chronic stages which induce increased costs and socioeconomic and
 medical burdens.

 It is now well acknowledged that gut microbiota is modified in some metabolic disease such as
 type-2 diabetes but also in inflammatory diseases. However, gut microbiota is still
 insufficiently explored in cardiovascular disease, although it could represent a useful,
 non-invasive and practical tool in the daily care of patients.

 Investigators aim to deepen the knowledge and characterization of gut microbiota in patients
 going from metabolic diseases such as metabolic syndrome, obesity and type 2 diabetes (which
 are risks factors for cardiovascular diseases) to overt coronary artery diseases (from the
 first event to end stage heart failure). Investigators will use a system medicine approach
 whose aim is to integrate numerous data coming from different technologies (including
 environment, transcriptomics, metabolomics, metagenomics, lipidomics and bioinformatics).
 These integrated approaches are needed to translate basic science findings into clinical
 practice for the benefit of the patients.

 Investigators aim to uncover new microbial signatures that could help diagnose and/or predict
 both the natural evolution of cardiometabolic diseases and the response to treatment.
 Investigators aim to go forward personalized medicine.

 Patients will be approached for enrolment during their hospitalization in the 3 centers
 during the 24-month enrolment phase (WP3). Once the informed consent completed, each patient
 will be assessed for CMD phenotypes including clinical examination, environmental and food
 habit evaluation, blood urine and feces samples. In each group of patients, a sub-sample of
 30 to 50 subjects will be included in one or more advanced phenotyping items. This will
 include whole body composition by absorptiometry (DXA), abdominal visceral fat by
 tomodensitometry, Oral Glucose Tolerance Test (OGTT) (glucose, insulin, incretins),
 subcutaneous fat biopsy, cardiac echocardiography, intima media thickness, pulse wave
 velocity. For the obese patients undergoing bariatric surgery: liver and subcutaneous and
 omental adipose tissue biopsies will be obtained during surgery.

 This group of patient will be followed at 3, 6 and 12 months after their surgery and will
 have the same examination as mentioned above.
Inclusion criteria :

 Group 1 : metabolic syndrome As defined by the IDF

 -  Central obesity: defined as waist circumference > 94 cm for European men and > 80 cm
 for European women (with knowledge on ethnicity for other groups)

 -  plus 2 of the following criteria out of 4:

 -  Elevated blood pressure with systolic ≥ 130 mmHg and/or diastolic ≥85 mmHg (or
 patients receiving anti-hypertensive drug treatment)

 -  Triglycerides ≥1.50mg/dl (1.71mmol/l) (or patients receiving drug treatment for
 elevated triglycerides)

 -  HDL-c<40mg/dl (1.03 mmol/l) in males or HDL-c<50mg/dl (1.29mmol/l) in females (or
 patients receiving drug treatment that reduces HDL-c)

 -  Elevated fasting glucose: Glycemia ≥100mg/dl

 -  Aged 18 to 75 years old

 To avoid overlapping with the other groups (in particular group III): only patients with
 normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and/or impaired fasting
 glucose (IFG) and an HbA1c < 6.5 % will be included in this group.

 Group II: severely Obese patients

 -  Aged 18 to 75 years old

 -  BMI ≥35kg/m²

 -  Half of the effective will be standard obese patients (150 in Paris and 150 in
 Leipzig)

 -  Half of the effective will be patients candidate to a bariatric surgery either Sleeve
 gastrectomy or Roux-en-Y bypass (with the following clinical conditions: according to
 European and national guidelines for obesity surgery):

 -  BMI ≥40 kg/m² or

 -  BMI ≥35kg/m² with at least 1 obesity-related comorbidity (Hypertension,
 dyslipidemia, obstructive sleep apnea, joints disease and even type 2
 diabetes).those can have past history of coronary diseases.

 These patients will be followed during the first year after surgery. The clinical and
 research investigation time points will be 3, 6 and 12 months after the surgery.

 Group 3: type 2 diabetes

 Patients with known type 2 diabetes ie:

 -  Fasting plasma glucose (FPG) ≥7 mM (=1.26g/l) without treatment or Patients with HbA1c
 ≥ 6.5% (48 mmol/mol) without treatment or Patients treated with any anti diabetic
 agent whatever the HbA1c level at the day of the study <10%

 -  BMI ≥ 25kg/m²

 -  No symptomatic CAD and previous CVD events

 -  with all stages of albuminuria

 -  Aged 18-75 years old

 Group 4

 - Aged 18-75 years ACS without persistent ST elevation (ST-) Or ACS with persistent ST
 elevation (STEMI)

 Group 5

 -  Aged 18-75 years

 -  Stable CAD is defined by

 -  CAD:ie (Previous documented ACS or previous coronary dilatation >6 months or previous
 planned PCI showing a significant CAD (coronary stenosis > 30 % in at least on major
 coronary artery) leading or not to a PCI / stent implantation) and Stable ie:
 (previous surgical coronary revascularization (CABG > 6 month) or no symptoms or
 stable angina for 6 months and Without heart failure ie: (Left ventricular ejection
 fraction ≥ 45 %)

 Group 6 Part of this group will be recruited during or immediately after a hospitalization
 for acute heart failure and Another part of the group will be at the stage in chronic heart
 failure with no recent acute event (no acute decompensation < 3 month)

 chronic Cardiac disease :ie Duration of chronic heart failure > 6 months, or NYHA 2-4 or
 past history of clinical insufficiency decompensation or CHF due to LV systolic dysfunction
 (LV ejection fraction < 45 %) and Past history of ACS and /or documented CAD ie (stenosis >
 30 % in > 1 coronary artery or previous revascularization >6months) and Aged 18 to 75 years
 old

 Group 7 Half of this group will be recruited during or immediately after a hospitalization
 for acute heart failure (< 1 month) and half in chronic stable heart failure (no acute
 decompensation < 3 month) chronic cardiac disease non ischemic ie: (Documented coronary
 angiogram showing non-significant CAD) cardiac insufficiency ie: (LV ejection fraction < 45
 %, or NYHA 2-4 or past history of clinical insufficiency decompensation) and No valvular
 etiology and No symptoms and no angina and Aged 18 to 75 years old Group 8

 -  Age and sex matched to the patients cohorts

 -  Lean (19kg/m² < BMI <25 kg/m²)

 -  Aged 18 to 75 years old

 Exclusion criteria :

 Definitive exclusion criteria:

 -  <18 or >75 years old

 -  Past history of abdominal cancer+/- radiation therapy on the abdomen

 -  past history of intestinal resection except for appendicectomy

 -  Participants with acute or chronic inflammatory or infectious diseases (including VHC,
 VHB and HIV)

 -  Organ transplantation

 -  Patient on Immunosuppressive therapy

 -  Patients with severe kidney failure and or patients on dialysis therapy or eGFR < 50
 ml/min per 1.73 m2 body surface area)

 -  Non affiliated to social security

 -  Patients who do not understand the research procedures or those that are
 institutionalized, or those unable to give informed consent

 -  Patients who decline participation

 -  Patients with drug or alcohol addiction

 Temporary exclusion criteria:

 -  Recent lost of weight >10 kilos in the past 3 months

 -  Recent antibiotic treatment (<2months)

 -  Patients on non-steroid anti-inflammatory treatment for the past 48 hours

 -  Patients on laxative therapy that could modify the bowel transit in the past week

 -  Patients on therapy that can modify transit time (orlistat and acarbose)

 -  Pregnant women or breast feeding women

 -  Patients who are already included in a clinical study which implies testing any
 pharmaceutical drug. On the other hand, patients recruited in other observational
 studies can be recruited in METACARDIS

 Specific exclusion criteria per group Group I : Type-2 diabetic patients or patients on
 anti-diabetic agent Clinical signs of CAD Past history of coronary syndrome

 Group II : Obese

 IIa:

 Type 2 diabetic patients Past history of coronary syndrome Clinical signs of CAD

 IIb:

 Patients with previous bariatric surgery

 Group III Past history of coronary syndrome Clinical signs of CAD Known auto-immune
 diabetes mellitus Patients with a HbA1c > 10 % We will exclude secondary diabetes mellitus
 or type 1 or Idiopathic diabetes or Other specific types of diabetes Genetic defects of the
 β-cell or Genetic defects in insulin action or Diseases of the exocrine pancreas or
 Endocrinopathies or Drug- or chemical-induced diabetes or diabetes due to pancreatic
 resection

 Group IV Past history of coronary syndrome Left ventricular dysfunction FeVG<45%

 Group V Left ventricular dysfunction FeVG<45%

 Group VII Significant documented CAD Past history of coronary syndrome

 Group VIII Patients with known chronic inflammatory diseases Patients with either type 2
 diabetes, cardiovascular diseases, Patients with treatment for dyslipidemia or for
 hypertension Patients with chronic inflammatory diseases, Patients with diseases of the
 gastrointestinal tract, including prior major abdominal surgery on the gastrointestinal
 tract Patients on non-steroid anti-inflammatory treatment or after a wash-up period of 2
 days