BIO-2-HEART: Identification of Biomarkers in T2DM and Heart Failure

Study Overview
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Brief Summary
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The primary aim of the current study is a better understanding of the role of Type 2 Diabetes Mellitus (T2DM) in heart failure and, in particular, changes in cardiac metabolism, which may contribute to heart failure. Various biomarkers in the coronary artery blood, as well as in the arterial and peripheral venous blood, are to be identified for this purpose. Included are patients with and without T2DM, who have a clinically indicated and guidance-appropriate Cardiac Resynchronisation Therapy (CRT) implantation due to their cardiac insufficiency. Not all patients currently benefit from the implantation of a CRT system (so-called non-responder). Despite narrow inclusion criteria, these non-responders cannot be unmasked in advance of the implantation. A further aim of this study is to identify biomarkers, which can be determined in advance of implantation to differentiate between responders and non-responders.

Detailed Description
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The primary aim of the current study is a better understanding of the role of Type 2 Diabetes Mellitus (T2DM) in heart failure and, in particular, changes in cardiac metabolism, which may contribute to heart failure. Various biomarkers in the coronary artery blood, as well as in the arterial and peripheral venous blood, are to be identified for this purpose. Included are patients with and without T2DM, who have a clinically indicated and guidance-appropriate Cardiac Resynchronisation Therapy (CRT) implantation due to their cardiac insufficiency. Not all patients currently benefit from the implantation of a CRT system (so-called non-responder). Despite narrow inclusion criteria, these non-responders cannot be unmasked in advance of the implantation. Thus, a further aim of this study is to identify biomarkers, which can be determined in advance of implantation to differentiate between responders and non-responders. Patient selection is based on the previously defined inclusion and exclusion criteria. The patient is informed by the physician and gives written consent to participate in the study. Prior to the implantation of the CRT system, the patient first responds to a study-related questionnaire and performs a 6-minute walk test. Afterwards the clinically indicated, elective CRT implantation is performed by experienced physicians of the Medical Clinic I. Routinely, an arterial pressure catheter for invasive blood pressure monitoring (usually arteria radialis) is inserted. In addition, 2 peripheral venous accesses are established. The system of the CRT system is carried out via a small pectoral section. The cardiac probes are inserted into the heart via the subclavian vein. First, the probe is implanted in the right ventricle and, if necessary, a probe is placed in the right atrium. To establish the coronary sinus (CS) probe, the intubation of the coronary sinus is performed by means of a guide catheter, which can be used to take blood samples. After intubation of the coronary sinus, the coronary artery blood is taken from the guide catheter for the study as well as arterially via the underlying pressure catheter as well as peripheral venous over a horizontal venous catheter. The blood sampling does not take more than 1-2 minutes. The surgery is then terminated as planned and postoperative care is performed according to the standard operation procedure (SOP) of the Medical Clinic I. Within the framework of a control visit routinely performed in the Medical Clinic I , an echocardiographic follow-up of heart failure, a history assessment and a laboratory-based blood analysis are performed 6 months after CRT implantation. In the context of this visit peripheral venous blood is collected again for the study. In addition, the 6-minute walk test is performed once more and the patient receives the same questionnaire again. Laboratory routine blood analysis is performed in the central laboratory of the University Hospital of Aachen and is independent of the study. The analysis measures standard parameters such as electrolytes, blood count, retention parameters, glucose, HbA1c, liver values, N-terminal Brain Natriuretic Peptide (NT-pro-BNP) etc. . A blood gas analysis of the study blood is performed out first. The remaining blood is processed and stored at -80 ° C, so-called biobank, for further biomarker analysis, e.g. metabolite analysis, peptides/proteins and RNA.

Official Title
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BIO-2-HEART Study (Identifying New BIOmarkers in Patients With Type 2 Diabetes Mellitus and HEArt Failure Receiving Cardiac Resynchronization Therapy Device Implantation)

Conditions
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Heart Failure, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Diagnostic Test: 6-minute walk test
* Diagnostic Test: Study specific questionnaire
* Procedure: Blood collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: guideline-appropriate clinical indication for CRT implantation age of majority written declaration of consent persons who are able to work and mentally able to follow the instructions of the study staff free access routes Exclusion Criteria: anemia Hb <8 mg / dl patients with acute infectious disease (e.g. pneumonia) non-intubatable coronary sinus patients who do not have access to the subclavian vein (e.g. thrombosis of the subclavian vein or superior vena cava) patients with idiopathic hypertrophic, restrictive or constrictive cardiomyopathy, or heart failure due to a known inflammatory or infiltrating disease (e.g. amyloidosis, sarcoidosis) or a constrictive disease patients with heart failure by sepsis persons with acute myocardial ischaemia, e.g. by angina pectoris or ECG changes under load patients with acute coronary syndrome are not implanted in the past 3 months patients who were hospitalized during the last month due to heart failure and who had to be treated intravenously with diuretics or inotropic substances patients with mechanical aortic valve or tricuspid valve patients with heart transplant. patients with acute liver or renal failure pregnant and lactating women patients placed under an official or judicial order in an institution patients who are in a dependency or employment relationship with the sponsor or auditor taking an investigational medicinal product 30 days before the start of the study

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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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No diabetes<br>Patients without diabetes | Diagnostic Test: 6-minute walk test<br>* The 6-minute walk test is a functional test established in the clinic to assess the performance of a patient. The patient walks continuously for 6 minutes without interruption as far as possible. Breaks, speed changes and running are allowed. Test is performed prior the CRT implantation and 6 months after the CRT implantation.<br>Diagnostic Test: Study specific questionnaire<br>* Study specific questionnaire The questionnaire is performed prior the CRT implantation and 6 months after the CRT implantation.<br>Procedure: Blood collection<br>* Blood collection during surgery: coronary sinus arterial peripheral venous Blood collection 6 months after surgery: - peripheral venous<br>|
| Type 2 diabetes<br>Patients with diagnosis of type 2 diabetes (new/established) | Diagnostic Test: 6-minute walk test<br>* The 6-minute walk test is a functional test established in the clinic to assess the performance of a patient. The patient walks continuously for 6 minutes without interruption as far as possible. Breaks, speed changes and running are allowed. Test is performed prior the CRT implantation and 6 months after the CRT implantation.<br>Diagnostic Test: Study specific questionnaire<br>* Study specific questionnaire The questionnaire is performed prior the CRT implantation and 6 months after the CRT implantation.<br>Procedure: Blood collection<br>* Blood collection during surgery: coronary sinus arterial peripheral venous Blood collection 6 months after surgery: - peripheral venous<br>|
| Prediabetes<br>Patients with an intermediate state of hyperglycemia with glycemic parameters above normal but below the diabetes threshold. | Diagnostic Test: 6-minute walk test<br>* The 6-minute walk test is a functional test established in the clinic to assess the performance of a patient. The patient walks continuously for 6 minutes without interruption as far as possible. Breaks, speed changes and running are allowed. Test is performed prior the CRT implantation and 6 months after the CRT implantation.<br>Diagnostic Test: Study specific questionnaire<br>* Study specific questionnaire The questionnaire is performed prior the CRT implantation and 6 months after the CRT implantation.<br>Procedure: Blood collection<br>* Blood collection during surgery: coronary sinus arterial peripheral venous Blood collection 6 months after surgery: - peripheral venous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen partial pressure (pO2) [mmHg] | Results of blood gas analysis: Oxygen partial pressure (pO2) [mmHg] | Directly prior to the CRT-implantation | 
| Oxygen partial pressure (pO2) [mmHg] | Results of blood gas analysis: Oxygen partial pressure (pO2) [mmHg] | 6 months after CRT-implantation | 
| Carbon dioxide partial pressure (pCO2) [mmHg] | Results of blood gas analysis: Carbon dioxide partial pressure (pCO2) [mmHg] | Directly prior to the CRT-implantation | 
| Carbon dioxide partial pressure (pCO2) [mmHg] | Results of blood gas analysis: Carbon dioxide partial pressure (pCO2) [mmHg] | 6 months after CRT-implantation | 
| potential of hydrogen (pH) value [-] | Results of blood gas analysis: pH value [-] | Directly prior to the CRT-implantation | 
| potential of hydrogen (pH) value [-] | Results of blood gas analysis: pH value [-] | 6 months after CRT-implantation | 
| Base excess [mmol] | Results of blood gas analysis: Base excess [mmol] | Directly prior to the CRT-implantation | 
| Base excess [mmol] | Results of blood gas analysis: Base excess [mmol] | 6 months after CRT-implantation | 
| Lactate [mmol/l] | Results of blood gas analysis: Lactate [mmol/l] | Directly prior to the CRT-implantation | 
| Lactate [mmol/l] | Results of blood gas analysis: Lactate [mmol/l] | 6 months after CRT-implantation | 
| Glucose [mg/dl] | Results of blood gas analysis: Glucose [mg/dl] | Directly prior to the CRT-implantation | 
| Glucose [mg/dl] | Results of blood gas analysis: Glucose [mg/dl] | 6 months after CRT-implantation | 
| Electrolytes (K+, Na2+, Ca2+) [mmol/l] | Results of blood gas analysis: Electrolytes (K+, Na2+, Ca2+) [mmol/l] | Directly prior to the CRT-implantation | 
| Electrolytes (K+, Na2+, Ca2+) [mmol/l] | Results of blood gas analysis: Electrolytes (K+, Na2+, Ca2+) [mmol/l] | 6 months after CRT-implantation | 
| High-sensitive troponin T [µg/L] | Markers of myocardial ischemia and heart failure: High-sensitive troponin T [µg/L] | Directly prior to the CRT-implantation | 
| High-sensitive troponin T [µg/L] | Markers of myocardial ischemia and heart failure: High-sensitive troponin T [µg/L] | 6 months after CRT-implantation | 
| Total creatine kinase [µg/L] | Markers of myocardial ischemia and heart failure: Total creatine kinase [µg/L] | Directly prior to the CRT-implantation | 
| Total creatine kinase [µg/L] | Markers of myocardial ischemia and heart failure: Total creatine kinase [µg/L] | 6 months after CRT-implantation | 
| Creatinine kinase-myocardial band (CK-MB) [µg/L] | Markers of myocardial ischemia and heart failure: Creatinine kinase-myocardial band (CK-MB) [µg/L] | Directly prior to the CRT-implantation | 
| Creatinine kinase-myocardial band (CK-MB) [µg/L] | Markers of myocardial ischemia and heart failure: Creatinine kinase-myocardial band (CK-MB) [µg/L] | 6 months after CRT-implantation | 
| Aspartate aminotransferase [µg/L] | Markers of myocardial ischemia and heart failure: Aspartate aminotransferase [µg/L] | Directly prior to the CRT-implantation | 
| Aspartate aminotransferase [µg/L] | Markers of myocardial ischemia and heart failure: Aspartate aminotransferase [µg/L] | 6 months after CRT-implantation | 
| Lactate dehydrogenase [µg/L] | Markers of myocardial ischemia and heart failure: Lactate dehydrogenase [µg/L] | Directly prior to the CRT-implantation | 
| Lactate dehydrogenase [µg/L] | Markers of myocardial ischemia and heart failure: Lactate dehydrogenase [µg/L] | 6 months after CRT-implantation | 
| N-terminal pro-B-type natriuretic peptide (NT-proBNP) [µg/L] | Markers of myocardial ischemia and heart failure: N-terminal pro-B-type natriuretic peptide (NT-proBNP) [µg/L] | Directly prior to the CRT-implantation | 
| N-terminal pro-B-type natriuretic peptide (NT-proBNP) [µg/L] | Markers of myocardial ischemia and heart failure: N-terminal pro-B-type natriuretic peptide (NT-proBNP) [µg/L] | 6 months after CRT-implantation | 
| High-sensitive C-reactive protein (CRP) [µg/L] | Cytokines and inflammation markers: High-sensitive C-reactive protein (CRP) [µg/L] | Directly prior to the CRT-implantation | 
| High-sensitive C-reactive protein (CRP) [µg/L] | Cytokines and inflammation markers: High-sensitive C-reactive protein (CRP) [µg/L] | 6 months after CRT-implantation | 
| Procalcitonin (PCT) [µg/L] | Cytokines and inflammation markers: Procalcitonin (PCT) [µg/L] | Directly prior to the CRT-implantation | 
| Procalcitonin (PCT) [µg/L] | Cytokines and inflammation markers: Procalcitonin (PCT) [µg/L] | 6 months after CRT-implantation | 
| Interleukin 6 (IL-6) [µg/L] | Cytokines and inflammation markers: Interleukin 6 (IL-6) [µg/L] | Directly prior to the CRT-implantation | 
| Interleukin 6 (IL-6) [µg/L] | Cytokines and inflammation markers: Interleukin 6 (IL-6) [µg/L] | 6 months after CRT-implantation |