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

Heart Failure Clinical Trial

— BIO-2-HEART  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03323216
• Other study ID #: 16-132
• Status: Recruiting
• Start date: April 1, 2018
• Est. completion date: December 31, 2026

Study information

• Verified date: May 2024
• Source: RWTH Aachen University
• Contact: Ben Kappel, MD PhD
• Phone: 0241 800
• Email: bakppel[@]ukaachen.de
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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 and with or without heart failure (HFpEF, HFmrEF, HFrEF), who have a clinically indicated and guidance-appropriate Cardiac Resynchronisation Therapy (CRT) implantation or pulmonary vein ablation/electrophysiological examination.

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.

Description:

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 and patients who have a clinically indicated electrophysiological examination (EPU) or pulmonary vein ablation (PVI).

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 electrophysiological examination(EPU)/pulmonary vein ablation(PVI), the patient first responds to a study-related questionnaire and performs a 6-minute walk test.

Afterwards the clinically indicated, elective CRT implantation/EPU/PVI 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. For EPU/PVI a femoral vein acsess is established.

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. During EPU/PVI the coronary sinus has also to be intubated due to the ablation protocol. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. guideline-appropriate clinical indication for CRT implantation/electrophysiologial examination/pulmonary vein ablation

2. age of majority

3. written declaration of consent

4. persons who are able to work and mentally able to follow the instructions of the study staff

5. free access routes

Exclusion Criteria:

1. anemia Hb <8 mg / dl

2. patients with acute infectious disease (e.g. pneumonia)

3. non-intubatable coronary sinus

4. patients who do not have access to the subclavian vein (e.g. thrombosis of the subclavian vein or superior vena cava)

5. 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

6. patients with heart failure by sepsis

7. persons with acute myocardial ischaemia, e.g. by angina pectoris or ECG changes under load

8. patients with acute coronary syndrome are not implanted in the past 3 months

9. patients who were hospitalized during the last month due to heart failure and who had to be treated intravenously with diuretics or inotropic substances

10. patients with mechanical aortic valve or tricuspid valve

11. patients with heart transplant.

12. patients with acute liver or renal failure

13. pregnant and lactating women

14. patients placed under an official or judicial order in an institution

15. patients who are in a dependency or employment relationship with the sponsor or auditor

16. taking an investigational medicinal product 30 days before the start of the study

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Heart Failure

Intervention

Diagnostic Test:
• 6-minute walk test
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 intervention and 6 months after the intervention.
• Study specific questionnaire
Study specific questionnaire The questionnaire is performed prior and 6 months after the intervention.

Procedure:
• Blood collection
Blood collection during surgery: coronary sinus arterial peripheral venous Blood collection 6 months after surgery: - peripheral venous

Locations

Country	Name	City	State
Germany	University Hospital RWTH Aachen	Aachen	NRW

Sponsors (1)

Lead Sponsor	Collaborator
RWTH Aachen University

Country where clinical trial is conducted

Germany, 

References & Publications (10)

Askoxylakis V, Thieke C, Pleger ST, Most P, Tanner J, Lindel K, Katus HA, Debus J, Bischof M. Long-term survival of cancer patients compared to heart failure and stroke: a systematic review. BMC Cancer. 2010 Mar 22;10:105. doi: 10.1186/1471-2407-10-105. — View Citation

Bahtiyar G, Gutterman D, Lebovitz H. Heart Failure: a Major Cardiovascular Complication of Diabetes Mellitus. Curr Diab Rep. 2016 Nov;16(11):116. doi: 10.1007/s11892-016-0809-4. — View Citation

Bergman BC, Tsvetkova T, Lowes B, Wolfel EE. Myocardial glucose and lactate metabolism during rest and atrial pacing in humans. J Physiol. 2009 May 1;587(Pt 9):2087-99. doi: 10.1113/jphysiol.2008.168286. Epub 2009 Mar 16. — View Citation

Costello-Boerrigter LC, Lapp H, Boerrigter G, Lerman A, Bufe A, Macheret F, Heublein DM, Larue C, Burnett JC Jr. Secretion of prohormone of B-type natriuretic peptide, proBNP1-108, is increased in heart failure. JACC Heart Fail. 2013 Jun;1(3):207-12. doi: 10.1016/j.jchf.2013.03.001. Epub 2013 Jun 3. — View Citation

Kappel BA, Marx N, Federici M. Oral hypoglycemic agents and the heart failure conundrum: Lessons from and for outcome trials. Nutr Metab Cardiovasc Dis. 2015 Aug;25(8):697-705. doi: 10.1016/j.numecd.2015.06.006. Epub 2015 Jun 18. — View Citation

Marques FZ, Vizi D, Khammy O, Mariani JA, Kaye DM. The transcardiac gradient of cardio-microRNAs in the failing heart. Eur J Heart Fail. 2016 Aug;18(8):1000-8. doi: 10.1002/ejhf.517. Epub 2016 Apr 12. — View Citation

Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 Jul 14;37(27):2129-2200. doi: 10.1093/eurheartj/ehw128. Epub 2016 May 20. No abstract available. Erratum In: Eur Heart J. 2016 Dec 30;: — View Citation

Sun H, Guan Y, Wang L, Zhao Y, Lv H, Bi X, Wang H, Zhang X, Liu L, Wei M, Song H, Su G. Influence of diabetes on cardiac resynchronization therapy in heart failure patients: a meta-analysis. BMC Cardiovasc Disord. 2015 Mar 21;15:25. doi: 10.1186/s12872-015-0018-0. — View Citation

Truong QA, Januzzi JL, Szymonifka J, Thai WE, Wai B, Lavender Z, Sharma U, Sandoval RM, Grunau ZS, Basnet S, Babatunde A, Ajijola OA, Min JK, Singh JP. Coronary sinus biomarker sampling compared to peripheral venous blood for predicting outcomes in patients with severe heart failure undergoing cardiac resynchronization therapy: the BIOCRT study. Heart Rhythm. 2014 Dec;11(12):2167-75. doi: 10.1016/j.hrthm.2014.07.007. Epub 2014 Jul 8. — View Citation

Watson CJ, Ledwidge MT, Phelan D, Collier P, Byrne JC, Dunn MJ, McDonald KM, Baugh JA. Proteomic analysis of coronary sinus serum reveals leucine-rich alpha2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure. Circ Heart Fail. 2011 Mar;4(2):188-97. doi: 10.1161/CIRCHEARTFAILURE.110.952200. Epub 2011 Jan 31. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Oxygen partial pressure (pO2) [mmHg]	Results of blood gas analysis: Oxygen partial pressure (pO2) [mmHg]	Directly prior to the CRT-implantation
Primary	Oxygen partial pressure (pO2) [mmHg]	Results of blood gas analysis: Oxygen partial pressure (pO2) [mmHg]	6 months after CRT-implantation
Primary	Carbon dioxide partial pressure (pCO2) [mmHg]	Results of blood gas analysis: Carbon dioxide partial pressure (pCO2) [mmHg]	Directly prior to the CRT-implantation
Primary	Carbon dioxide partial pressure (pCO2) [mmHg]	Results of blood gas analysis: Carbon dioxide partial pressure (pCO2) [mmHg]	6 months after CRT-implantation
Primary	potential of hydrogen (pH) value [-]	Results of blood gas analysis: pH value [-]	Directly prior to the CRT-implantation
Primary	potential of hydrogen (pH) value [-]	Results of blood gas analysis: pH value [-]	6 months after CRT-implantation
Primary	Base excess [mmol]	Results of blood gas analysis: Base excess [mmol]	Directly prior to the CRT-implantation
Primary	Base excess [mmol]	Results of blood gas analysis: Base excess [mmol]	6 months after CRT-implantation
Primary	Lactate [mmol/l]	Results of blood gas analysis: Lactate [mmol/l]	Directly prior to the CRT-implantation
Primary	Lactate [mmol/l]	Results of blood gas analysis: Lactate [mmol/l]	6 months after CRT-implantation
Primary	Glucose [mg/dl]	Results of blood gas analysis: Glucose [mg/dl]	Directly prior to the CRT-implantation
Primary	Glucose [mg/dl]	Results of blood gas analysis: Glucose [mg/dl]	6 months after CRT-implantation
Primary	Electrolytes (K+, Na2+, Ca2+) [mmol/l]	Results of blood gas analysis: Electrolytes (K+, Na2+, Ca2+) [mmol/l]	Directly prior to the CRT-implantation
Primary	Electrolytes (K+, Na2+, Ca2+) [mmol/l]	Results of blood gas analysis: Electrolytes (K+, Na2+, Ca2+) [mmol/l]	6 months after CRT-implantation
Primary	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
Primary	High-sensitive troponin T [µg/L]	Markers of myocardial ischemia and heart failure: High-sensitive troponin T [µg/L]	6 months after CRT-implantation
Primary	Total creatine kinase [µg/L]	Markers of myocardial ischemia and heart failure: Total creatine kinase [µg/L]	Directly prior to the CRT-implantation
Primary	Total creatine kinase [µg/L]	Markers of myocardial ischemia and heart failure: Total creatine kinase [µg/L]	6 months after CRT-implantation
Primary	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
Primary	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
Primary	Aspartate aminotransferase [µg/L]	Markers of myocardial ischemia and heart failure: Aspartate aminotransferase [µg/L]	Directly prior to the CRT-implantation
Primary	Aspartate aminotransferase [µg/L]	Markers of myocardial ischemia and heart failure: Aspartate aminotransferase [µg/L]	6 months after CRT-implantation
Primary	Lactate dehydrogenase [µg/L]	Markers of myocardial ischemia and heart failure: Lactate dehydrogenase [µg/L]	Directly prior to the CRT-implantation
Primary	Lactate dehydrogenase [µg/L]	Markers of myocardial ischemia and heart failure: Lactate dehydrogenase [µg/L]	6 months after CRT-implantation
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Procalcitonin (PCT) [µg/L]	Cytokines and inflammation markers: Procalcitonin (PCT) [µg/L]	Directly prior to the CRT-implantation
Primary	Procalcitonin (PCT) [µg/L]	Cytokines and inflammation markers: Procalcitonin (PCT) [µg/L]	6 months after CRT-implantation
Primary	Interleukin 6 (IL-6) [µg/L]	Cytokines and inflammation markers: Interleukin 6 (IL-6) [µg/L]	Directly prior to the CRT-implantation
Primary	Interleukin 6 (IL-6) [µg/L]	Cytokines and inflammation markers: Interleukin 6 (IL-6) [µg/L]	6 months after CRT-implantation