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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Diabetes Mellitus, Type 2
• Intervention / Treatment: Procedure: Blood collection; Diagnostic test: 6-minute walk test; Diagnostic test: Study specific questionnaire

Detailed 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.

• Study Type: Observational
• Enrollment (Estimated): 400

Contacts and Locations

• Study Contact: Name: Christina Kalvelage, M. Sc.; Phone Number: 0241 80 36485; Email: ckalvelage@ukaachen.de
• Study Contact Backup: Name: Ben Kappel, MD PhD; Phone Number: 0241 800; Email: bakppel@ukaachen.de

Study Locations

• Germany
  • NRW
    • Aachen, NRW, Germany, 52074
      • Recruiting
      • University Hospital RWTH Aachen
      • Contact: Ben A Kappel, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients with and without heart failure (HFrEF, HFmrEF, HFpEF) plus known status of type 2 diabetes (yes/no)

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
No diabetes; Patients without diabetes	Procedure: Blood collection; Blood collection during surgery: coronary sinus; arterial; peripheral venous Blood collection 6 months after surgery: - peripheral venous; 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.; Diagnostic test: Study specific questionnaire; Study specific questionnaire The questionnaire is performed prior and 6 months after the intervention.
Type 2 diabetes; Patients with diagnosis of type 2 diabetes (new/established)	Procedure: Blood collection; Blood collection during surgery: coronary sinus; arterial; peripheral venous Blood collection 6 months after surgery: - peripheral venous; 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.; Diagnostic test: Study specific questionnaire; Study specific questionnaire The questionnaire is performed prior and 6 months after the intervention.
Prediabetes; Patients with an intermediate state of hyperglycemia with glycemic parameters above normal but below the diabetes threshold.	Procedure: Blood collection; Blood collection during surgery: coronary sinus; arterial; peripheral venous Blood collection 6 months after surgery: - peripheral venous; 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.; Diagnostic test: Study specific questionnaire; Study specific questionnaire The questionnaire is performed prior and 6 months after the intervention.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: RWTH Aachen University
• Investigators: Principal Investigator: Ben Kappel, MD PhD, Uniklinik RWTH Aachen

Publications and helpful links

General Publications

• 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;:
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2018
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: September 26, 2017
• First Submitted That Met QC Criteria: October 23, 2017
• First Posted (Actual): October 26, 2017

Study Record Updates

• Last Update Posted (Actual): May 9, 2024
• Last Update Submitted That Met QC Criteria: May 7, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Heart Failure; Diabetes Mellitus; Diabetes Mellitus, Type 2
• Other Study ID Numbers: 16-132

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No