Early signs of myocardial systolic dysfunction in patients with type 2 diabetes are strongly associated with myocardial microvascular dysfunction independent of myocardial fibrosis: a prospective cohort study.

"Declarations Ethics approval and consent to participateThe study complied with the declaration of Helsinki and the study was approved by the local ethics committee of Region Zealand (SJ-490). All participants provided both oral and written informed consent before enrolment; the full description of the study design has been registered on clinicaltrials.gov (NCT02684331). Consent for publicationNot applicable. Competing interestsNo potential conflicts of interest relevant to this article were reported. Competing interests No potential conflicts of interest relevant to this article were reported."

"Funding This study received funding and assistance from the local research foundation at NSR Hospital, the research foundation of region Zealand, and the Danish Heart Association. All founding was received as unrestricted grants. The funders did not contribute to the design, analysis, or interpretation of the study results."

"Our study protocol has been detailed before [, ]. In short, the study was a prospective cross-sectional study of 296 patients with a confirmed diagnosis of type 2 diabetes. The study was registered at www.clinicaltrials.gov (unique identifier NCT02684331). All patients were recruited from the outpatient clinic at Naestved-Slagelse-Ringsted Hospital Department of Endocrinology. The protocol complied with the Declaration of Helsinki and was approved by the local ethics committee of region Zealand (SJ-490) and by the Danish Data Protection Agency (REG-167-2015). The patients were after written informed consent enrolled during the period from 2016 to 2019. We aimed at recruiting a broad population and kept inclusion and exclusion criteria few and simple. Patients were adults between 18 and 80 years of age, with type 2 diabetes for at least 3 months or more. We excluded patients with contraindications to gadolinium-based contrast agents or magnetic resonance imaging or where poor quality (e.g. arrhythmias) would be expected. Thus, we excluded patients with claustrophobia, permanent atrial fibrillation, an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, or patients with an implanted pacemaker or cardio-defibrillator (contraindication to CMR). Further, for this study, we wanted to assess the effects of microvascular dysfunction not caused by significant macrovascular coronary artery dysfunction. Thus, we excluded patients with confirmed coronary artery disease, with a positive myocardial perfusion imaging test (visually detectable sub-endocardial perfusion defects), or with ischemic late gadolinium enhancement lesions on CMR (sub-endocardial or transmural lesions). Additionally, we included 25 control subjects without diabetes, without cardiopulmonary symptoms, and without known heart disease. In this group, mild hypertension requiring a maximum of one drug treatment as well as statin treatment was allowed. Data on the control population was only used in Table  with the purpose of providing the reader with a better understanding of the diabetes population. For all other analyses, only data from patients with diabetes were used. Declarations: Ethics approval and consent to participateThe study complied with the declaration of Helsinki and the study was approved by the local ethics committee of Region Zealand (SJ-490). All participants provided both oral and written informed consent before enrolment; the full description of the study design has been registered on clinicaltrials.gov (NCT02684331).: Consent for publicationNot applicable.: Competing interestsNo potential conflicts of interest relevant to this article were reported. Ethics approval and consent to participate: The study complied with the declaration of Helsinki and the study was approved by the local ethics committee of Region Zealand (SJ-490). All participants provided both oral and written informed consent before enrolment; the full description of the study design has been registered on clinicaltrials.gov (NCT02684331)."