Impact of Diabetes Mellitus on Myocardial Fibrosis in Patients with Hypertension: the REMODEL Study

BACKGROUND Compared to patients with hypertension only (HTN), those with hypertension and diabetes (HTN/DM) have worse prognosis. We aimed to characterize morphological differences between HTN and HTN/DM using cardiovascular magnetic resonance (CMR); and compare differentially expressed proteins associated with myocardial fibrosis using high throughput multiplex assays. METHODS Asymptomatic patients underwent CMR: 438 patients with HTN (60±8 years; 59% males) and 167 age- and sex-matched patients with HTN/DM (60±10 years; 64% males). Replacement myocardial fibrosis was defined as non-ischemic late gadolinium enhancement on CMR. Extracellular volume (ECV) fraction was used as a marker of diffuse myocardial fibrosis. A total of 184 serum proteins (Olink Target CVD II and III panels) were measured to identify unique signatures associated with myocardial fibrosis in all patients. RESULTS Despite similar left ventricular (LV) mass (P=0.344) and systolic blood pressure (P=0.086), patients with HTN/DM had increased concentricity and worse multi-directional strain (P<0.001 for comparison of all strain measures) compared to HTN only. Replacement myocardial fibrosis was present in 28% of patients with HTN/DM compared 16% of those with HTN (P<0.001). NT-proBNP was the only protein differentially upregulated in HTN patients with replacement myocardial fibrosis and independently associated with ECV. In patients with HTN/DM, GDF-15 was independently associated with replacement myocardial fibrosis and ECV. Ingenuity Pathway Analysis demonstrated a strong association between increased inflammatory response/immune cell trafficking and myocardial fibrosis in patients with HTN/DM. CONCLUSIONS Adverse cardiac remodeling was observed in patients with HTN/DM. The novel proteomic signatures and associated biological activities of increased immune and inflammatory response may partly explain these observations. CLINICAL PERSPECTIVES Myocardial fibrosis is a hallmark of heart failure and predicts worse cardiovascular outcomes in patients with hypertension. There is increasing interest to target the myocardial interstitium to improve diagnosis, risk stratification and to discover novel therapies. Our study demonstrates that myocardial fibrosis is a heterogeneous pathology resulting from cardiac disease-specific biology. In hypertensive patients, concomitant diabetes mellitus accelerates adverse cardiac remodeling. This observation endorses the importance to consider early risk stratification by imaging and/or biomarker profiling in these patients. Whether patients with hypertension and diabetes would derive incremental anti-fibrotic benefits from therapies targeting inflammation/immune activate require further investigations. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study was supported by the Ministry of Health and National Medical Research Council (MOH-CSAINV17nov-0002; NMRC/CGAug16M006 and NMRC/CGAug16C006). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted according to the Declaration of Helsinki and approved by the SingHealth Centralized Institutional Review Board (2015/2603). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the corresponding author. * CMR : Cardiovascular Magnetic Resonance CVD : Cardiovascular Disease EDV : End-Diastolic Volume HTN : Hypertension HTN/DM : Hypertension and Diabetes Mellitus LGE : Late Gadolinium Enhancement LVH : Left Ventricular Hypertrophy M/V : Mass/End-Diastolic Volume RI : Remodeling Index SBP : Systolic Blood Pressure