Prospective associations of circulating thrombospondin-2 level with heart failure hospitalization, left ventricular remodeling and diastolic function in type 2 diabetes

Abstract

Background Circulating thrombospondin-2 (TSP2) levels were associated with the development of heart failure (HF) in recent studies. However, these studies included only a minority of patients with type 2 diabetes, which is associated with an increased HF risk. As hyperglycemia induces TSP2 expression and its tissue expression increases in type 2 diabetes, we investigated the prospective association of circulating TSP2 with incident HF hospitalization (HHF), and its associations with longitudinal changes of echocardiographic parameters in type 2 diabetes. Methods Baseline serum TSP2 levels were measured in 4949 patients with type 2 diabetes to determine its association with incident HHF using multivariable Cox regression analysis. In the echocardiographic study, baseline serum TSP2 levels were measured in another 146 patients with type 2 diabetes but without cardiovascular diseases who underwent detailed transthoracic echocardiography at baseline and after 1 year. Results Over a median follow-up of 7.8 years, 330 of 4949 patients (6.7%) developed incident HHF. Baseline serum TSP2 levels were independently associated with the development of HHF (HR 1.31, 95%CI 1.06–1.62, p = 0.014) after adjustments for baseline conventional cardiovascular risk factors, atrial fibrillation, estimated glomerular filtration rate, albuminuria and high-sensitivity C-reactive protein level, use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, loop-diuretics, aspirin, insulin, metformin and sodium-glucose co-transporter 2 inhibitors. Moreover, baseline serum TSP2 levels were independently associated with increase in average E/e’ and left atrial volume index (p = 0.04 and < 0.01, respectively). Conclusion Serum TSP2 levels were independently associated with both incident HHF and deterioration in diastolic function in type 2 diabetes. Trial registration Not Applicable

Serum thrombospondin‐2 level changes with liver stiffness improvement in patients with type 2 diabetes

“…In addition to hepatic fibrosis, ECM remodelling is also a key pathogenic event in other diabetic complications, such as diabetic kidney disease and heart failure (HF) 35–37 . Recently, we demonstrated that baseline circulating TSP2 was associated with rapid kidney function decline and incident HF hospitalization in T2D patients 38,39 . Our current findings therefore provided further clinical support to develop circulating TSP2 as a useful biomarker for all these fibrotic complications that commonly occur in T2D patients.…”

“…[35][36][37] Recently, we demonstrated that baseline circulating TSP2 was associated with rapid kidney function decline and incident HF hospitalization in T2D patients. 38,39 Our current findings therefore provided further clinical support to develop circulating TSP2 as a useful biomarker for all these fibrotic complications that commonly occur in T2D patients.…”

Proteomics, Human Environmental Exposure, and Cardiometabolic Risk

“…Moreover, top proteins related to pollution exposures (specifically PM 2.5 ) were in pathways of DNA damage repair (APEX1 [DNA-(apurinic or apyrimidinic site) lyase], 46 a main AP endonuclease; RECQL [RecQ like helicase] 47 ), mitochondrial metabolism (COQ9 [coenzyme Q9] 48 ), proteins at the lung-pollutant interface (SP-D [pulmonary surfactant-associated protein D] 49 ), inflammation, and transcriptional/translational processing (ribosomal and nuclear proteins). Both unbiased analysis and per-protein review did not suggest a predominant pathway signature of the social vulnerability proteome but did include several mediators previously implicated in CMD pathogenesis (GDF15 [growth/differentiation factor], 50 RARRES2 [retinoic acid receptor responder 2], 51 and THBS2 [thrombospondin-2], 52 among them). Molecular pathways implicated by temperature appeared analogous to the pollution and built environmental proteome, likely reflecting some correlation between measures of temperature, elements of pollution, and built structures (Figure 1B).…”

“…Although a deep survey per-protein exposition is out of scope for this report, we did note overlap across environmental exposures in pathways relevant to CMD that were consistent with the pathway analysis. For example, proteins related to the built environment included downstream mediators of broad fibrosis and immune signaling pathways, including 51 and THBS2 [thrombospondin-2], 52 among them). Molecular pathways implicated by temperature appeared analogous to the pollution and built environmental proteome, likely reflecting some correlation between measures of temperature, elements of pollution, and built structures (Figure 1B).…”

Association of plasma proteomics with incident coronary heart disease in individuals with and without type 2 diabetes: results from the population-based KORA study

“…subclinical CHD [ 36 ]. Furthermore, we identified THBS2 as a marker of incident CHD, which is a matricellular protein facilitating cell-matrix interactions, that was positively associated with both incident heart failure (HF) hospitalization and deterioration in diastolic function in a recent study [ 37 ]. TGF-alpha, which directly activates the transcription factor NF-κB through the epidermal growth factor receptor pathway, was previously found to be associated with higher cardiovascular mortality in patients with chronic CHD [ 38 ].…”