Gonca Suna

T1-Mapping and Outcome in Nonischemic Cardiomyopathy: All-Cause Mortality and Heart Failure

OBJECTIVES The study sought to examine prognostic relevance of T1 mapping parameters (based on a T1 mapping method) in nonischemic dilated cardiomyopathy (NIDCM) and compare them with conventional markers of adverse outcome. BACKGROUND NIDCM is a recognized cause of poor clinical outcome. NIDCM is characterized by intrinsic myocardial remodeling due to complex pathophysiological processes affecting myocardium diffusely. Lack of accurate and noninvasive characterization of diffuse myocardial disease limits recognition of early cardiomyopathy and effective clinical management in NIDCM. Cardiac magnetic resonance (CMR) supports detection of diffuse myocardial disease by T1 mapping. METHODS This is a prospective observational multicenter longitudinal study in 637 consecutive patients with dilated NIDCM (mean age 50 years [interquartile range: 37 to 76 years]; 395 males [62%]) undergoing CMR with T1 mapping and late gadolinium enhancement (LGE) at 1.5-T and 3.0-T. The primary endpoint was all-cause mortality. A composite of heart failure (HF) mortality and hospitalization was a secondary endpoint. RESULTS During a median follow-up period of 22 months (interquartile range: 19 to 25 months), we observed a total of 28 deaths (22 cardiac) and 68 composite HF events. T1 mapping indices (native T1 and extracellular volume fraction), as well as the presence and extent of LGE, were predictive of all-cause mortality and HF endpoint (p < 0.001 for all). In multivariable analyses, native T1 was the sole independent predictor of all-cause and HF composite endpoints (hazard ratio: 1.1; 95% confidence interval: 1.06 to 1.15; hazard ratio: 1.1; 95% confidence interval: 1.05 to 1.1; p < 0.001 for both), followed by the models including the extent of LGE and right ventricular ejection fraction, respectively. CONCLUSIONS Noninvasive measures of diffuse myocardial disease by T1 mapping are significantly predictive of all-cause mortality and HF events in NIDCM. We provide a basis for a novel algorithm of risk stratification in NIDCM using a complementary assessment of diffuse and regional disease by T1 mapping and LGE, respectively.

Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques

BACKGROUND. The identification of patients with high-risk atherosclerotic plaques prior to the manifestation of clinical events remains challenging. Recent findings question histology- and imaging-based definitions of the “vulnerable plaque,” necessitating an improved approach for predicting onset of symptoms. METHODS. We performed a proteomics comparison of the vascular extracellular matrix and associated molecules in human carotid endarterectomy specimens from 6 symptomatic versus 6 asymptomatic patients to identify a protein signature for high-risk atherosclerotic plaques. Proteomics data were integrated with gene expression profiling of 121 carotid endarterectomies and an analysis of protein secretion by lipid-loaded human vascular smooth muscle cells. Finally, epidemiological validation of candidate biomarkers was performed in two community-based studies. RESULTS. Proteomics and at least one of the other two approaches identified a molecular signature of plaques from symptomatic patients that comprised matrix metalloproteinase 9, chitinase 3-like-1, S100 calcium binding protein A8 (S100A8), S100A9, cathepsin B, fibronectin, and galectin-3-binding protein. Biomarker candidates measured in 685 subjects in the Bruneck study were associated with progression to advanced atherosclerosis and incidence of cardiovascular disease over a 10-year follow-up period. A 4-biomarker signature (matrix metalloproteinase 9, S100A8/S100A9, cathepsin D, and galectin-3-binding protein) improved risk prediction and was successfully replicated in an independent cohort, the SAPHIR study. CONCLUSION. The identified 4-biomarker signature may improve risk prediction and diagnostics for the management of cardiovascular disease. Further, our study highlights the strength of tissue-based proteomics for biomarker discovery. FUNDING. UK: British Heart Foundation (BHF); King’s BHF Center; and the National Institute for Health Research Biomedical Research Center based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London in partnership with King’s College Hospital. Austria: Federal Ministry for Transport, Innovation and Technology (BMVIT); Federal Ministry of Science, Research and Economy (BMWFW); Wirtschaftsagentur Wien; and Standortagentur Tirol.

Extracellular Matrix Proteomics Reveals Interplay of Aggrecan and Aggrecanases in Vascular Remodeling of Stented Coronary Arteries

Background: Extracellular matrix (ECM) remodeling contributes to in-stent restenosis and thrombosis. Despite its important clinical implications, little is known about ECM changes post–stent implantation. Methods: Bare-metal and drug-eluting stents were implanted in pig coronary arteries with an overstretch under optical coherence tomography guidance. Stented segments were harvested 1, 3, 7, 14, and 28 days post-stenting for proteomics analysis of the media and neointima. Results: A total of 151 ECM and ECM-associated proteins were identified by mass spectrometry. After stent implantation, proteins involved in regulating calcification were upregulated in the neointima of drug-eluting stents. The earliest changes in the media were proteins involved in inflammation and thrombosis, followed by changes in regulatory ECM proteins. By day 28, basement membrane proteins were reduced in drug-eluting stents in comparison with bare-metal stents. In contrast, the large aggregating proteoglycan aggrecan was increased. Aggrecanases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family contribute to the catabolism of vascular proteoglycans. An increase in ADAMTS-specific aggrecan fragments was accompanied by a notable shift from ADAMTS1 and ADAMTS5 to ADAMTS4 gene expression after stent implantation. Immunostaining in human stented coronary arteries confirmed the presence of aggrecan and aggrecan fragments, in particular, at the contacts of the stent struts with the artery. Further investigation of aggrecan presence in the human vasculature revealed that aggrecan and aggrecan cleavage were more abundant in human arteries than in human veins. In addition, aggrecan synthesis was induced on grafting a vein into the arterial circulation, suggesting an important role for aggrecan in vascular plasticity. Finally, lack of ADAMTS-5 activity in mice resulted in an accumulation of aggrecan and a dilation of the thoracic aorta, confirming that aggrecanase activity regulates aggrecan abundance in the arterial wall and contributes to vascular remodeling. Conclusions: Significant differences were identified by proteomics in the ECM of coronary arteries after bare-metal and drug-eluting stent implantation, most notably an upregulation of aggrecan, a major ECM component of cartilaginous tissues that confers resistance to compression. The accumulation of aggrecan coincided with a shift in ADAMTS gene expression. This study provides the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting.

T1 values by conservative septal postprocessing approach are superior in relating to the interstitial myocardial fibrosis: findings from patients with severe aortic stenosis

Background Accumulation of diffuse interstitial myocardial fibrosis in severe aortic stenosis relates to left ventricular (LV) functional impairment and determines the postoperative outcome in these patients. T1 mapping has been proposed for non-invasive quantification of diffuse interstitial fibrosis. We examined associations between T1 values and collagen volume fraction from endomyocardial biopsies from patients with severe aortic stenosis. We compared whether these relationships differ with respect to the post-processing approach.

Comparison of MOLLI, shMOLLLI, and SASHA in discrimination between health and disease and relationship with histologically derived collagen volume fraction

Aims To determine the bioequivalence of several T1 mapping sequences in myocardial characterization of diffuse myocardial fibrosis. Methods and results We performed an intra-individual sequence comparison of three types of T1 mapping sequences [MOdified Look-Locker Inversion recovery (MOLLI), Shortened MOdified Look-Locker Inversion recovery ((sh)MOLLI), and SAturation recovery single-SHot Acquisition (SASHA)]. We employed two model diseases of diffuse interstitial fibrosis [patients with non-ischaemic dilated cardiomyopathy (NIDCM), n = 32] and aortic stenosis [(AS), n = 25)]. Twenty-six healthy individuals served as controls. Relationship with collagen volume fraction (CVF) was assessed using endomyocardial biopsies (EMB) intraoperatively in 12 AS patients. T2 mapping (GraSE) was also performed. Myocardial native T1 with MOLLI and shMOLLI showed, firstly, an excellent discriminatory accuracy between health and disease [area under the curves (P-value): 0.94 (0.88-0.99); 0.87 (0.79-0.94); 0.61 (0.49-0.72)], secondly, relationship between histological CVF [native T1 MOLLI vs. shMOLLI vs. SASHA: r = 0.582 (P = 0.027), r = 0.524 (P = 0.046), r = 0.443 (P = 0.150)], and thirdly, with native T2 [r = 0.628(P < 0.001), r = 0.459 (P = 0.003), r = 0.211 (P = 0.083)]. The respective relationships for extracellular volume fraction with CVF [r = 0.489 (P = 0.044), r = 0.417 (0.071), r = 0.353 (P = 0.287)] were significant for MOLLI, but not other sequences. In AS patients, native T2 was significantly higher compared to controls, and associated with levels of C-reactive protein and troponin. Conclusion T1 mapping sequences differ in their bioequivalence for discrimination between health and disease as well as associations with diffuse myocardial fibrosis.

Tracing the Proteomic Fingerprint of the Diabetic Aorta

Diabetes mellitus is a worldwide epidemic, and the percentage of the US population diagnosed with diabetes mellitus between 1980 and 2010 increased from 2.5% to 6.9%.1 Nearly 27% of people >65 years of age have diabetes mellitus. If current trends continue, 1 in 3 US adults will experience diabetes mellitus by 2050. This can be attributed to lifestyle choices contributing to obesity.2 One of the main causes of death and disability in patients with diabetes mellitus are vascular complications, affecting both the macro- and the microvasculature.3 Macrovascular manifestations include atherosclerosis leading to coronary artery disease, peripheral arterial disease, and stroke. Microvascular changes, on the other hand, encompass diabetic nephropathy, retinopathy, and neuropathy. Article see p 161 Although there is compelling evidence for the association of diabetes mellitus and vascular disease, the underlying pathophysiological mechanisms remain to be elucidated. Advanced glycation end products, as well as reactive oxygen species, are suggested to be 2 of the major culprits leading to vascular damage.4,5 Extracellular matrix proteins can become glycated by nonenzymatic reactions of sugar moieties, which alter protein function in target tissues.6 Major histological changes are apparent in diabetic vessels, including increased intima–media thickness and excessive extracellular matrix deposition.5 Yet, despite many patients with diabetes mellitus following a tight glycemic control regime, they are still experiencing vascular complications. Notably, …