Genetic Variants Associated With Sudden Cardiac Death in Victims With Single Vessel Coronary Artery Disease and Left Ventricular Hypertrophy With or Without Fibrosis

Objective: Cardiac hypertrophy with varying degrees of myocardial fibrosis is commonly associated with coronary artery disease (CAD) related sudden cardiac death (SCD), especially in young victims among whom patterns of coronary artery lesions do not entirely appear to explain the cause of SCD. Our aim was to study the genetic background of hypertrophy, with or without fibrosis, among ischemic SCD victims with single vessel CAD.Methods: The study population was derived from the Fingesture study, consisting of all autopsy-verified SCDs in Northern Finland between the years 1998 and 2017 (n = 5,869). We carried out targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function in 95 ischemic-SCD victims (mean age 63.6 ± 10.3 years; 88.4% males) with single-vessel CAD in the absence of previously diagnosed CAD and cardiac hypertrophy with or without myocardial fibrosis at autopsy.Results: A total of 42 rare variants were detected in 43 subjects (45.3% of the study subjects). Five variants in eight subjects (8.4%) were classified as pathogenic or likely pathogenic. We observed 37 variants of uncertain significance in 39 subjects (40.6%). Variants were detected in myocardial structure protein coding genes, associated with arrhythmogenic right ventricular, dilated, hypertrophic and left ventricular non-compaction cardiomyopathies. Also, variants were detected in ryanodine receptor 2 (RYR2), a gene associated with both cardiomyopathies and catecholaminergic polymorphic ventricular tachycardias.Conclusions: Rare variants associated with cardiomyopathies, in the absence of anatomic evidence of the specific inherited cardiomyopathies, were common findings among CAD-related SCD victims with single vessel disease and myocardial hypertrophy found at autopsies, suggesting that these variants may modulate the risk for fatal arrhythmias and SCD in ischemic disease.

Cell Surface and Functional Features of Cortical Bone Stem Cells

The newly established mouse cortical-bone-derived stem cells (mCBSCs) are unique stem cells compared to mouse mesenchymal stem cells (mMSCs). The mCBSC-treated hearts after myocardial infarction have been reported to have greater improvement in myocardial structure and functions. In this study, we examined the stemness features, cell surface glycan profiles, and paracrine functions of mCBSCs compared with mMSCs. The stemness analysis revealed that the self-renewing capacity of mCBSCs was greater than mMSCs; however, the differentiation capacity of mCBSCs was limited to the chondrogenic lineage among three types of cells (adipocyte, osteoblast, chondrocyte). The cell surface glycan profiles by lectin array analysis revealed that α2-6sialic acid is expressed at very low levels on the cell surface of mCBSCs compared with that on mMSCs. In contrast, the lactosamine (Galβ1-4GlcNAc) structure, poly lactosamine- or poly N-acetylglucosamine structure, and α2-3sialic acid on both N- and O-glycans were more highly expressed in mCBSCs. Moreover, we found that mCBSCs secrete a greater amount of TGF-β1 compared to mMSCs, and that the TGF-β1 contributed to the self-migration of mCBSCs and activation of fibroblasts. Together, these results suggest that unique characteristics in mCBSCs compared to mMSCs may lead to advanced utility of mCBSCs for cardiac and noncardiac repair.

Senescence and Type 2 Diabetic Cardiomyopathy: How Young Can You Die of Old Age?

Inflammation is well understood to be a physiological process of ageing however it also underlies many chronic diseases, including conditions without an obvious pathogenic inflammatory element. Recent findings have unequivocally identified type 2 diabetes (T2D) as a chronic inflammatory disease characterized by inflammation and immune senescence. Immunosenescence is a hallmark of the prolonged low-grade systemic inflammation, in particular associated with metabolic syndrome and can be a cause as well as a consequence of T2D. Diabetes is a risk factor for cardiovascular mortality and remodelling and with particular changes to myocardial structure, function, metabolism and energetics collectively resulting in diabetic cardiomyopathy. Both cardiomyocytes and immune cells undergo metabolic remodelling in T2D and as a result become trapped in a vicious cycle of lost metabolic flexibility, thus losing their key adaptive mechanisms to dynamic changes in O2 and nutrient availability. Immunosenescence driven by metabolic stress may be both the cause and key contributing factor to cardiac dysfunction in diabetic cardiomyopathy by inducing metabolic perturbations that can lead to impaired energetics, a strong predictor of cardiac mortality. Here we review our current understanding of the cross-talk between inflammaging and cardiomyocytes in T2D cardiomyopathy. We discuss potential mechanisms of metabolic convergence between cell types which, we hypothesize, might tip the balance between resolution of the inflammation versus adverse cardiac metabolic remodelling in T2D cardiomyopathy. A better understanding of the multiple biological paradigms leading to T2D cardiomyopathy including the immunosenescence associated with inflammaging will provide a powerful target for successful therapeutic interventions.

Impact of left ventricular fibrosis and longitudinal systolic strain on outcomes in low gradient aortic stenosis

Background The clinical utility of comprehensive cardiac magnetic resonance (CMR) for the assessment of myocardial structure and function remains unknown in patients with low gradient (LG) aortic stenosis (AS). Purpose This study sought to compare CMR characteristics of myocardial structure and function according to different flow / gradient patterns of AS: classical low flow LG (LFLG); paradoxical LFLG; normal flow LG; and high gradient, and to evaluate their impact on the outcomes of these patients. Methods International multicentric prospective study included 147 patients with LG moderate to severe AS and 18 patients with high gradient severe AS who underwent comprehensive CMR evaluation of left ventricular global longitudinal strain (LVGLS), extracellular volume fraction (ECV), and late gadolinium enhancement (LGE). Results Patients with classical LFLG (n=90) had more LV adverse remodeling and impaired longitudinal function including higher ECV, and higher LGE and volume, and worst LVGLS, compared to other patterns of AS. Over a median follow-up of 2-years, 43 deaths and 48 composite outcomes of death or heart failure hospitalization occurred in LG AS patients. As LVGLS or ECV worsened, risks of adverse events also increased (per tertile of LVGLS: HR [95% CI] for mortality, 1.50 [1.02–2.20]; p=0.04; HR [95% CI] for composite outcome, 1.45 [1.01–2.09]; p<0.05) (per tertile of ECV: HR [95% CI] for mortality, 1.63 [1.07–2.49]; p=0.02; HR [95% CI] for composite outcome, 1.54 [1.02–2.33]; p=0.04). LGE presence was also associated with higher mortality (HR [95% CI], 2.27 [1.01–5.11]; p<0.05) and risk of the composite outcome (HR [95% CI], 3.00 [1.16–7.73]; p=0.02). The risk of all-cause death and of the composite outcome increased in proportion to the number of impaired components (i.e. LVGLS, ECV and LGE) (Figure) with and without adjustment for age, true severe AS, classical LFLG, and aortic valve replacement as a time-varying covariate. Conclusions In this international multicentric study of LG AS, comprehensive CMR assessment of myocardial structure and function provides independent prognostic value that is cumulative and incremental to clinical and echocardiographic characteristics. FUNDunding Acknowledgement Type of funding sources: None.

Impact of afterload and infiltration on coexisting aortic stenosis and transthyretin amyloidosis

ObjectiveThe coexistence of wild-type transthyretin cardiac amyloidosis (ATTR) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). However, the impact of ATTR and AS on the resultant AS-ATTR is unclear and poses diagnostic and management challenges. We therefore used a multicohort approach to evaluate myocardial structure, function, stress and damage by assessing age-related, afterload-related and amyloid-related remodelling on the resultant AS-ATTR phenotype.MethodsWe compared four samples (n=583): 359 patients with AS, 107 with ATTR (97% Perugini grade 2), 36 with AS-ATTR (92% Perugini grade 2) and 81 age-matched and ethnicity-matched controls. 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy was used to diagnose amyloidosis (Perugini grade 1 was excluded). The primary end-point was NT-pro Brain Natriuretic Peptide (BNP) and secondary end-points related to myocardial structure, function and damage.ResultsCompared with older age controls, the three disease cohorts had greater cardiac remodelling, worse function and elevated NT-proBNP/high-sensitivity Troponin-T (hsTnT). NT-proBNP was higher in AS-ATTR (2844 (1745, 4635) ng/dL) compared with AS (1294 (1077, 1554)ng/dL; p=0.002) and not significantly different to ATTR (3272 (2552, 4197) ng/dL; p=0.63). Diastology, hsTnT and prevalence of carpal tunnel syndrome were statistically similar between AS-ATTR and ATTR and higher than AS. The left ventricular mass indexed in AS-ATTR was lower than ATTR (139 (112, 167) in AS-ATTR was lower than ATTR (139 (112, 167) in AS-ATTR was lower than ATTR (139 (112, 167) vs 180 (167, 194) g; p=0.013) and non-significantly different to AS (120 (109, 130) g; p=0.179).ConclusionsThe AS-ATTR phenotype likely reflects an early stage of amyloid infiltration, but the combined insult resembles ATTR. Even after treatment of AS, ATTR-specific therapy is therefore likely to be beneficial.

Multiomics reveals the genomic, proteomic and metabolic influences of histidyl dipeptides on heart

Histidyl dipeptides, are synthesized in the heart via enzyme carnosine synthase (Carns), which facilitates glycolysis and glucose oxidation by proton buffering and attenuate ischemia and reperfusion injury. However, a composite understanding of the histidyl dipeptide mediated responses in the heart are lacking. We performed multilayer omics in the cardio specific Carns overexpressing mice, showing higher myocardial levels of histidyl dipeptides lead to extensive changes in microRNAs that could target the expression of contractile proteins and enzymes involved in β-fatty acid oxidation and citric acid cycle (TCA). Similarly, global proteomics showed contractile function, fatty acid degradation and TCA cycle, pathways were enriched in the CarnsTg heart. Parallel with these changes, free fatty acids, and TCA intermediate-succinic acid were lower under aerobic and significantly attenuated under anaerobic conditions in the CarnsTg heart. Integration of multiomics data shows β-fatty acid oxidation and TCA cycle exhibit correlative changes at all three levels in CarnsTg heart, suggesting histidyl dipeptides are critical regulators of myocardial structure, function and energetics.

Multiparametric CMR Imaging of Myocardial Structure and Function Changes in Diabetic Mini-pigs With Preserved LV Function : A Preliminary Study

Background: The purpose of this study is to dynamically monitor the myocardial structure and function changes in diabetic mini-pigs by 1.5T cardiac magnetic resonance. Methods: Cardiac magnetic resonance (CMR) T1 mapping was performed in three male streptozotocin-induced diabetic mini-pigs. T1-mapping and ECV-mapping were acquired at basal, mid and apical segments. CMR feature-tracking (CMR-FT) is used to quantify left ventricle global longitudinal (LVGLS), circumferential (LVGCS) and radial strain(LVGRS). Epicardial adipose tissue (EAT) was evaluated using a commercially available software.Results: Left ventricular mass (LVM), myocardial T1 value and extracellular volume (ECV) value increased gradually after 3, 4.5 and 6 months of modeling, while LVGLS decreased gradually after 3 months of modeling（Modeling 3M VS 1.5M：LVM，34.0 ± 1.9 VS 26.4 ± 1.3，P=0.027；T1，1012.3 ± 9.6 VS 1002.2 ± 11.4, P=0.014; ECV，24.3 ± 1.6 VS 22.4 ± 1.6，P=0.014；GLS：-20.8 ± 1.3 VS -23.0 ± 1.6，P=0.014；Modeling 4.5M VS 3M：LVM，37.5 ± 1.3 VS 34.0 ± 1.9，P=0.005；T1, 1017.8 ± 9.5 VS 1012.3 ± 9.6, P＜0.001；ECV，26.2 ± 1.5 VS 24.3 ± 1.6，P=0.037；GLS：-19.4 ± 1.4 VS -20.8 ± 1.3，P=0.016；Modeling 6M VS 4.5M：LVM，42.9 ± 1.6 ± 1.9 VS 37.5 ± 1.3，P=0.008；T1，1026.6 ± 10.2 VS 1017.8 ± 9.5, P=0.003；ECV，28.6 ± 1.8 VS 26.2 ± 1.5，P=0.016；GLS：-17.9 ± 1.1 VS -19.4 ± 1.4，P=0.019). EAT did not increase significantly until the sixth month (Modeling 6M VS 4.5M, EAT: 24.1 ± 3.1 VS 20.2 ± 2.4, P= 0.043).Conclusion: The progressive impairments in LV structure and myocardial deformation occurs in diabetic mini-pigs. T1 mapping and CMR-FT technology are promising to monitor abnormal changes of diabetic myocardium in early stage of diabetic cardiomyopathy.

A New Trick for an Old Dog? Myocardial-Specific Roles for Prostaglandins as Mediators of Ischemic Injury and Repair

The small lipid-derived paracrine signalling molecules known as prostaglandins have been recognized for their ability to modulate many facets of cardiovascular physiology since their initial discovery more than 85 years ago. While the role of prostaglandins in the vasculature has gained significant attention across time, a handful of historical studies have also directly implicated the cardiomyocyte in both prostaglandin synthesis and release. Recently our understanding of how prostaglandin receptor modulation impacts and contributes to myocardial structure and function has gained attention while leaving most other components of myocardial prostaglandin metabolism and signalling unexplored. This mini-review highlights both the key historical studies that underpin modern prostaglandin research in the heart, while concurrently presenting the latest findings related to how prostaglandin metabolism and signalling impact myocardial injury and repair.