Marker Of Myocardial Fibrosis Research Articles

Overexpression of zinc-finger protein 418 inhibits pathological cardiac remodelling after acute myocardial infarction.

Zinc-finger protein 418 (ZNF418) has been confirmed to be expressed in myocardial tissue. However, the role and mechanism of ZNF418 in pathological myocardial remodelling after myocardial infarction (MI) have not been reported. This study was to elucidate the effect and mechanism of ZNF418 on ventricular remodelling after MI in mice. MI mice and H9c2 cardiomyocytes were used to conduct in vivo and in vitro experiments, respectively. ZNF418 expression was regulated by adeno-associated virus 9 and adenovirus vectors. Pathological analysis, echocardiography, and molecular analysis were performed. ZNF418 was down-regulated in the left ventricular tissues of post-MI mice. In contrast, ZNF418 overexpression decreased mortality and improved cardiac function in MI mice. The MI mice exhibited a significantly increased cross-sectional area of myocardial cells and elevated protein expression levels of myocardial hypertrophy markers ANP, BNP, and β-MHC (all P<0.05). Moreover, a significantly increased area of myocardial fibrosis and protein expression levels of myocardial fibrosis markers collagen I, collagen III, and CTGF were observed in MI mice (all P<0.05) in MI mice. All of the above negative effects in MI mice were ameliorated in ZNF418 overexpressed mice (all P<0.05). Mechanistically, ZNF418 overexpression inhibited the activation of the MAPK signalling pathway, as evidenced by the in vivo and in vitro experiments. Overexpression of ZNF418 could improve cardiac function and inhibit pathological cardiac remodelling by inhibiting the MAPK signalling pathway in post-MI mice.

Regional Distribution of Extracellular Volume Quantified by Cardiac CT in Aortic Stenosis: Insights Into Disease Mechanisms and Impact on Outcomes.

Extracellular volume fraction (ECV) is a marker for myocardial fibrosis and infiltration, can be quantified using cardiac computed tomography (ECVCT), and has prognostic utility in several diseases. This study aims to map out regional differences in ECVCT to obtain greater insights into the pathophysiological mechanisms of ECV expansion and its clinical implications. Three prospective cohorts were included: patients with aortic stenosis (AS) and coexisting AS and transthyretin cardiac amyloidosis were referred for a transcatheter aortic valve replacement and had ECG-gated CT angiography and Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy to differentiate between the 2 cohorts. Controls had CT angiography and cardiac magnetic resonance demonstrating no significant coronary artery disease or infarction. Global and regional ECVCT was analyzed, and its association with mortality was assessed for patients with AS. In 199 patients, controls (n=65; 66% male), AS (n=115), and coexisting AS and transthyretin cardiac amyloidosis (n=19) had a global ECVCT of 26.1 (25.0-27.8%) versus 29.1 (27.5-31.1%) versus 37.4 (32.5-46.6%), respectively; P<0.001. Across cohorts, ECVCT was higher at the base (versus apex), the inferoseptum (versus anterolateral wall), and the subendocardium (versus subepicardium); P<0.05 for all. Among patients with AS, epicardial ECVCT, rather than any other regional value or global ECVCT, was the strongest predictor of mortality at a median of 3.9 (max 6.3) years (adjusted hazard ratio, 1.21 [95% CI, 1.08-1.36]; P=0.002). Regional differences in ECVCT suggest a predilection for fibrosis and amyloid infiltration at the base, subendocardium, inferior wall, and septum more than the anterior and lateral myocardium. ECVCT can predict long-term mortality with the subepicardium demonstrating the strongest discriminatory power. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03029026 and NCT03094143.

Features of cardiovascular magnetic resonance native T1 mapping in maintenance hemodialysis patients and their related factors

Purpose Increased myocardial T1 values on cardiovascular MRI (CMRI) have been shown to be a surrogate marker for myocardial fibrosis. The use of CMRI in patients on hemodialysis (HD) remains limited. This research aimed to explore the characteristics of native T1 values in HD patients and identify factors related to T1 values. Methods A total of thirty-two patients on HD and fourteen healthy controls were included in this study. All participants underwent CMRI. Using modified Look-Locker inversion recovery (MOLLI) sequence, native T1 mapping was achieved. Native CMRI T1 values were compared between the two groups. In order to analyze the relationship between T1 values and clinical parameters, correlation analysis was performed in patients on HD. Results Patients on HD exhibited elevated global native T1 values compared to control subjects. In the HD group, the global native T1 value correlated positively with intact parathyroid hormone (iPTH) (r = 0.418, p = 0.017) and negatively with triglycerides (r= −0.366, p = 0.039). Moreover, the global native T1 value exhibited a positive correlation with the left ventricular end-diastolic volume indexed to body surface area (BSA; r = 0.528, p = 0.014), left ventricular end-systolic volume indexed to BSA (r = 0.506, p = 0.019), and left ventricular mass indexed to BSA (r = 0.600, p = 0.005). A negative correlation was observed between the global native T1 value and ejection fraction (r = 0.-0.551, p = 0.010). Conclusion The global native T1 value was prolonged in HD patients compared with controls. In the HD group, the global T1 value correlated strongly with iPTH, triglycerides, and cardiac structural and functional parameters.

Improvement in Cardiac Morphology Demonstrated by Cardiac Magnetic Resonance Imaging and Echocardiography after Haploidentical Hematopoietic Cell Transplantation in Adults with Sickle Cell Disease

Cardiopulmonary complications account for approximately 40% of deaths in patients with sickle cell disease (SCD). Diffuse myocardial fibrosis, elevated tricuspid regurgitant jet velocity (TRV) and iron overload are all associated with early mortality. While HLA-matched sibling hematopoietic cell transplant (HCT) offers a potential cure, fewer than 20% of patients have a suitable donor. Haploidentical HCT allows for an increased donor pool and has recently demonstrated improved safety and efficacy. Our group has reported improved cardiac morphology via echocardiography at one year after HCT. Herein, we describe the first use of cardiac magnetic resonance imaging (CMR), the gold standard for measuring volume, mass, and ventricular function, to evaluate changes in cardiac morphology post-HCT in adults with SCD. We analyzed baseline and 1-year data from 12 adults with SCD who received nonmyeloablative haploidentical peripheral blood HCT at the NIH. Patients underwent non-contrast CMR at 3T, echocardiography, and laboratory studies. One year after HCT, patients showed marked improvement in cardiac chamber morphology by CMR, including left ventricular (LV) mass and volume (70.2 to 60.1 g/m2, p = 0.02; 114.5 to 90.6 mL/m2, p = 0.001). Furthermore, mean TRV normalized by 1 year, suggesting that HCT may offer a survival benefit. Fewer patients had pathologically prolonged native myocardial T1 times, an indirect marker of myocardial fibrosis at 1 year; these data showed a trend toward significance. In this small sample, CMR was very sensitive in detecting cardiac mass and volume changes after HCT and provided complementary information to echocardiography. Notably, post-HCT improvement in cardiac parameters can be attributed only in part to the resolution of anemia; further studies are required to determine the role of myocardial fibrosis reversal, improved blood flow, and survival impact after HCT for SCD.

Regional differences in extracellular volume increase arrhythmia vulnerability in aortic stenosis patients with and without diffuse fibrosis: a computational study

Abstract Background Extracellular volume (ECV) determined by magnetic resonance imaging (MRI) is considered a marker of myocardial fibrosis and a predictor of mortality. In addition to diffuse fibrosis, aortic stenosis (AS) patients present increased ECV. However, the impact of regional ECV differences on arrhythmia vulnerability in AS patients has not been assessed. Purpose To investigate regional ECV differences in AS patients and to determine their impact on ventricular arrhythmia vulnerability. Methods MRI was performed in 51 AS patients (32 males, 19 females) before and 3 months after aortic valve replacement (AVR). Regional differences in ECV were measured between mid-ventricular and basal planes. To investigate their impact on arrhythmia vulnerability, a computational biventricular model was developed from MRI data of the patient who presented the highest ECV difference between the planes in absence of a scar determined by late gadolinium enhancement (male 75y, post-AVR, ECV mid 25.5%, ECV base 31.3%, Figure A). The model was divided in two regions and extracellular conductivities (GE) were adjusted in each region as described previously (1), with additional GE reduction in the high ECV region representing increased interstitial fibrosis. This approach resulted in GE being 26.4% lower for ECV of 31.3% when compared to ECV of 25.5%. A model with uniform ECV of 25.5% was used as a control. Myocardial tissue was modelled with a cell radius of 16 micrometers, as reported in AS patients (2). The right ventricular apex was paced with S1=750 ms for 10 beats, followed by rapid pacing with different cycle lengths spanning the 20 ms window before the loss of stimulus capture to test arrhythmia inducibility. The simulations were repeated with an additional GE reduction by 30% and 60% in both regions to mimic conduction delays from diffuse fibrosis. Results Cardiac MRI showed significantly higher ECV in the basal plane of AS patients when compared to the mid-ventricular plane, both before and after AVR (Figure B), with the largest ECV found after AVR (mid-ventricular: p&amp;lt;0.0001; basal: p=0.0011). No sex-specific differences were found. Simulations in the model with patient-derived ECV showed slightly longer QRS and lower CV than the model with uniform ECV (Table). By contrast, myocardial fibrosis had a larger impact on CV slowing. Arrhythmia was inducible when either diffuse fibrosis was present or ECV at the ventricular base was increased (Table). Conclusion Regional differences in ECV were found in the ventricles of AS patients. Computer simulations suggest that these differences have a minimal effect on ventricular conduction when compared to diffuse fibrosis. However, they might increase arrhythmia vulnerability even in the absence of diffuse fibrosis. Additional studies are necessary to investigate the effects of each on arrhythmia maintenance and cardiac mechanics.

Comprehensive Myocardial Assessment by Computed Tomography: Impact on Short-Term Outcomes After Transcatheter Aortic Valve Replacement

BackgroundQuantification of myocardial changes in severe aortic stenosis (AS) is prognostically important. The potential for comprehensive myocardial assessment pre–transcatheter aortic valve replacement (TAVR) by computed tomography angiography (CTA) is unknown. ObjectivesThis study sought to evaluate whether quantification of left ventricular (LV) extracellular volume—a marker of myocardial fibrosis—and global longitudinal strain—a marker of myocardial deformation—at baseline CTA associate with post-TAVR outcomes. MethodsConsecutive patients with symptomatic severe AS between January 2021 and June 2022 who underwent pre-TAVR CTA were included. Computed tomography extracellular volume (CT-ECV) was derived from septum tracing after generating the 3-dimensional CT-ECV map. Computed tomography global longitudinal strain (CT-GLS) used semi-automated feature tracking analysis. The clinical endpoint was the composite outcome of all-cause mortality and heart failure hospitalization. ResultsAmong the 300 patients (80.0 ± 9.4 years of age, 45% female, median Society of Thoracic Surgeons Predicted Risk of Mortality score 2.80%), the left ventricular ejection fraction (LVEF) was 58% ± 12%, the median CT-ECV was 28.5% (IQR: 26.2%-32.1%), and the median CT-GLS was −20.1% (IQR: −23.8% to −16.3%). Over a median follow-up of 16 months (IQR: 12-22 months), 38 deaths and 70 composite outcomes occurred. Multivariable Cox proportional hazards model, accounting for clinical and echocardiographic variables, demonstrated that CT-ECV (HR: 1.09 [95% CI: 1.02-1.16]; P = 0.008) and CT-GLS (HR: 1.07 [95% CI: 1.01-1.13]; P = 0.017) associated with the composite outcome. In combination, elevated CT-ECV and CT-GLS (above median for each) showed a stronger association with the outcome (HR: 7.14 [95% CI: 2.63-19.36]; P < 0.001). ConclusionsComprehensive myocardial quantification of CT-ECV and CT-GLS associated with post-TAVR outcomes in a contemporary low-risk cohort with mostly preserved LVEF. Whether these imaging biomarkers can be potentially used for the decision making including timing of AS intervention and post-TAVR follow-up will require integration into future clinical trials.

Myocardial fibrosis associates with lupus anticoagulant in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that carries increased risk of cardiovascular disease; however, the underlying pathophysiological mechanisms remain poorly understood. We aimed to investigate the prevalence and degree of myocardial fibrosis in SLE patients and associated disease characteristics. Forty-nine SLE patients (89% female, mean age 52 ± 13 years, median disease duration 19 (11–25) years) and 79 sex-and age-matched healthy controls were included. CMR with T1 mapping was performed on SLE patients and healthy controls. Fifty-one SLE patients received gadolinium contrast for the evaluation of late gadolinium enhancement (LGE) and extra cellular volume (ECV). Multiple linear regression analyses were performed to investigate the association between markers of myocardial fibrosis on CMR (LGE, T1, ECV) and SLE-related variables [clinical disease activity, lupus nephritis, chronic kidney disease, anti-cardiolipin and/or anti-beta-2 glycoprotein I antibodies, and lupus anticoagulant (LAC)] with adjustment for traditional risk factors. T1 values were elevated in SLE patients compared to healthy controls (1031 ± 36 ms vs. 1019 ± 25 ms, p = 0.01). LGE was present in 20% of SLE patients who received gadolinium contrast. On multivariable analysis, LAC was associated with LGE in SLE patients (β = 3.87, p = 0.02). Neither T1 nor ECV associated with SLE disease characteristics; however, there was a trend towards an association between LAC and T1 (β = 16.9, p = 0.08). SLE patients displayed signs of myocardial fibrosis on CMR that were associated with the presence of LAC. These findings support the pathophysiological understanding of LAC as a mediator of microvascular and subsequent myocardial dysfunction.Graphical abstract

Evaluation of right ventricular diastolic function, systolic function, and circulating galectin-3 concentrations in dogs with pulmonary stenosis.

Cardiovascular diseases with increased right ventricular (RV) afterload induce RV diastolic and systolic dysfunction, and myocardial fibrosis in humans. Studies in dogs with pulmonary stenosis (PS) evaluating RV diastolic function and markers of myocardial fibrosis are lacking. Dogs with PS have echocardiographic evidence of RV diastolic and systolic dysfunction and increased serum concentrations of galectin-3 (Gal-3), a surrogate biomarker for myocardial fibrosis. Forty client-owned dogs (10 controls, 30 with PS). Prospective study. All dogs had systemic blood pressure measurement, serum biochemical analysis, echocardiography, and measurement of serum Gal-3 concentration performed. Variables of RV diastolic function were obtained in 39/40 dogs. Trans-tricuspid flow velocity in early diastole to trans-tricuspid flow velocity in late diastole ratios (RV E/A) were lower (P < .001) in dogs with PS (median, 0.94; range, 0.62-2.04) compared to controls (1.78; 1.17-2.35). Trans-tricuspid flow velocity in early diastole to tricuspid annular myocardial velocity in early diastole ratios (RV E/e') were higher (P < .001) in dogs with PS (11.55; 4.69-28) compared to control (6.21; 5.16-7.21). Variables of RV systolic function were lower in dogs with PS (P = <.001). Serum Gal-3 concentration was higher (P = .002) in dogs with PS (285.1 pg/mL; 94.71-406.97) compared to control dogs (162.83 pg/mL; 52.3-232.82). Dogs with PS have RV diastolic and systolic dysfunction, and increased Gal-3 concentrations. These findings suggest the presence of RV myocardial fibrosis in dogs with PS, which could impact clinical management.

Bidirectional negative feedback actions of DNMT3A and miR-145 in regulating autophagy in cardiac fibroblasts and affecting myocardial fibrosis.

Epigenetic regulation has crucial implications for myocardial fibrosis. It has been reported that autophagy, regulated by miR-145, is implicated in the proliferation and fibrosis of cardiac fibroblasts (CFs). However, how it works during the process remains unclear. This study explored the exact effects of epigenetic regulation of miR-145 expression on autophagy, proliferation, and fibrosis of CFs. To examine the expression levels of myocardial fibrosis markers (α-SMA and collagen I), autophagy-related proteins (LC3I, LC3II, p62), DNMT3A, and miR-145, qRT-PCR and western blot were employed. And the proliferation of CFs was detected by CCK-8 and ErdU. As for the determination of the binding relationship between DNMT3A and miR-145, dual-luciferase assay was conducted. Next, the detection of the methylation level of the pre-miR-145 promoter region was completed by MSP. And the verification of the effect of the DNMT3A/miR-145 axis on myocardial fibrosis was accomplished by constructing mouse myocardial infarction (MI) models based on the ligation of the left anterior descending method. In TGF-β1-activated CFs, remarkable up-regulation of DNMT3 and considerable down-regulation of miR-145 were observed. And further experiments indicated that DNMT3A was able to down-regulate miR-145 expression by maintaining the hypermethylation level of the pre-miR-145 promoter region. In addition, DNMT3A expression could be directly targeted and negatively modulated by miR-145. Moreover, in vitro cell experiments and mouse MI models demonstrated that DNMT3A overexpression could inhibit autophagy, and promote cell proliferation and fibrosis of CFs. However, this kind of effect could be reversed by miR-145 overexpression. In summary, myocardial fibroblast autophagy can be regulated by bidirectional negative feedback actions of DNMT3A and miR-145, thus affecting myocardial fibrosis. This finding will provide a potential target for the clinical treatment of myocardial fibrosis.

Evaluation of QRS Fragmentation and BMI in Obese and Non-Obese Children

Background: Fragmented QRS (fQRS) on electrocardiography is a marker of myocardial fibrosis and scar formation. We aimed to investigate whether the fQRS complex in children with and without obesity correlates with Body Mass Index (BMI).&#x0D; Methods: In this cross-sectional study, 104 children (5 to 17 years) referred to the pediatric clinic were studied. We divided participants into normal and obese groups. Standard 12-lead ECGs, anthropometric data, and blood pressure were recorded. All ECGs were analyzed blindly by two independent clinicians. Surveyed parameters of the ECG included heart rate, QRS duration, QT interval, presence of Q waves, and fQRS.&#x0D; Results: Among 104 participants, 52 patients had normal BMI and 52 cases were obese. Systolic blood pressure (p=0.001), pulse pressure (p=0.007), mean blood pressure (p=0.006), and heart rate (p=0.009) were meaningfully different between the two groups. We found fQRS in four children with obesity. The frequency of fQRS was significantly different between children with obesity and children in the control group (p=0.041). We have found that each unit change of weight and BMI at 1.07 and 1.45, respectively, could be useful in prediction of the occurrence of fQRS complex in children.&#x0D; Conclusion: This study suggested a significant association between the fQRS in children’s ECG and their weight and BMI. It would appear that each unit increasing weight and BMI predicts an increasing the occurrence of fQRS. The ECG may consider using fQRS as a cardiac risk marker in children with obesity.

Is myocardial fibrosis appropriately assessed by calibrated and 2D strain derived integrated backscatter?

AimsIncreased collagen content of the myocardium modifies tissue reflectivity and integrated backscatter (IBS) indexes are suggested as markers of myocardial fibrosis (MF). We sought to assess the correlation between calibrated (c) IBS and bidimensional (2D) strain derived IBS with left ventricular (LV) MF in patients with severe aortic stenosis (AS).Methods and resultsWe made a prospective observational cohort study including 157 patients with severe AS referred for surgical aortic valve replacement (AVR), with complete preoperative transthoracic echocardiography, cardiac magnetic resonance (CMR) and endomyocardial biopsy (EMB) obtained from the anterior basal septum at the time of surgery. Two groups of 30 patients were specifically evaluated, with and without late gadolinium enhancement (LGE) at CMR. IBS was obtained at QRS peak from both parasternal long axis (PLAX) and apical-three-chamber (AP3C) views and measured in decibels (dB). Whole-cardiac cycle IBS at basal anterior septum was obtained from 2D longitudinal strain. Correlation analysis of reflectivity indexes was performed with global and segmental (anterior basal septum) values of native T1 and extracellular volume (ECV), and EMB collagen volume fraction (CVF) (Masson´s Trichrome). IBS values were compared in both group of patients (LGE + vs. LGE –). 60 patients (74 [36–74] years, 45% male) with high gradient (mean gradient: 63 ± 20mmHg), normal flow (45 ± 10mL/m2) AS and preserved left ventricular ejection fraction (60 ± 9%) were included. Basal septum cIBS was − 17.45 (–31.2–10.95) and − 9.17 ± 9.45dB from PLAX and A3C views, respectively. No significant correlations were found between IBS and both non-invasive CMR tissue characterization and CVF: median MF of 9.7(2.1–79.9)%. Acoustic indexes were not significantly different according to the presence of pre-operative LGE.ConclusionIn this group of patients with classical severe AS, IBS reflectivity indexes are of no added value to discriminate the presence of MF.Graphical

Chemotherapy effect on myocardial fibrosis markers in patients with gynecologic cancer and low cardiovascular risk.

Patients with gynecologic cancers experience side effects of chemotherapy cardiotoxicity. We aimed to quantify cardiac magnetic resonance (CMR) markers of myocardial fibrosis in patients with gynecologic cancer and low cardiovascular risk who undergo chemotherapy. This study is part of a registered clinical research. CMR T1 mapping was performed in patients with gynecologic cancer and low cardiovascular risk undergoing chemotherapy. The results were compared with those of age-matched healthy control subjects. 68 patients (median age = 50 years) and 30 control subjects were included. The median number of chemotherapy cycles of patients was 9.0 (interquartile range [IQR] 3.3-17.0). Extracellular volume fraction (ECV) (27.2% ± 2.7% vs. 24.5% ± 1.7%, P < 0.001) and global longitudinal strain (-16.2% ± 2.8% vs. -17.4% ± 2.0%, P = 0.040) were higher in patients compared with controls. Patients with higher chemotherapy cycles (>6 cycles) (n=41) had significantly lower intracellular mass indexed (ICMi) compared with both patients with lower chemotherapy cycles (≤6 cycles) (n=27) (median 27.44 g/m2 [IQR 24.03-31.15 g/m2] vs. median 34.30 g/m2 [IQR 29.93-39.79 g/m2]; P = 0.002) and the control group (median 27.44 g/m2 [IQR 24.03-31.15 g/m2] vs. median 32.79 g/m2 [IQR 27.74-35.76 g/m2]; P = 0.002). Patients with two or more chemotherapy regimens had significantly lower ICMi compared with both patients with one chemotherapy regimen (27.45 ± 5.16 g/m2 vs. 33.32 ± 6.42 g/m2; P< 0.001) and the control group (27.45 ± 5.16 g/m2 vs. 33.02 ± 5.52 g/m2; P < 0.001). The number of chemotherapy cycles was associated with an increase in the ECV (Standard regression coefficient [β] = 0.383, P = 0.014) and a decrease in the ICMi (β = -0.349, P = 0.009). Patients with gynecologic cancer and low cardiovascular risk who undergo chemotherapy have diffuse extracellular volume expansion, which is obvious with the increase of chemotherapy cycles. Myocyte loss may be part of the mechanism in patients with a higher chemotherapy load. http://www.chictr.org.cn, identifier ChiCTR-DDD-17013450.

Features of coronary pathology and its relationship with myocardial fibrosis markers in patients with resistant hypertension

Aim. To evaluate the severity of coronary atherosclerosis and its association with biochemical markers of fibrosis in patients with coronary artery disease (CAD) and resistant hypertension (RHT).Material and methods. The study included 39 patients with CAD and RHT. All patients underwent 24-hour blood pressure (BP) monitoring, office BP numbers were measured. Laboratory diagnostics included routine tests, as well as determination of serum lipocalin, plasma concentration of matrix metalloproteinases 2 and 9 (­MMP-2, MMP-9), tissue inhibitor of matrix metalloproteinases-1 (TIMP 1). Coronary atherosclerosis in patients was assessed retrospectively according to medical records with an assessment of the protocols of invasive coronary angiography and multislice computed tomography, performed no more than a year ago from the moment of inclusion in the study with no clinical signs of CAD progression. Obstructive atherosclerosis was considered a coronary artery narrowing by more than 50%.Results. Considering the results of previous coronary angiography, the patients were divided into two groups. In the first group (n=20), coronary artery stenosis was &lt;50%, in the second (n=19) &gt;50% (p&lt;0,05). The compared groups of patients were comparable in sex, age, duration of hypertension, blood pressure level, and the number of antihypertensive drugs taken. There were no differences in blood lipid profile, basal glycemia, uric acid levels, and the frequency of previous cerebral accidents. However, the incidence of diabetes in group 2 was significantly higher (p&lt;0,05). Additionally, there was a significant difference in serum levels of lipocalin and MMP-2 with higher values of these indicators in patients with coronary atherosclerosis stenosis (p=0,02).Conclusion. In patients with RHT with symptoms and signs of myocardial ische­­mia, the incidence of obstructive coronary atherosclerosis according to coronary angiography is 50%. Diabetes in this category of patients indicates a more frequent obstruction of coronary bed. An increase in the level of MMP-2 and lipocalin in this category of patients is associated with more severe coronary damage and can be considered as an indirect indicator of obstructive coronary atherosclerosis.

Cardiac Toxicity Induced by Long-Term Environmental Levels of MC-LR Exposure in Mice.

Cyanobacterial blooms are considered a serious global environmental problem. Recent studies provided evidence for a positive association between exposure to microcystin-LR (MC-LR) and cardiotoxicity, posing a threat to human cardiovascular health. However, there are few studies on the cardiotoxic effects and mechanisms of long-term low-dose MC-LR exposure. Therefore, this study explored the long-term toxic effects and toxic mechanisms of MC-LR on the heart and provided evidence for the induction of cardiovascular disease by MC-LR. C57BL/6 mice were exposed to 0, 1, 30, 60, 90, and 120 μg/L MC-LR via drinking water for 9 months and subsequently necropsied to examine the hearts for microstructural changes using H&E and Masson staining. The results demonstrated fibrotic changes, and qPCR and Western blots showed a significant up-regulation of the markers of myocardial fibrosis, including TGF-β1, α-SMA, COL1, and MMP9. Through the screening of signaling pathways, it was found the expression of PI3K/AKT/mTOR signaling pathway proteins was up-regulated. These data first suggested MC-LR may induce myocardial fibrosis by activating the PI3K/AKT/mTOR signaling pathway. This study explored the toxicity of microcystins to the heart and preliminarily explored the toxic mechanisms of long-term toxicity for the first time, providing a theoretical reference for preventing cardiovascular diseases caused by MC-LR.

Therapeutic effects on the development of heart failure with preserved ejection fraction by the sodium-glucose cotransporter 2 inhibitor dapagliflozin in type 2 diabetes

BackgroundHeart failure with preserved ejection fraction (HFpEF) is a common disease with high morbidity and lacks effective treatment. We investigated the protective effects of the long-term application of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin on diabetes-associated HFpEF in a rat model. Serum proteomics and metabolomics analysis were also conducted in type 2 diabetic patients with HFpEF treated with dapagliflozin.MethodsMale Zucker diabetic fatty (ZDF) rats were used as a model of diabetic cardiomyopathy. From weeks 16 to 28, animals were given a vehicle or dapagliflozin (1 mg/kg) once daily. Primary blood biochemistry indices, echocardiography, histopathology, and cardiac hemodynamics were determined during the study period. The key markers of myocardial fibrosis, nitro-oxidative stress, inflammation, apoptosis, autophagy, and AMPK/mTOR signaling were examined. Additionally, healthy controls and individuals with type 2 diabetes were enrolled and 16 serum samples from 4 groups were randomly selected. Serum proteome and metabolome changes after dapagliflozin treatment were analyzed in diabetic individuals with HFpEF.ResultsDapagliflozin effectively prevented the development of HFpEF in rats with diabetes by mitigating nitro-oxidative stress, pro-inflammatory cytokines, myocardial hypertrophy, and fibrosis, reducing apoptosis, and restoring autophagy through AMPK activating and mTOR pathway repressing. Proteomics and metabolomics revealed that cholesterol and high-density lipoprotein particle metabolism, nicotinate and nicotinamide metabolism, arginine biosynthesis, and cAMP and peroxisome proliferator-activated receptor (PPAR) signaling are the major disturbed pathways in HFpEF patients treated with dapagliflozin.ConclusionLong-term treatment with dapagliflozin significantly prevented the development of HFpEF in diabetic rats. Dapagliflozin could be a promising therapeutic strategy in managing HFpEF individuals with type 2 diabetes.

Cardiac Computed Tomography for Quantification of Myocardial Extracellular Volume Fraction: A Systematic Review and Meta-Analysis

BackgroundExtracellular volume (ECV) is a quantitative measure of extracellular compartment expansion, and an increase in ECV is a marker of myocardial fibrosis. Although cardiac magnetic resonance (CMR) is considered the standard imaging tool for ECV quantification, cardiac computed tomography (CT) has also been used for ECV assessment. ObjectivesThe aim of this meta-analysis was to evaluate the correlation and agreement in the quantification of myocardial ECV by CT and CMR. MethodsPubMed and Web of Science were searched for relevant publications reporting on the use of CT for ECV quantification compared with CMR as the reference standard. The authors employed a meta-analysis using the restricted maximum-likelihood estimator with a random-effects method to estimate summary correlation and mean difference. A subgroup analysis was performed to compare the correlation and mean differences between single-energy CT (SECT) and dual-energy CT (DECT) techniques for the ECV quantification. ResultsOf 435 papers, 13 studies comprising 383 patients were identified. The mean age range was 57.3 to 82 years, and 65% of patients were male. Overall, there was an excellent correlation between CT-derived ECV and CMR-derived ECV (mean: 0.90 [95% CI: 0.86-0.95]). The pooled mean difference between CT and CMR was 0.96% (95% CI: 0.14%-1.78%). Seven studies reported correlation values using SECT, and 4 studies reported those using DECT. The pooled correlation from studies utilizing DECT for ECV quantification was significantly higher compared with those with SECT (mean: 0.94 [95% CI: 0.91-0.98] vs 0.87 [95% CI: 0.80-0.94], respectively; P = 0.01). There was no significant difference in pooled mean differences between SECT vs DECT (P = 0.85). ConclusionsCT-derived ECV showed an excellent correlation and mean difference of <1% with CMR-derived ECV. However, the overall quality of the included studies was low, and larger, prospective studies are needed to examine the accuracy and diagnostic and prognostic utility of CT-derived ECV.

Longitudinal Changes in Ventricular Mechanics in Adolescents After the Fontan Operation

Ventricular dysfunction is a significant clinical challenge in the long-term follow-up of patients with single-ventricle (SV) physiology. Ventricular function and myocardial mechanics can be studied using speckle-tracking echocardiography, which provides information on myocardial deformation. Limited information is available on serial changes in SV myocardial mechanics after the Fontan operation. The aim of this study was to describe serial changes in myocardial mechanics in children after the Fontan operation and the relationship of these changes with myocardial fibrosis markers as obtained by cardiac magnetic resonance and exercise performance parameters. The authors hypothesized that ventricular mechanics decline in patients with SVs over time and are associated with increased myocardial fibrosis and reduced exercise performance. A single-center retrospective cohort study including adolescents after the Fontan operation was conducted. Ventricular strain and torsion were assessed using speckle-tracking echocardiography. Cardiac magnetic resonance and cardiopulmonary exercise testing data closest to the latest echocardiographic examinations were performed. The most recent follow-up echocardiographic and cardiac magnetic resonance data were compared with those from sex- and age-matched control subjects and with individual patients' early post-Fontan data. Fifty patients with SVs (31 left ventricle, 13 right ventricle [RV], and six codominant) were included. Median time at follow-up echocardiography from the time of Fontan was 12.8years (interquartile range [IQR], 10.6 to 16.6years). Compared with early post-Fontan echocardiography, follow-up assessment showed reduced global longitudinal strain (-17.5% [IQR, -14.5% to -19.5%] vs -19.8% [IQR, -16.0% to -21.7%], P=.01], circumferential strain (-15.7% [IQR, -11.4% to -18.7%] vs -18.9% [IQR, -15.2% to -25.0%], P=.009), and torsion (1.28°/cm [IQR, 0.51°/cm to 1.74°/cm] vs 1.72°/cm [IQR, 0.92°/cm to 2.34°/cm], P=.02), with decreased apical rotation but no significant change in basal rotation. Single RVs had lower torsion compared with single left ventricles (1.04°/cm [IQR, 0.12°/cm to 2.20°/cm] vs 1.25°/cm [IQR, 0.25°/cm to 2.51°/cm], P=.01). T1 values were higher in patients with SV compared with control subjects (1,009±36 vs 958±40msec, P=.004) and in those with single RVs compared with single left ventricles (1,023±19 vs 1,006±17msec, P=.02). T1 was correlated with circumferential strain (r=0.59, P=.04) and inversely correlated with O2 saturation (r=-0.67, P<.001) and torsion (r=-0.71, P=.02). Peak oxygen consumption was correlated with torsion (r=0.52, P=.001) and untwist rates (r=0.23, P=.03). After the Fontan procedures, there is a progressive decrease in myocardial deformation parameters. The progressive decrease in SV torsion is related to a decrease in apical rotation, which is more pronounced in single RVs. Decreased torsion is associated with increased markers of myocardial fibrosis and lower maximal exercise capacity. Torsional mechanics may be an important parameter to monitor after Fontan palliation, but further prognostic information is required.

Overall fibrosis content rather than regional differences in extracellular volume alters ventricular conduction in aortic stenosis patients

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 research and innovation program under the ERA-NET co-fund action No. 680969 with ANR (ERA-CVD SICVALVES) and Agence Nationale de la Recherche Background Extracellular volume (ECV) determined by magnetic resonance imaging (MRI) is considered a marker of myocardial fibrosis and a predictor of mortality. In addition to diffuse fibrosis, aortic stenosis (AS) patients present increased ECV. However, the impact of regional ECV differences on ventricular conduction in AS patients has not been assessed. Purpose To investigate regional ECV differences in AS patients and to determine their impact on ventricular conduction. Methods MRI was performed in 22 AS patients (11 males, 11 females) before and 3 months after aortic valve replacement (AVR). Regional differences in ECV were determined between mid-ventricular and basal planes. To investigate the impact of these differences on conduction, a computational model of ventricular tissue (9x1x1 cm) was developed with human fiber orientation and transmural/apicobasal electrophysiology. The model was divided in two regions (Fig 1A), each representing tissue with different ECV. Extracellular conductivities (GE) in each region were adjusted to the patient with the highest difference in ECV between the planes (male 75y, post-AVR, ECV mid 25.5%, ECV base 31.3%) so that GE was 26.4% less for ECV of 31.3% compared to 25.5%. A model with uniform ECV of 25.5% was used as a control. The models were paced from the apical face with a S1-S2 protocol (S1: 750 ms, n=10, S2: 700-350 ms, n=1). To compare the results to conduction slowing from diffuse myocardial fibrosis, the simulations were repeated with an additional GE reduction by 40% in both regions to mimic conduction delays observed in fibrotic hearts. Ventricular conduction was compared between the models by analyzing conduction velocity (CV) measured between two points at the endocardium (Fig 1A, blue dots) and the occurrence of abnormalities in the form of non-uniform conduction, and/or conduction block after S2 (Fig 1B). Results Significantly higher ECV was found in the basal plane of AS patients when compared to the mid-ventricular plane before and after AVR (Fig 2), with the largest ECV found after AVR (mid-ventricular: p=0.0021; basal: p=0.0048). No sex-specific differences were found. The model representing the patient with the largest regional ECV difference showed slightly lower CV than the model with uniform ECV (92.9 vs. 96.0 cm/s, S2=500 ms). By contrast, myocardial fibrosis had a larger impact on CV slowing (92.9 vs. 79.2 cm/s, S2=500 ms, patient model, Fig 1C). Conduction block and non-uniform conduction occurred at comparable cycle lengths for all models (Fig 1D). Conclusion Regional differences in ECV were found in the ventricles of AS patients, but computer simulations suggest that these differences have a minimal effect on ventricular conduction when compared to diffuse fibrosis. Although the results suggest a limited electrophysiological relevance, additional studies are necessary to investigate whether these ECV differences have a more significant impact on cardiac mechanics.

Diagnostic and prognostic role of late gadolinium enhancement in cardiomyopathies.

Late gadolinium enhancement (LGE) is the most relevant tool of cardiac magnetic resonance for tissue characterization, and it plays a pivotal role for diagnostic and prognostic assessment of cardiomyopathies. The pattern of presentation of LGE allows differential diagnosis between ischaemic and non-ischaemic heart disease with high diagnostic accuracy, and among different cardiomyopathies, specific presentation of LGE may help to make a diagnosis. Late gadolinium enhancement may be caused by conditions that significantly increase the interstitial space or, less frequently, that slow down Gd exit, like myocardial fibrosis. In chronic myocardial infarction, hypertrophic cardiomyopathies (HCM), dilated cardiomyopathy, Fabry disease, and other conditions, LGE is a marker of myocardial fibrosis, but also in patients with acute myocarditis where LGE may be also explained by the increase of interstitial space caused by interstitial oedema or by tissue infiltration of inflammatory cells. In cardiac amyloidosis, LGE represents myocardial fibrosis but the interstitial overload of amyloid proteins should also be considered as a potential cause of LGE. The identification of the pattern of presentation of LGE is also very important. In the ischaemic pattern, LGE always involves the subendocardial layer with more or less transmural extent, it is confluent, and every single scar should be located in the territory of one coronary artery. In the non-ischaemic pattern, LGE does not fulfil the previous criteria, being midwall, subepicardial, or mixed, not necessarily confluent or confined to a territory of one coronary artery. For cardiomyopathies, the exact pattern of non-ischaemic LGE is important. Quantitative analysis of LGE is required in some specific conditions as in HCM. Magnetic resonance imaging with LGE technique should be performed in every patient with suspect of cardiomyopathy. The lack of standardization of pulse sequence and mostly of quantification methods is the main limitation of LGE technique.

Genetics of myocardial interstitial fibrosis in the human heart and association with disease.

Myocardial interstitial fibrosis is associated with cardiovascular disease and adverse prognosis. Here, to investigate the biological pathways that underlie fibrosis in the human heart, we developed a machine learning model to measure native myocardial T1 time, a marker of myocardial fibrosis, in 41,505 UK Biobank participants who underwent cardiac magnetic resonance imaging. Greater T1 time was associated with diabetes mellitus, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation, conduction disease and rheumatoid arthritis. Genome-wide association analysis identified 11 independent loci associated with T1 time. The identified loci implicated genes involved in glucose transport (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Using a transforming growth factor β1-mediated cardiac fibroblast activation assay, we found that 9 of the 11 loci consisted of genes that exhibited temporal changes in expression or open chromatin conformation supporting their biological relevance to myofibroblast cell state acquisition. By harnessing machine learning to perform large-scale quantification of myocardial interstitial fibrosis using cardiac imaging, we validate associations between cardiac fibrosis and disease, and identify new biologically relevant pathways underlying fibrosis.