ABSTRACT
Rotational mechanics is a fundamental determinant of left ventricular ejection fraction (LVEF). The coding system currently employed in clinical practice does not distinguish between rotational patterns. We propose an alternative coding system that makes possible to identify the rotational pattern of the LV and relate it to myocardial function. Echocardiographic images were used to generate speckle tracking-derived transmural global longitudinal strain (tGLS) and rotational parameters. The existence of twist (basal and apical rotations in opposite directions) is expressed as a rotational gradient with a positive value that is the sum of the basal and apical rotation angles. Conversely, when there is rigid rotation (basal and apical rotations in the same direction) the resulting gradient is assigned a negative value that is the subtraction between the two rotation angles. The rotational patterns were evaluated in 87 healthy subjects and 248 patients with LV hypertrophy (LVH) and contrasted with their myocardial function. Our approach allowed us to distinguish between the different rotational patterns. Twist pattern was present in healthy controls and 104 patients with LVH and normal myocardial function (tGLS ≥ 17%, both). Among 144 patients with LVH and myocardial dysfunction (tGLS < 17%), twist was detected in 83.3% and rigid rotation in 16.7%. LVEF was < 50% in 34.7%, and all patients with rigid rotation had a LVEF < 50%. The gradient rotational values showed a close relationship with LVEF (r = 0.73; p < 0.001). The proposed coding system allows us to identify the rotational patterns of the LV and to relate their values with LVEF.
Subject(s)
Echocardiography , Humans , Male , Female , Middle Aged , Aged , Rotation , Heart Ventricles/physiopathology , Heart Ventricles/diagnostic imaging , Adult , Hypertrophy, Left Ventricular/physiopathology , Hypertrophy, Left Ventricular/diagnostic imaging , Ventricular Function, Left/physiology , Stroke Volume/physiologyABSTRACT
BACKGROUND: Differentiation between exercise induced adaptive myocardial hypertrophy (athlete's heart) and hypertrophic cardiomyopathy (HCM) is currently based on echocardiographic and cardiac magnetic resonance (CMR) criteria, but these may be insufficient in patients with subtle phenotype expression. This study aimed to assess whether left ventricular (LV) fractal pattern could permit to differentiate athlete's heart from HCM. METHODS: We recruited retrospectively 61 elite marathon runners, 67 patients with HCM, and 33 healthy subjects. A CMR study was performed in all subjects and the LV trabeculae fractal dimension (FD) was measured in end-diastolic frames of each short-axis cine sequence. For group comparison, the ratio of maximal myocardial wall thickness (mMWT)/indexed LV end-diastolic volume (LVED) was determined. RESULTS: As compared with athletes, patients with HCM had significantly (p < 0.001) greater FD in the LV basal (1.30 ± 0.07 vs. 1.23 ± 0.05) and apical (1.38 ± 0.06 vs. 1.30 ± 0.07) regions and in the whole heart (1.34 ± 0.05 vs. 1.27 ± 0.05). FD increased with age, left atrial area and indexed left ventricular mass (p < 0.05 for all) and correlated negatively with LV and RV end-diastolic volumes (p < 0.05 each). The addition of whole heart FD to the ratio of maximal myocardial wall thickness/indexed LVEDV lead to an improvement in the ability to discriminate HCM with a net reclassification index (NRI) of 71%. CONCLUSIONS: The FD regional distribution of the LV trabeculae differentiates patients with athlete's heart from patients with HCM. The addition of whole heart FD to the mMWT/indexed LVEDV ratio improves the predictive capacity of the model to differentiate both entities.
Subject(s)
Cardiomegaly, Exercise-Induced , Cardiomyopathy, Hypertrophic , Cardiomyopathy, Hypertrophic/diagnostic imaging , Fractals , Heart Ventricles/diagnostic imaging , Humans , Hypertrophy, Left Ventricular , Retrospective StudiesABSTRACT
Few studies have analyzed the potential of biophysical parameters as markers of cardiac remodeling post-myocardial infarction (MI), particularly in human hearts. Fourier transform infrared spectroscopy (FTIR) illustrates the overall changes in proteins, nucleic acids and lipids in a single signature. The aim of this work was to define the FTIR and lipidomic pattern for human left ventricular remodeling post-MI. A total of nine explanted hearts from ischemic cardiomyopathy patients were collected. Samples from the right ventricle (RV), left ventricle (LV) and infarcted left ventricle (LV INF) were subjected to biophysical (FTIR and differential scanning calorimetry, DSC) and lipidomic (liquid chromatography-high-resolution mass spectrometry, LC-HRMS) studies. FTIR evidenced deep alterations in the myofibers, extracellular matrix proteins, and the hydric response of the LV INF compared to the RV or LV from the same subject. The lipid and esterified lipid FTIR bands were enhanced in LV INF, and both lipid indicators were tightly and positively correlated with remodeling markers such as collagen, lactate, polysaccharides, and glycogen in these samples. Lipidomic analysis revealed an increase in several species of sphingomyelin (SM), hexosylceramide (HexCer), and cholesteryl esters combined with a decrease in glycerophospholipids in the infarcted tissue. Our results validate FTIR indicators and several species of lipids as useful markers of left ventricular remodeling post-MI in humans.
Subject(s)
Lipidomics , Myocardial Infarction/metabolism , Ventricular Remodeling , Biomarkers/metabolism , Female , Humans , Male , Middle AgedABSTRACT
BACKGROUND: Beyond lipid-lowering, statins exert cardioprotective effects. High-dose statin treatment seems to reduce cardiovascular complications in high-risk patients. The ideal timing and administration regime remain unknown. OBJECTIVES: This study compared the cardioprotective effects of intravenous statin administration during myocardial infarction (MI) with oral administration immediately post-MI. METHODS: Hypercholesterolemic pigs underwent MI induction (90 min of ischemia) and were kept for 42 days. Animals were distributed in 3 arms (A): A1 received an intravenous bolus of atorvastatin during MI; A2 received an intravenous bolus of vehicle during MI; and A3 received oral atorvastatin within 2 h post-MI. A1 and A3 remained on daily oral atorvastatin for the following 42 days. Cardiac magnetic resonance analysis (days 3 and 42 post-MI) and molecular/histological studies were performed. RESULTS: At day 3, A1 showed a 10% reduction in infarct size compared with A3 and A2 and a 50% increase in myocardial salvage. At day 42, both A1 and A3 showed a significant decrease in scar size versus A2; however, A1 showed a further 24% reduction versus A3. Functional analyses revealed improved systolic performance in A1 compared with A2 and less wall motion abnormalities in the jeopardized myocardium versus both groups at day 42. A1 showed enhanced collagen content and AMP-activated protein kinase activation in the scar, increased vessel density in the penumbra, higher tumor necrosis factor α plasma levels and lower peripheral blood mononuclear cell activation versus both groups. CONCLUSIONS: Intravenous administration of atorvastatin during MI limits cardiac damage, improves cardiac function, and mitigates remodeling to a larger extent than when administered orally shortly after reperfusion. This therapeutic approach deserves to be investigated in ST-segment elevation MI patients.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/drug therapy , Administration, Intravenous , Administration, Oral , Animals , Drug Administration Schedule , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Hypercholesterolemia/blood , Hypercholesterolemia/diagnostic imaging , Hypercholesterolemia/drug therapy , Myocardial Infarction/blood , Random Allocation , SwineABSTRACT
The role of circular RNAs (circRNAs) as biomarkers remains poorly characterized. Here, we investigated the performance of the circRNA hsa_circ_0001445 as a biomarker of coronary artery disease (CAD) in a real-world clinical practice setting. Plasma hsa_circ_0001445 was measured in a study population of 200 consecutive patients with suspected stable CAD who had undergone coronary computed tomographic angiography (CTA). Multivariable logistic models were constructed combining conventional risk factors with established biomarkers and hsa_circ_0001445. Model robustness was internally validated by the bootstrap technique. Biomarker accuracy was evaluated using the C-index. The integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were also calculated. Risk groups were developed via classification tree models. The stability of plasma hsa_circ_0001445 was evaluated under different clinical conditions. hsa_circ_0001445 levels were associated with higher coronary atherosclerosis extent and severity with a 2-fold increase across tertiles (28.4%-50.0%). Levels of hsa_circ_0001445 were proportional to coronary atherosclerotic burden, even after comprehensive adjustment for cardiovascular risk factors, medications, and established biomarkers (fully adjusted OR = 0.432 for hsa_circ_0001445 as a continuous variable and fully adjusted OR = 0.277 for hsa_circ_0001445 as a binary variable). The classification of patients was improved with the incorporation of hsa_circ_0001445 into a base clinical model (CM) composed of conventional cardiovascular risk factors, showing an IDI of 0.047 and NRI of 0.482 for hsa_circ_0001445 as a continuous variable and an IDI of 0.056 and NRI of 0.373 for hsa_circ_0001445 as a binary variable. A trend toward higher discrimination capacity was also observed (C-indexCM = 0.833, C-indexCM+continuous hsa_circ_0001445 = 0.856 and C-indexCM+binary hsa_circ_0001445 = 0.855). Detailed analysis of stability showed that hsa_circ_0001445 was present in plasma in a remarkably stable form. In vitro, hsa_circ_0001445 was downregulated in extracellular vesicles secreted by human coronary smooth muscle cells upon exposure to atherogenic conditions. In patients with suspected stable CAD referred for coronary CTA, plasma hsa_circ_0001445 improves the identification of coronary artery atherosclerosis.
Subject(s)
Biomarkers/blood , Coronary Artery Disease/blood , Coronary Artery Disease/metabolism , RNA, Circular/blood , RNA, Circular/metabolism , Aged , Female , Humans , Male , Middle Aged , Multivariate Analysis , Myocytes, Smooth Muscle/metabolism , RNA Stability/genetics , RNA Stability/physiologyABSTRACT
Epicardial adipose tissue (EAT) constitutes a novel parameter for cardiometabolic risk assessment and a target for therapy. Here, we evaluated for the first time the plasma microRNA (miRNA) profile as a source of biomarkers for epicardial fat volume (EFV). miRNAs were profiled in plasma samples from 180 patients whose EFV was quantified using multidetector computed tomography. In the screening study, 54 deregulated miRNAs were identified in patients with high EFV levels (highest tertile) compared with matched patients with low EFV levels (lowest tertile). After filtering, 12 miRNAs were selected for subsequent validation. In the validation study, miR-15b-3p, miR-22-3p, miR-148a-3p miR-148b-3p and miR-590-5p were directly associated with EFV, even after adjustment for confounding factors (p value < 0.05 for all models). The addition of miRNA combinations to a model based on clinical variables improved the discrimination (area under the receiver-operating-characteristic curve (AUC) from 0.721 to 0.787). miRNAs correctly reclassified a significant proportion of patients with an integrated discrimination improvement (IDI) index of 0.101 and a net reclassification improvement (NRI) index of 0.650. Decision tree models used miRNA combinations to improve their classification accuracy. These results were reproduced using two proposed clinical cutoffs for epicardial fat burden. Internal validation corroborated the robustness of the models. In conclusion, plasma miRNAs constitute novel biomarkers of epicardial fat burden.
ABSTRACT
OBJECTIVES: To explore the diagnostic performance of circulating microRNAs (miRNAs) as biomarkers in patients with suspected stable coronary artery disease (CAD). METHODS: Plasma samples were collected from 237 consecutive patients referred for coronary computed tomography angiography (CCTA). Presence, extension and severity of coronary stenosis were evaluated using the indexes: presence of diameter stenosis ≥ 50%, segment involvement score (SIS), segment stenosis score (SSS) and 3-vessel plaque score. A panel of 10 miRNAs previously associated with CAD was analysed using RT-qPCR. Multivariate analyses were used to analyse the associations between biomarkers and indexes. Discrimination was evaluated using the area under the ROC curve (AUC). Decision trees were generated using chi-squared Automatic Interaction Detector (CHAID) prediction models. RESULTS: After comprehensive adjustment including cardiovascular risk factors, medication use, confounding factors and protein-based biomarkers (hs-TnT and hs-CRP), several circulating miRNAs were inversely associated with coronary atherosclerosis extension (SIS and 3-vessel plaque score) and severity (SSS). In the whole population, circulating miRNAs showed a poor discrimination value for all indexes (AUC = 0.539-0.644) and did not increase the discrimination capacity of a clinical model of coronary stenosis presence, extension and severity based on conventional cardiovascular risk factors. Conversely, the inclusion of circulating miRNAs in decision trees produces models that improve the classification of cases and controls in specific patient subgroups. CONCLUSIONS: This study identifies a group of circulating miRNAs that failed to improve the discrimination capacity of cardiovascular risk factors but that has the potential to define specific subpopulations of patients with suspected stable CAD.
Subject(s)
Circulating MicroRNA/metabolism , Coronary Artery Disease/diagnostic imaging , Biomarkers/metabolism , Computed Tomography Angiography/methods , Coronary Angiography/methods , Coronary Artery Disease/blood , Female , Humans , Male , Middle Aged , Prospective Studies , ROC CurveABSTRACT
OBJECTIVES: Cardiovascular magnetic resonance (CMR) provides information on myocardial ischemia through stress perfusion studies. In clinical practice, the grading of induced perfusion defects is performed by visual estimation of their extension. The aim of our study is to devise a score of the degree of ischemia and to test its prognostic value. METHODS: Between 2009 and 2011, patients with diagnosed or suspected coronary artery disease underwent stress perfusion CMR. A score of ischemic burden was calculated on the basis of (1) stress-induced perfusion defect, (2) persistence, (3) transmurality, and (4) stress-induced contractile defect. Follow-up was censored after 4 years and primary end-point was defined by a composite of death, heart failure episode, acute coronary syndrome, and ventricular arrhythmias. Univariate and multivariate logistic regressions were used to assess the strength of the association between the CMR ischemic variables, and the composite outcome. RESULTS: Forty-four of the 128 patients (34%) presented with adverse events, while 84 (66%) did not. Sixty-one patients (48%) had negative perfusion studies while 67 (52%) showed perfusion defect. Patients with positive perfusion studies and adverse events (n = 39) had higher number of segments with persistent defect (3.3 vs 1.3, p = 0.001) and highest score (19.6 vs 13.3 p = 0.012) than patients with positive perfusion studies and absence of events (n = 28). The number of segments with persistent defect showed the strongest predictive value of adverse events (OR 1.54; CI 1.19-2.00; p < 0.001). CONCLUSIONS: The score of ischemic burden proposed herein has prognostic value. Persistence of a perfusion defect has the strongest impact on prognosis. KEY POINTS: ⢠Cardiovascular magnetic resonance provides information on myocardial ischemia by visual estimation of the presence of perfusion defects induced by stress. ⢠There is not a standardized method for grading perfusion defects which, in practice, is performed by visual estimation of their extension. ⢠As proven in this study, the integration of several parameters of perfusion defects (in addition to extension) into a semiquantitative score has prognostic value.
Subject(s)
Coronary Artery Disease/diagnostic imaging , Magnetic Resonance Imaging/methods , Myocardial Perfusion Imaging/methods , Acute Coronary Syndrome/etiology , Adenosine , Aged , Arrhythmias, Cardiac/etiology , Coronary Artery Disease/complications , Female , Heart Failure/etiology , Humans , Magnetic Resonance Imaging/adverse effects , Male , Middle Aged , Myocardial Perfusion Imaging/adverse effects , Predictive Value of Tests , PrognosisABSTRACT
There is still some controversy about the benignity of structural changes observed in athlete's heart, especially regarding the observation of increased biomarkers and the presence of myocardial fibrosis (MF). AIM: Our purpose was to evaluate by cardiovascular magnetic resonance (CMR) the presence of diffuse as well as focal MF in a series of high-performance veteran endurance athletes. METHODS: Thirty-four veteran healthy male endurance athletes, still being in regular training, with more than 10 years of training underwent a CMR. A cardiopulmonary exercise test was also performed to assess their maximal physical performance. The control group consisted in 12 non-trained normal individuals. RESULTS: We found an increase in both, right and left ventricular (LV) volumes in the athlete's group when compared with controls. There was no increase in indexed LV myocardial mass despite of a significantly increased maximal myocardial wall thickness in comparison to controls. Native T1 values and extracellular volume (ECV) were normal in all cases. We did not find differences in native T1 values and ECV between both groups. In three athletes (9%), non-ischaemic late gadolinium enhancement (LGE) was observed. We did not find a correlation between total training volume and presence of LGE or with the ECV value. CONCLUSIONS: Our results show that the majority of veteran endurance athletes present with myocardial remodelling without MF as a physiological adaptive phenomenon. In the only three athletes with focal MF, the LGE pattern observed suggests an intercurrent event not related with the remodelling phenomenon.
ABSTRACT
Aims: P2Y12 antagonists are the standard in antiplatelet therapy but their potential effects on functional myocardial recovery and cardioprotection post-myocardial infarction (MI) are unknown. We investigated in a preclinical model of MI whether ticagrelor and clopidogrel differently affect cardiac repair post-MI. Methods and results: Pigs either received: (i) clopidogrel (600 mg; 75 mg/qd); (ii) ticagrelor (180 mg; 90 mg/bid); and (iii) placebo control. MI was induced by mid-left anterior descending coronary artery balloon occlusion (60 min) and animals received the maintenance doses for the following 42 days. Serial cardiac magnetic resonance was performed at Day 3 and Day 42 for the assessment of global and regional cardiac parameters. We determined cardiac AMP-activated protein kinase (AMPK), Akt/PKB, aquaporin-4, vascular density, and fibrosis. In comparison to controls, both P2Y12 antagonists limited infarct expansion at Day 3, although ticagrelor induced a further 5% reduction (P < 0.05 vs. clopidogrel) whereas oedema was only reduced by ticagrelor (≈23% P < 0.05). Scar size decreased at Day 42 in ticagrelor-treated pigs vs. controls but not in clopidogrel-treated pigs. Left ventricular ejection fraction was higher 3 days post-MI in ticagrelor-treated pigs and persisted up to Day 42 (P < 0.05 vs. post-MI). Regional analysis revealed that control and clopidogrel-treated pigs had severe and extensive wall motion abnormalities in the jeopardized myocardium and a reduced myocardial viability that was not as evident in ticagrelor-treated pigs (χ2P < 0.05 vs. ticagrelor). Only ticagrelor enhanced myocardial AMPK and Akt/PKB activation and reduced aquaporin-4 levels (P < 0.05 vs. control and clopidogrel). No differences were observed in vessel density and fibrosis markers among groups. Conclusions: Ticagrelor is more efficient than clopidogrel in attenuating myocardial structural and functional alterations post-MI and in improving cardiac healing. These benefits are associated with persistent AMPK and Akt/PKB activation.
Subject(s)
Clopidogrel/pharmacology , Heart Ventricles/drug effects , Myocardial Infarction/drug therapy , Myocytes, Cardiac/drug effects , Purinergic P2Y Receptor Antagonists/pharmacology , Receptors, Purinergic P2/drug effects , Ticagrelor/pharmacology , AMP-Activated Protein Kinases/metabolism , Animals , Disease Models, Animal , Echocardiography , Fibrosis , Heart Ventricles/diagnostic imaging , Heart Ventricles/metabolism , Heart Ventricles/physiopathology , Magnetic Resonance Imaging, Cine , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/metabolism , Myocardial Infarction/physiopathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2Y12 , Signal Transduction/drug effects , Stroke Volume/drug effects , Sus scrofa , Time Factors , Ventricular Function, Left/drug effects , Ventricular Remodeling/drug effectsABSTRACT
Our aim was to identify biophysical biomarkers of ventricular remodelling in tachycardia-induced dilated cardiomyopathy (DCM). Our study includes healthy controls (N = 7) and DCM pigs (N = 10). Molecular analysis showed global myocardial metabolic abnormalities, some of them related to myocardial hibernation in failing hearts, supporting the translationality of our model to study cardiac remodelling in dilated cardiomyopathy. Histological analysis showed unorganized and agglomerated collagen accumulation in the dilated ventricles and a higher percentage of fibrosis in the right (RV) than in the left (LV) ventricle (P = .016). The Fourier Transform Infrared Spectroscopy (FTIR) 1st and 2nd indicators, which are markers of the myofiber/collagen ratio, were reduced in dilated hearts, with the 1st indicator reduced by 45% and 53% in the RV and LV, respectively, and the 2nd indicator reduced by 25% in the RV. The 3rd FTIR indicator, a marker of the carbohydrate/lipid ratio, was up-regulated in the right and left dilated ventricles but to a greater extent in the RV (2.60-fold vs 1.61-fold, P = .049). Differential scanning calorimetry (DSC) showed a depression of the freezable water melting point in DCM ventricles - indicating structural changes in the tissue architecture - and lower protein stability. Our results suggest that the 1st, 2nd and 3rd FTIR indicators are useful markers of cardiac remodelling. Moreover, the 2nd and 3rd FITR indicators, which are altered to a greater extent in the right ventricle, are associated with greater fibrosis.
Subject(s)
Carbohydrates/chemistry , Cardiomyopathy, Dilated/diagnosis , Heart Ventricles/metabolism , Lipids/chemistry , Myocardial Stunning/metabolism , Tachycardia/diagnosis , Ventricular Remodeling , Animals , Biomarkers/chemistry , Calorimetry, Differential Scanning , Cardiomyopathy, Dilated/etiology , Cardiomyopathy, Dilated/metabolism , Cardiomyopathy, Dilated/pathology , Case-Control Studies , Collagen/metabolism , Female , Heart Ventricles/pathology , Humans , Myocardial Stunning/pathology , Myocardium/metabolism , Myocardium/pathology , Myofibrils/metabolism , Spectroscopy, Fourier Transform Infrared , Swine , Tachycardia/complications , Tachycardia/metabolism , Tachycardia/pathologyABSTRACT
BACKGROUND: Myocardial microvascular loss after myocardial infarction (MI) remains a therapeutic challenge. Autologous stem cell therapy was considered as an alternative; however, it has shown modest benefits due to the impairing effects of cardiovascular risk factors on stem cells. Allogenic adipose-derived stem cells (ASCs) may overcome such limitations, and because of their low immunogenicity and paracrine potential may be good candidates for cell therapy. In the present study we investigated the effects of allogenic ASCs and their released products on cardiac rarefaction post MI. METHODS: Pig subcutaneous adipose tissue ASCs were isolated, expanded and GFP-labeled. ASC angiogenic function was assessed by the in-vivo chick chorioallantoic membrane (CAM) model. Pigs underwent MI induction and 7 days after were randomized to receive: allogenic ASCs (intracoronary infusion); conditioned media (CM; intravenous infusion); ASCs + CM; or PBS/placebo (control). Cardiac damage and function were monitored by 3-T cardiac magnetic resonance imaging upon infusion (baseline CMR) and 1 and 3 weeks thereafter. We assessed in the myocardium: microvessel density; angiogenic markers (CD105, CD31, TF, VEGFR2, VEGFR1, vWF, eNOS, CD62); collagen deposition; and reparative fibrosis (TGFß/TßRII/collagen). Differential proteomics of ASCs and CM was performed to characterize the ASC protein signature. RESULTS: CAM indicated a significant ASC proangiogenic capacity. In pigs after MI, only PBS/placebo animals displayed an impaired cardiac function 3 weeks after infusion (p < 0.05 vs baseline). Administration of ASCs + CM significantly enhanced neovessel formation and favored cardiac repair post MI (p < 0.05 vs the other groups). Molecular markers of angiogenesis were significantly upregulated both at transcriptional and protein levels (p < 0.05). The in-silico bioinformatics analysis of the ASC and CM proteome (interactome) indicated activation of a coordinated protein network involved in the formation of microvessels and the resolution of rarefaction. CONCLUSION: Coadministration of allogenic ASCs and their CM synergistically contribute to the neovascularization of the infarcted myocardium through a coordinated upregulation of the proangiogenic protein interactome.
Subject(s)
Myocardial Infarction/therapy , Myocardial Ischemia/therapy , Stem Cell Transplantation , Transplantation, Autologous , Adipose Tissue/cytology , Animals , Cell- and Tissue-Based Therapy , Humans , Microvessels/growth & development , Microvessels/physiopathology , Myocardial Infarction/physiopathology , Myocardial Ischemia/physiopathology , Myocardium/pathology , Risk Factors , Swine , Systems BiologyABSTRACT
AIMS: To analyze the impact of atherogenic lipoproteins on the miRNA signature of microvesicles derived from human coronary artery smooth muscle cells (CASMC) and to translate these results to familial hypercholesterolemia (FH) and coronary artery disease (CAD) patients. METHODS: Conditioned media was collected after exposure of CASMC to atherogenic lipoproteins. Plasma samples were collected from two independent populations of diagnosed FH patients and matched normocholesterolemic controls (Study population 1, N=50; Study population 2, N=24) and a population of patients with suspected CAD (Study population 3, N=50). Extracellular vesicles were isolated and characterized using standard techniques. A panel of 30 miRNAs related to vascular smooth muscle cell (VSMC) (patho-)physiology was analyzed using RT-qPCR. RESULTS: Atherogenic lipoproteins significantly reduced levels of miR-15b-5p, -24-3p, -29b-3p, -130a-3p, -143-3p, -146a-3p, -222-3p, -663a levels (P<0.050) in microvesicles (0.1µm-1µm in diameter) released by CASMC. Two of these miRNAs, miR-24-3p and miR-130a-3p, were reduced in circulating microvesicles from FH patients compared with normocholesterolemic controls in a pilot study (Study population 1) and in different validation studies (Study populations 1 and 2) (P<0.050). Supporting these results, plasma levels of miR-24-3p and miR-130a-3p were also downregulated in FH patients compared to controls (P<0.050). In addition, plasma levels of miR-130a-3p were inversely associated with coronary atherosclerosis in a cohort of suspected CAD patients (Study population 3) (P<0.050). CONCLUSIONS: Exposure to atherogenic lipoproteins modifies the miRNA profile of CASMC-derived microvesicles and these alterations are reflected in patients with FH. Circulating miR-130a-3p emerges as a potential biomarker for coronary atherosclerosis.
Subject(s)
Coronary Artery Disease/blood , Coronary Vessels/metabolism , Hypercholesterolemia/blood , MicroRNAs/blood , Aged , Atherosclerosis/blood , Atherosclerosis/genetics , Atherosclerosis/pathology , Biomarkers/blood , Cell-Derived Microparticles , Coronary Artery Disease/genetics , Coronary Artery Disease/pathology , Coronary Vessels/pathology , Female , Humans , Hypercholesterolemia/genetics , Hypercholesterolemia/pathology , Male , Middle Aged , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathologyABSTRACT
No disponible
Subject(s)
Humans , Male , Aged , Saphenous Vein/transplantation , Coronary Artery Bypass/methods , Aneurysm, False/complications , Risk Factors , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: The P2Y12 receptor antagonist ticagrelor has been shown to be clinically superior to clopidogrel. Although the underlying mechanisms remain elusive, ticagrelor may exert off-target effects through adenosine-related mechanisms. We aimed to investigate whether ticagrelor reduces myocardial injury to a greater extent than clopidogrel after myocardial infarction (MI) at a similar level of platelet inhibition and to determine the underlying mechanisms. METHODS: Pigs received the following before MI induction: (1) placebo-control; (2) a loading dose of clopidogrel (600 mg); (3) a loading dose of ticagrelor (180 mg); or (4) a loading dose of ticagrelor followed by an adenosine A1/A2-receptor antagonist [8-(p-sulfophenyl)theophylline, 4 mg/kg intravenous] to determine the potential contribution of adenosine in ticagrelor-related cardioprotection. Animals received the corresponding maintenance doses of the antiplatelet agents during the following 24 hours and underwent 3T-cardiac MRI analysis. Platelet inhibition was monitored by ADP-induced platelet aggregation. In the myocardium, we assessed the expression and activation of proteins known to modulate edema formation, including aquaporin-4 and AMP-activated protein kinase and its downstream effectors CD36 and endothelial nitric oxide synthase and cyclooxygenase-2 activity. RESULTS: Clopidogrel and ticagrelor exerted a high and consistent antiplatelet effect (68.2% and 62.2% of platelet inhibition, respectively, on challenge with 20 µmol/L ADP) that persisted up to 24 hours post-MI (P<0.05). All groups showed comparable myocardial area-at-risk and cardiac worsening after MI induction. 3T-Cardiac MRI analysis revealed that clopidogrel- and ticagrelor-treated animals had a significantly smaller extent of MI than placebo-control animals (15.7 g left ventricle and 12.0 g left ventricle versus 22.8 g left ventricle, respectively). Yet, ticagrelor reduced infarct size to a significantly greater extent than clopidogrel (further 23.5% reduction; P=0.0026), an effect supported by troponin-I assessment and histopathologic analysis (P=0.0021). Furthermore, in comparison with clopidogrel, ticagrelor significantly diminished myocardial edema by 24.5% (P=0.004), which correlated with infarct mass (r=0.73; P<0.001). 8-(p-Sulfophenyl)theophylline administration abolished the cardioprotective effects of ticagrelor over clopidogrel. At a molecular level, aquaporin-4 expression decreased and the expression and activation of AMP-activated protein kinase signaling and cyclooxygenase-2 increased in the ischemic myocardium of ticagrelor- versus clopidogrel-treated animals (P<0.05). These protein changes were not observed in those animals administered the adenosine receptor blocker 8-(p-sulfophenyl)theophylline. CONCLUSIONS: Ticagrelor, beyond its antiplatelet efficacy, exerts cardioprotective effects by reducing necrotic injury and edema formation via adenosine-dependent mechanisms.
Subject(s)
Adenosine/analogs & derivatives , Cardiotonic Agents/pharmacology , Myocardial Infarction/drug therapy , Ticlopidine/analogs & derivatives , Adenosine/pharmacology , Animals , Blood Platelets/drug effects , Clopidogrel , Cyclooxygenase 2/metabolism , Myocardial Infarction/enzymology , Myocardial Infarction/pathology , Platelet Aggregation Inhibitors/pharmacology , Random Allocation , Swine , Ticagrelor , Ticlopidine/pharmacologySubject(s)
Aneurysm, False/diagnostic imaging , Coronary Artery Bypass , Postoperative Complications/diagnostic imaging , Saphenous Vein/diagnostic imaging , Aged , Coronary Artery Disease/surgery , Echocardiography , Humans , Magnetic Resonance Imaging , Male , Saphenous Vein/transplantation , Tomography, X-Ray ComputedABSTRACT
La insuficiencia mitral es la valvulopatía más prevalente en Estados Unidos y la segunda en Europa. Una vez se establecen los síntomas o produce una repercusión significativa en la función cardiaca, la insuficiencia mitral grave tiene un pronóstico adverso con tratamiento médico. A pesar de ello, no se opera hasta la mitad de los pacientes con insuficiencia mitral grave sintomática por edad avanzada, disfunción ventricular y otras comorbilidades. Se ha demostrado que la cirugía obtiene mayor supervivencia a las insuficiencias mitrales orgánicas por prolapso, pero no se ha podido demostrar un beneficio clínico de intervenir insuficiencias mitrales funcionales. En este escenario, la reparación percutánea de la insuficiencia mitral nativa permite intervenir la valvulopatía en pacientes con alto riesgo quirúrgico. La reparación percutánea de la insuficiencia mitral es un campo en expansión con gran dependencia de las técnicas de imagen tanto para el diagnóstico de la anatomía funcional que reparar como para guiar el procedimiento (AU)
Mitral regurgitation is the most prevalent valvular heart disease in the United States and the second most prevalent in Europe. Patients with severe mitral regurgitation have a poor prognosis with medical therapy once they become symptomatic or develop signs of significant cardiac dysfunction. However, as many as half of these patients are inoperable because of advanced age, ventricular dysfunction, or other comorbidities. Studies have shown that surgery increases survival in patients with organic mitral regurgitation due to valve prolapse but has no clinical benefit in those with functional mitral regurgitation. In this scenario, percutaneous repair for mitral regurgitation in native valves provides alternative management of valvular heart disease in patients at high surgical risk. Percutaneous repair for mitral regurgitation is a growing field that relies heavily on imaging techniques to diagnose functional anatomy and guide repair procedures (AU)
Subject(s)
Humans , Mitral Valve Insufficiency , Angioplasty/methods , Echocardiography, Transesophageal/methods , Surgery, Computer-Assisted/methods , Magnetic Resonance Imaging, Interventional/methods , Tomography, X-Ray Computed , Mitral Valve/anatomy & histologyABSTRACT
Mitral regurgitation is the most prevalent valvular heart disease in the United States and the second most prevalent in Europe. Patients with severe mitral regurgitation have a poor prognosis with medical therapy once they become symptomatic or develop signs of significant cardiac dysfunction. However, as many as half of these patients are inoperable because of advanced age, ventricular dysfunction, or other comorbidities. Studies have shown that surgery increases survival in patients with organic mitral regurgitation due to valve prolapse but has no clinical benefit in those with functional mitral regurgitation. In this scenario, percutaneous repair for mitral regurgitation in native valves provides alternative management of valvular heart disease in patients at high surgical risk. Percutaneous repair for mitral regurgitation is a growing field that relies heavily on imaging techniques to diagnose functional anatomy and guide repair procedures.
Subject(s)
Diagnostic Techniques, Cardiovascular , Heart Valve Prosthesis Implantation/methods , Mitral Valve Insufficiency/surgery , Mitral Valve/diagnostic imaging , Surgery, Computer-Assisted/methods , Humans , Mitral Valve/surgery , Mitral Valve Insufficiency/diagnosisABSTRACT
The benefits of chronic total coronary occlusion (CTO) revascularization are not well established. In this prospective cohort study, 47 consecutive patients with successful percutaneous recanalization of CTO underwent adenosine stress cardiac magnetic resonance (CMR), 6-minute walk test (6MWT), and the Short Form-36 Health Survey before and 6 months after the procedure. Successful recanalization of a CTO was followed by significant improvement of (1) global physical and mental health status; (2) the distance walked in the 6MWT; (3) the incidence of chest pain at the end of the 6MWT; and (4) the score of a novel CMR ischemic burden index on the basis of the characteristics of adenosine stress perfusion defects (extension, persistence, transmurality, and induced contractile regional dysfunction). Patients with greater CMR ischemic index before percutaneous revascularization showed better improvement in the 6MWT. In conclusion, successful recanalization of a CTO leads to a concurrent improvement in ischemic burden, exercise tolerance, angina frequency, and quality of life scores. Patients with a high ischemic CMR score before CTO recanalization showed the better improvement in exercise tolerance.