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Purpose To investigate if aortic stiffening as detected with cardiac MRI is an early phenomenon in the development and progression of heart failure with preserved ejection fraction (HFpEF). Materials and Methods Both clinical and preclinical studies were performed. The clinical study was a secondary analysis of the prospective HFpEF stress trial (August 2017 through September 2019) and included 48 participants (median age, 69 years [range, 65-73 years]; 33 female, 15 male) with noncardiac dyspnea (NCD, n = 21), overt HFpEF at rest (pulmonary capillary wedge pressure [PCWP] ≥ 15 mm Hg, n = 14), and masked HFpEF at rest diagnosed during exercise stress (PCWP ≥ 25 mm Hg, n = 13) according to right heart catheterization. Additionally, all participants underwent echocardiography and cardiac MRI at rest and during exercise stress. Aortic pulse wave velocity (PWV) was calculated. The mechanistic preclinical study characterized cardiac function and structure in transgenic mice with induced arterial stiffness (Runx2-smTg mice). Statistical analyses comprised nonparametric and parametric comparisons, Spearman correlations, and logistic regression models. Results Participants with HFpEF showed increased PWV (NCD vs masked HFpEF: 7.0 m/sec [IQR: 5.0-9.5 m/sec] vs 10.0 m/sec [IQR: 8.0-13.4 m/sec], P = .005; NCD vs overt HFpEF: 7.0 m/sec [IQR: 5.0-9.5 m/sec] vs 11.0 m/sec [IQR: 7.5-12.0 m/sec], P = .01). Increased PWV correlated with higher PCWP (P = .006), left atrial and left ventricular long-axis strain (all P < .02), and N-terminal pro-brain natriuretic peptide levels (P < .001). Participants with overt HFpEF had higher levels of myocardial fibrosis, as demonstrated by increased native T1 times (1199 msec [IQR: 1169-1228 msec] vs 1234 msec [IQR: 1208-1255 msec], P = .009). Aortic stiffness was independently associated with HFpEF on multivariable analyses (odds ratio, 1.31; P = .049). Runx2-smTG mice exhibited an "HFpEF" phenotype compared with wild-type controls, with preserved left ventricular fractional shortening but an early and late diastolic mitral annulus velocity less than 1 (mean, 0.67 ± 0.39 [standard error of the mean] vs 1.45 ± 0.47; P = .004), increased myocardial collagen deposition (mean, 11% ± 1 vs 2% ± 1; P < .001), and increased brain natriuretic peptide levels (mean, 171 pg/mL ± 23 vs 101 pg/mL ± 10; P < .001). Conclusion This study provides translational evidence that increased arterial stiffness might be associated with development and progression of HFpEF and may facilitate its early detection. Keywords: MR Functional Imaging, MR Imaging, Animal Studies, Cardiac, Aorta, Heart ClinicalTrials.gov identifier NCT03260621 Supplemental material is available for this article. © RSNA, 2024.
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Progressão da Doença , Insuficiência Cardíaca , Volume Sistólico , Rigidez Vascular , Humanos , Rigidez Vascular/fisiologia , Feminino , Masculino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/diagnóstico por imagem , Idoso , Volume Sistólico/fisiologia , Animais , Camundongos , Estudos Prospectivos , Imagem Cinética por Ressonância Magnética/métodos , Ecocardiografia , Imageamento por Ressonância Magnética , Análise de Onda de PulsoRESUMO
BACKGROUND: Increasing arterial stiffness is a prominent feature of the aging cardiovascular system. Arterial stiffening leads to fundamental alterations in central hemodynamics with widespread detrimental implications for organ function resulting in significant morbidity and death, and specific therapies to address the underlying age-related structural arterial remodeling remain elusive. The present study investigates the potential of the recently clinically available dual angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) to counteract age-related arterial fibrotic remodeling and stiffening in 1-year-old mice. METHODS AND RESULTS: Treatment of in 1-year-old mice with ARNI (sacubitril/valsartan), in contrast to angiotensin receptor blocker monotherapy (valsartan) and vehicle treatment (controls), significantly decreases structural aortic stiffness (as measured by in vivo pulse-wave velocity and ex vivo aortic pressure myography). This phenomenon appears, at least partly, independent of (indirect) blood pressure effects and may be related to a direct antifibrotic interference with aortic smooth muscle cell collagen production. Furthermore, we find aortic remodeling and destiffening due to ARNI treatment to be associated with improved parameters of cardiac diastolic function in aged mice. CONCLUSIONS: This study provides preclinical mechanistic evidence indicating that ARNI-based interventions may counteract age-related arterial stiffening and may therefore be further investigated as a promising strategy to improve cardiovascular outcomes in the elderly.
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Aminobutiratos , Insuficiência Cardíaca , Rigidez Vascular , Humanos , Idoso , Pessoa de Meia-Idade , Camundongos , Animais , Lactente , Neprilisina , Angiotensinas , Tetrazóis/uso terapêutico , Receptores de Angiotensina , Valsartana/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Combinação de Medicamentos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Volume SistólicoRESUMO
(1) Background: Acute aortic dissection (AAD) is caused by an endothelial entry tear followed by intimomedial delamination of the outer layers of the vessel wall. The established risk factors include hypertension and smoking. Another rising candidate risk factor is excessive alcohol consumption. This experimental study explores the effects of nicotine (Nic), angiotensin II (Ang II), and ethanol (EtOH) on human aortic endothelial cells (hAoEC). (2) Methods: HAoECs were exposed to Nic, Ang II, and EtOH at different dose levels. Cell migration was studied using the scratch assay and live-cell imaging. The metabolic viability and permeability capacity was investigated using the water-soluble tetrazolium (WST)-1 assay and an in vitro vascular permeability assay. Cell adherence was studied by utilizing the hanging drop assay. The transcriptional and protein level changes were analyzed by RT-qPCR, Western blotting and immunohistochemistry for major junctional complexing proteins. (3) Results: We observed reduced metabolic viability following Ang II and EtOH exposure vs. control. Further, cell adherence was enhanced by EtOH exposure prior to trituration and by all risk factors after trituration, which correlated with the increased gene and protein expression of VE-cadherin upon EtOH exposure. The cell migration capacity was reduced upon EtOH exposure vs. controls. (4) Conclusion: Marked functional changes were observed upon exposure to established and potential risk factors for AAD development in hAoECs. Our findings advocate for an enhanced mechanical rigidity in hAoECs in response to the three substances studied, which in turn might increase endothelial rigidity, suggesting a novel mechanism for developing an endothelial entry tear due to reduced deformability in response to increased shear and pulsatile stress.
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PURPOSE: Endovascular aortic repair (EVAR) is the method of choice for most abdominal aortic aneurysm (AAA) patients requiring intervention. However, chronic aortic neck dilatation (AND) following EVAR progressively weakens the structural seal between vessel and endograft and compromises long-term results of the therapy. This experimental ex vivo study seeks to investigate mechanisms of AND. MATERIALS AND METHODS: Porcine abdominal aortas (n=20) were harvested from slaughterhouse pigs and connected to a mock circulation. A commercially available endograft was implanted (n=10) or aortas were left untreated as controls (n=10). Vascular circumferential strain was assessed via ultrasound in defined aortic segments as a parameter of aortic stiffness. Histology and aortic gene expression analysis were performed to investigate potential changes of aortic wall structure and molecular differences due to endograft implantation. RESULTS: We found that endograft implantation acutely induces a significant stiffness gradient directly at the interface between stented and unstented aortic segments under pulsatile pressure. Comparing stented aortas with unstented controls, we detected increased aortic expression levels of inflammatory cytokines (Il6 and Ccl2) and matrix metalloproteinases (Mmp2 and Mmp9) after 6 hours of pulsatile pressurization. This effect, however, was abolished when repeating the same experiment under 6 hours of static pressure. CONCLUSIONS: We identified endograft-induced aortic stiffness gradients as an early trigger of inflammatory aortic remodeling processes that might promote AND. These results highlight the importance of adequate endograft designs to minimize vascular stiffness gradients and forestall late complications, such as AND. CLINICAL IMPACT: AND may compromise the long-term results following endovascular aortic repair. However, the mechanisms behind the underlying detrimental aortic remodeling are still unclear. In this study we find that endograft-induced aortic stiffness gradients induce an inflammatory aortic remodeling response consistent with AND. This novel pathomechanistic insight may guide the design of new aortic endografts that minimize vascular stiffness gradients and forestall late complications such as AND.
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BACKGROUND: The prevalence of diabetes mellitus has risen considerably and currently affects more than 422 million people worldwide. Cardiovascular diseases including myocardial infarction and heart failure represent the major cause of death in type 2 diabetes (T2D). Diabetes patients exhibit accelerated aortic stiffening which is an independent predictor of cardiovascular disease and mortality. We recently showed that aortic stiffness precedes hypertension in a mouse model of diabetes (db/db mice), making aortic stiffness an early contributor to cardiovascular disease development. Elucidating how aortic stiffening develops is a pressing need in order to halt the pathophysiological process at an early time point. METHODS: To assess EndMT occurrence, we performed co-immunofluorescence staining of an endothelial marker (CD31) with mesenchymal markers (α-SMA/S100A4) in aortic sections from db/db mice. Moreover, we performed qRT-PCR to analyze mRNA expression of EndMT transcription factors in aortic sections of db/db mice and diabetic patients. To identify the underlying mechanism by which EndMT contributes to aortic stiffening, we used aortas from db/db mice and diabetic patients in combination with high glucose-treated human umbilical vein endothelial cells (HUVECs) as an in vitro model of diabetes-associated EndMT. RESULTS: We demonstrate robust CD31/α-SMA and CD31/S100A4 co-localization in aortic sections of db/db mice which was almost absent in control mice. Moreover, we demonstrate a significant upregulation of EndMT transcription factors in aortic sections of db/db mice and diabetic patients. As underlying regulator, we identified miR-132-3p as the most significantly downregulated miR in the micronome of db/db mice and high glucose-treated HUVECs. Indeed, miR-132-3p was also significantly downregulated in aortic tissue from diabetic patients. We identified Kruppel-like factor 7 (KLF7) as a target of miR-132-3p and show a significant upregulation of KLF7 in aortic sections of db/db mice and diabetic patients as well as in high glucose-treated HUVECs. We further demonstrate that miR-132-3p overexpression and KLF7 downregulation ameliorates EndMT in high glucose-treated HUVECs. CONCLUSIONS: We demonstrate for the first time that EndMT contributes to aortic stiffening in T2D. We identified miR-132-3p and KLF7 as novel EndMT regulators in this context. Altogether, this gives us new insights in the development of aortic stiffening in T2D.
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New technologies have greatly shaped the scientific and medical landscape within the last years. The unprecedented expansion of data and information on RNA biology has led to the discovery of new RNA classes with unique functions and unexpected modifications. Today, the biggest challenge is to transfer the large number of findings in basic RNA biology into corresponding clinical RNA-based therapeutics. Lately, this research begins to yield positive outcomes. RNA drugs advance to the final phases of clinical trials or even receive FDA approval. Furthermore, the introduction of the RNA-guided gene-editing technology CRISPR and advances in the delivery of messenger RNAs have triggered a major progression in the field of RNA-therapeutics. Especially short interfering RNAs and antisense oligonucleotides are promising examples for novel categories of therapeutics. However, several issues need to be addressed including intracellular delivery, toxicity, and immune responses before utilizing RNAs in a clinical setting. In this review, we provide an overview on opportunities and challenges for clinical translation of RNA-based therapeutics, with an emphasis on advances in novel delivery technologies and abdominal aortic aneurysm disease where non-coding RNAs have been shown to play a crucial regulatory role.
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Patients with type 2 diabetes (T2D) are threatened by excessive cardiovascular morbidity and mortality. While accelerated arterial stiffening may represent a critical mechanistic factor driving cardiovascular risk in T2D, specific therapies to contain the underlying diabetic arterial remodeling have been elusive. The present translational study investigates the role of microRNA-29b (miR-29b) as a driver and therapeutic target of diabetic aortic remodeling and stiffening. Using a murine model (db/db mice), as well as human aortic tissue samples, we find that diabetic aortic remodeling and stiffening is associated with medial fibrosis, as well as fragmentation of aortic elastic layers. miR-29b is significantly downregulated in T2D and miR-29b repression is sufficient to induce both aortic medial fibrosis and elastin breakdown through upregulation of its direct target genes COL1A1 and MMP2 thereby increasing aortic stiffness. Moreover, antioxidant treatment restores aortic miR-29b levels and counteracts diabetic aortic remodeling. Concluding, we identify miR-29b as a comprehensive-and therefore powerful-regulator of aortic remodeling and stiffening in T2D that moreover qualifies as a (redox-sensitive) target for therapeutic intervention.
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BACKGROUND: Right heart catheterization using exercise stress is the reference standard for the diagnosis of heart failure with preserved ejection fraction (HFpEF) but carries the risk of the invasive procedure. We hypothesized that real-time cardiac magnetic resonance (RT-CMR) exercise imaging with pathophysiologic data at excellent temporal and spatial resolution may represent a contemporary noninvasive alternative for diagnosing HFpEF. METHODS: The HFpEF-Stress trial (CMR Exercise Stress Testing in HFpEF; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621. URL: https://dzhk.de/; Unique identifier: DZHK-17) prospectively recruited 75 patients with echocardiographic signs of diastolic dysfunction and dyspnea on exertion (E/e'>8, New York Heart Association class ≥II) to undergo echocardiography, right heart catheterization, and RT-CMR at rest and during exercise stress. HFpEF was defined according to pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during exercise stress). RT-CMR functional assessments included time-volume curves for total and early (1/3) diastolic left ventricular filling, left atrial (LA) emptying, and left ventricular/LA long axis strain. RESULTS: Patients with HFpEF (n=34; median pulmonary capillary wedge pressure at rest, 13 mm Hg; at stress, 27 mm Hg) had higher E/e' (12.5 versus 9.15), NT-proBNP (N-terminal pro-B-type natriuretic peptide; 255 versus 75 ng/L), and LA volume index (43.8 versus 36.2 mL/m2) compared with patients with noncardiac dyspnea (n=34; rest, 8 mm Hg; stress, 18 mm Hg; P≤0.001 for all). Seven patients were excluded because of the presence of non-HFpEF cardiac disease causing dyspnea on imaging. There were no differences in RT-CMR left ventricular total and early diastolic filling at rest and during exercise stress (P≥0.164) between patients with HFpEF and noncardiac dyspnea. RT-CMR revealed significantly impaired LA total and early (P<0.001) diastolic emptying in patients with HFpEF during exercise stress. RT-CMR exercise stress LA long axis strain was independently associated with HFpEF (adjusted odds ratio, 0.657 [95% CI, 0.516-0.838]; P=0.001) after adjustment for clinical and imaging measures and emerged as the best predictor for HFpEF (area under the curve at rest 0.82 versus exercise stress 0.93; P=0.029). CONCLUSIONS: RT-CMR allows highly accurate identification of HFpEF during physiologic exercise and qualifies as a suitable noninvasive diagnostic alternative. These results will need to be confirmed in multicenter prospective research studies to establish widespread routine clinical use. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621. URL: https://dzhk.de/; Unique identifier: DZHK-17.
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Teste de Esforço/métodos , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/diagnóstico , Imageamento por Ressonância Magnética/métodos , Volume Sistólico/fisiologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Marfan syndrome (MFS) is a connective tissue disorder that results in aortic root aneurysm formation. Reactive oxygen species (ROS) seem to play a role in aortic wall remodelling in MFS, although the mechanism remains unknown. MFS Fbn1C1039G/+ mouse root/ascending (AS) and descending (DES) aortic samples were examined using DHE staining, lucigenin-enhanced chemiluminescence (LGCL), Verhoeff's elastin-Van Gieson staining (elastin breakdown) and in situ zymography for protease activity. Fbn1C1039G/+ AS- or DES-derived smooth muscle cells (SMC) were treated with anti-TGF-ß antibody, angiotensin II (AngII), anti-TGF-ß antibody + AngII, or isotype control. ROS were detected during early aneurysm formation in the Fbn1C1039G/+ AS aorta, but absent in normal-sized DES aorta. Fbn1C1039G/+ mice treated with the unspecific NADPH oxidase inhibitor, apocynin reduced AS aneurysm formation, with attenuated elastin fragmentation. In situ zymography revealed apocynin treatment decreased protease activity. In vitro SMC studies showed Fbn1C1039G/+ -derived AS SMC had increased NADPH activity compared to DES-derived SMC. AS SMC NADPH activity increased with AngII treatment and appeared TGF-ß dependent. In conclusion, ROS play a role in MFS aneurysm development and correspond anatomically with aneurysmal aortic segments. ROS inhibition via apocynin treatment attenuates MFS aneurysm progression. AngII enhances ROS production in MFS AS SMCs and is likely TGF-ß dependent.
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Aneurisma/complicações , Aneurisma/metabolismo , Síndrome de Marfan/complicações , Síndrome de Marfan/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Acetofenonas/farmacologia , Angiotensina II , Animais , Aorta/metabolismo , Aorta/patologia , Modelos Animais de Doenças , Fibrilina-1/deficiência , Fibrilina-1/metabolismo , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NADPH Oxidases/metabolismoRESUMO
Aging has a significant impact not only on every single individual but on society as a whole. Today, people throughout the world exhibit an extended lifespan. Therefore, it becomes increasingly important to develop novel concepts that encourage a modern understanding of the aging process. The concept of healthy aging shifts the perception of aging as a burden towards aging as an opportunity for an extended healthy phase in later life. Morbidity and mortality in the elderly population are greatly defined by a raise in the incidence and prevalence of cardiovascular diseases. Consequently, it is critical to identify risk factors and underlying mechanisms that render the aging (cardio)vascular system prone to disease. In this review, we focus on structural mechanisms of arterial stiffening as a major manifestation of vascular aging and its functional implications for the concept of healthy aging.
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Envelhecimento Saudável , Rigidez Vascular , Envelhecimento/fisiologia , Humanos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismoRESUMO
Aim: Arterial stiffness is a significant risk factor for many cardiovascular diseases, including abdominal aortic aneurysms (AAA). Nicotine, the major active ingredient of e-cigarettes and tobacco smoke, induces acute vasomotor effects that may temporarily increase arterial stiffness. Here, we investigated the effects of long-term nicotine exposure on structural aortic stiffness. Methods: Mice (C57BL/6) were infused with nicotine for 40 days (20 mg/kg/day). Arterial stiffness of the thoracic (TS) and abdominal (AS) aortic segments was analyzed using ultrasound (PWV, pulse wave velocity) and ex vivo pressure myograph measurements. For mechanistic studies, aortic matrix-metalloproteinase (MMP) expression and activity as well as medial elastin architecture were analyzed. Results: Global aortic stiffness increased with nicotine. In particular, local stiffening of the abdominal segment occurred after 10 days, while thoracic aortic stiffness was only increased after 40 days, resulting in aortic stiffness segmentation. Mechanistically, nicotine exposure enhanced expression of MMP-2/-9 and elastolytic activity in both aortic segments. Elastin degradation occurred in both segments; however, basal elastin levels were higher in the thoracic aorta. Finally, MMP-inhibition significantly reduced nicotine-induced MMP activity, elastin destruction, and aortic stiffening. Conclusion: Chronic nicotine exposure induces aortic MMP expression and structural aortic damage (elastin fragmentation), irreversibly increasing aortic stiffness. This process predominantly affects the abdominal aortic segment, presumably due in part to a lower basal elastin content. This novel phenomenon may help to explain the role of nicotine as a major risk factor for AAA formation and has health implications for ECIGs and other modes of nicotine delivery.
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BACKGROUND: The pathophysiological significance of dyssynchrony and rotation in Takotsubo syndrome (TTS) is unknown. We aimed to define the influence of cardiovascular magnetic resonance feature tracking (CMR-FT) dyssynchrony and rotational mechanics in acute and during clinical course of TTS. METHODS: This multicenter study included 152 TTS patients undergoing CMR (mean 3â¯days after symptom onset). Apical, midventricular and basal short axis views were analysed in a core-laboratory. Systolic torsion, diastolic recoil and dyssynchrony expressed as circumferential and radial uniformity ratio estimates (CURE and RURE: 0 to 1; 1â¯=â¯perfect synchrony) were compared to a matched control group (nâ¯=â¯21). Follow-up CMR (nâ¯=â¯20 patients; mean 62â¯days, SD 7.2) and general follow-up (nâ¯=â¯136; mean 3.3â¯years, SD 2.4) were performed. RESULTS: CURE was initially reduced compared to controls (pâ¯=â¯0.001) and recovered at follow-up (pâ¯<â¯0.001) as opposed to RURE (pâ¯=â¯0.116 and pâ¯=â¯0.179). CURE and RURE discriminated between ballooning patterns (pâ¯=â¯0.001 and pâ¯=â¯0.045). Recoil was generally impaired during the acute phase (pâ¯=â¯0.015), torsion only in highly dyssynchronous patients (pâ¯=â¯0.024). Diabetes (pâ¯=â¯0.007), physical triggers (pâ¯=â¯0.013) and malignancies (pâ¯=â¯0.001) predicted mortality. The latter showed a distinct association with impaired torsion (pâ¯=â¯0.042) and dyssynchrony (pâ¯=â¯0.047). Physical triggers and malignancies were related to biventricular impairment (pâ¯=â¯0.004 and pâ¯=â¯0.026), showing higher dyssynchrony (pâ¯<â¯0.01), greater reduction of left ventricular function (pâ¯<â¯0.001) and a strong trend towards increased mortality (pâ¯=â¯0.074). CONCLUSION: Transient circumferential dyssynchrony and impaired rotational mechanics are distinct features of TTS with different severities according to the pattern of ballooning. Patients with malignancies and precipitating physical triggers frequently show biventricular affection, greater dyssynchrony and high mortality risk.
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Imagem Cinética por Ressonância Magnética/métodos , Rotação , Cardiomiopatia de Takotsubo/diagnóstico por imagem , Cardiomiopatia de Takotsubo/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Fenômenos Biomecânicos/fisiologia , Dor no Peito/diagnóstico por imagem , Dor no Peito/epidemiologia , Dor no Peito/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Cardiomiopatia de Takotsubo/epidemiologia , Fatores de TempoRESUMO
BACKGROUND: A substantial number of patients with Takotsubo syndrome (TTS) exhibit right ventricular (RV) dysfunction which has been associated with adverse outcome. The aim of this study was to assess the clinical and prognostic value of RV myocardial strain in TTS using cardiovascular magnetic resonance myocardial feature tracking (CMR-FT). METHODS: CMR-FT was performed in a core laboratory to determine RV longitudinal strain in 134 TTS patients undergoing CMR in median 2 days after admission to 2 experienced centers. For comparison, RV involvement was evaluated by sole visual assessment concerning RV contraction abnormalities. Both approaches were analyzed regarding their long-term prognostic value. RESULTS: The peak global RV longitudinal strain was in median -19%. Segmental analyses located contraction abnormalities primarily in the apical parts of the right ventricle. Sole visual assessment identified 38 patients (28%) with RV involvement. These patients showed a numerically higher long-term mortality without reaching statistical significance (17.1% versus 10.5%; hazard ratio 1.38 [95% confidence interval 0.49-3.88]; p = 0.31). The optimal RV strain cutoff value for risk prediction was -17.24%. Stratification according to this threshold categorized 41% of TTS patients (n = 55) in the high-risk group which demonstrated a significantly increased long-term mortality compared to patients with preserved global RV strain (20.0% versus 7.0%; hazard ratio 2.98 [95% confidence interval 1.02-8.73]; p = 0.03). CONCLUSIONS: The assessment of RV myocardial strain using CMR-FT enables an accurate evaluation of RV involvement in TTS and represents a promising approach for optimized risk stratification.
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Ventrículos do Coração/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Cardiomiopatia de Takotsubo/diagnóstico por imagem , Idoso , Feminino , Ventrículos do Coração/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Cardiomiopatia de Takotsubo/patologiaRESUMO
OBJECTIVES: This study assessed the applicability and prognostic value of cardiovascular magnetic resonance (CMR) left ventricular deformation analysis in Takotsubo syndrome (TTS). METHODS: CMR-feature tracking was performed blinded in a core laboratory to determine circumferential (CS), radial (RS) and longitudinal strain (LS) in 141 TTS patients participating in this cohort study. A subgroup of consecutive TTS patients (n = 20) was compared with age- and sex-matched controls with anterior ST-segment elevation myocardial infarction (STEMI) and non-STEMI as well as healthy subjects. RESULTS: Median global CS, RS and LS were -19%, 19% and -12%, respectively. Apical ballooning was associated with significantly lower global CS (p < 0.01) and LS (p < 0.01) compared with midventricular and basal ballooning. Global RS was lowest in patients with basal ballooning (p < 0.01). Segmental analysis resulted in a reliable discrimination of different ballooning patterns using CS and LS. Strain values were significantly lower in TTS compared with non-STEMI patients and healthy subjects, whereas STEMI patients showed similar values. While global CS and RS were not associated with long-term mortality, global LS (cutoff -14.75%) was identified as a potential parameter for long-term risk stratification (mortality rate 17.9% versus 2.5%; p = 0.02). CONCLUSIONS: The transient contraction abnormalities in TTS can be quantitatively assessed with CMR-feature tracking. GLS is a potential determinant of outcome in TTS, which, however, requires further validation. KEY POINTS: ⢠Cardiovascular magnetic resonance myocardial feature tracking enables accurate assessment of regional and global left ventricular dysfunction in Takotsubo syndrome (TTS). ⢠Global strain in TTS is similar to patients with anterior STEMI and lower compared with non-STEMI and healthy subjects. ⢠Global longitudinal strain is a potential tool for risk prediction in TTS patients.
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Ventrículos do Coração/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética/métodos , Miocárdio/patologia , Cardiomiopatia de Takotsubo/diagnóstico , Função Ventricular Esquerda/fisiologia , Idoso , Feminino , Seguimentos , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Cardiomiopatia de Takotsubo/fisiopatologiaRESUMO
Objective- Recruitment of immunologic competent cells to the vessel wall is a crucial step in formation of abdominal aortic aneurysms (AAA). Innate immunity effectors (eg, macrophages), as well as mediators of adaptive immunity (eg, T cells), orchestrate a local vascular inflammatory response. IL-10 (interleukin-10) is an immune-regulatory cytokine with a crucial role in suppression of inflammatory processes. We hypothesized that an increase in systemic IL-10-levels would mitigate AAA progression. Approach and Results- Using a single intravenous injection protocol, we transfected an IL-10 transcribing nonimmunogenic minicircle vector into the Ang II (angiotensin II)-ApoE-/- infusion mouse model of AAA. IL-10 minicircle transfection significantly reduced average aortic diameter measured via ultrasound at day 28 from 166.1±10.8% (control) to 131.0±5.8% (IL-10 transfected). Rates of dissecting AAA were reduced by IL-10 treatment, with an increase in freedom from dissecting AAA from 21.5% to 62.3%. Using flow cytometry of aortic tissue from minicircle IL-10-treated animals, we found a significantly higher percentage of CD4+/CD25+/Foxp3 (forkhead box P3)+ regulatory T cells, with fewer CD8+/GZMB+ (granzyme B) cytotoxic T cells. Furthermore, isolated aortic macrophages produced less TNF-α (tumor necrosis factor-α), more IL-10, and were more likely to be MRC1 (mannose receptor, C type 1)-positive alternatively activated macrophages. These results concurred with gene expression analysis of lipopolysaccharide-stimulated and Ang II-primed human peripheral blood mononuclear cells. Conclusions- Taken together, we provide an effective gene therapy approach to AAA in mice by enhancing antiinflammatory and dampening proinflammatory pathways through minicircle-induced augmentation of systemic IL-10 expression.
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Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/prevenção & controle , Dissecção Aórtica/prevenção & controle , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos , Interleucina-10/biossíntese , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/genética , Dissecção Aórtica/metabolismo , Angiotensina II , Animais , Aorta Abdominal/imunologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Células Cultivadas , Dilatação Patológica , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Interleucina-10/genética , Interleucina-10/imunologia , Ativação de Macrófagos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Regulação para CimaRESUMO
OBJECTIVE: There are currently no effective treatments for the prevention of dementia associated with vascular cognitive impairment. MicroRNAs regulate gene expression at the post-transcriptional level and play key roles in vascular disorders. TNFα (tumor necrosis factor-α) regulates blood-brain barrier breakdown through modification of cerebral tight junctions. Here, we sought key TNFα-responsive microRNAs that might influence blood-brain barrier breakdown via cerebral tight junction disruption in vascular cognitive impairment. APPROACH AND RESULTS: Using a mouse model of vascular cognitive impairment, chronic cerebral hypoperfusion within the white matter was induced with bilateral common carotid artery stenosis (BCAS) surgery. TNFα gene expression was increased in white matter post-BCAS surgery, and TNFα stimulation decreased claudin-5, ZO-1 (tight-junction protein 1), and occludin gene expression in murine brain endothelial cells. In silico analysis predicted 8 candidate microRNAs as regulators of claudin-5, ZO-1, and occludin gene expression. Of these, only miR-501-3p was upregulated by TNFα in vitro and was upregulated in the white matter after BCAS surgery. Further, miR-501-3p directly bound to the 3'-untranslated region of human ZO-1 and downregulated transendothelial electric resistance. In vivo administration of a locked nucleic acid -modified antisense oligonucleotide versus miR-501-3p suppressed BCAS-induced reduction of ZO-1 gene expression and blood-brain barrier disruption within the white matter and significantly ameliorated working memory deficits after BCAS surgery. CONCLUSIONS: We here provide the first evidence that the TNFα-miR-501-3p-ZO-1 axis plays an important role in the pathogenesis of cerebral hypoperfusion-induced working memory deficits and white matter lesions, as a result of blood-brain barrier breakdown via tight junction disruption. Therapeutic manipulation of miR-501-3p holds promise for limiting vascular cognitive impairment progression.
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Comportamento Animal , Barreira Hematoencefálica/fisiopatologia , Permeabilidade Capilar , Transtornos Cerebrovasculares/terapia , Transtornos Cognitivos/terapia , Cognição , Terapia Genética/métodos , MicroRNAs/genética , Oligonucleotídeos Antissenso/administração & dosagem , Regiões 3' não Traduzidas , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/fisiopatologia , Transtornos Cerebrovasculares/psicologia , Claudina-5/genética , Claudina-5/metabolismo , Transtornos Cognitivos/genética , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Modelos Animais de Doenças , Impedância Elétrica , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Ocludina/genética , Ocludina/metabolismo , Oligonucleotídeos Antissenso/genética , Junções Íntimas/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
miRNAs are potential regulators of carotid artery stenosis and concordant vulnerable atherosclerotic plaques. Hence, we analyzed miRNA expression in laser captured micro-dissected fibrous caps of either ruptured or stable plaques (n = 10 each), discovering that miR-21 was significantly downregulated in unstable lesions. To functionally evaluate miR-21 in plaque vulnerability, miR-21 and miR-21/apolipoprotein-E double-deficient mice (Apoe-/-miR-21-/-) were assessed. miR-21-/- mice lacked sufficient smooth muscle cell proliferation in response to carotid ligation injury. When exposing Apoe-/-miR-21-/- mice to an inducible plaque rupture model, they presented with more atherothrombotic events (93%) compared with miR-21+/+Apoe-/- mice (57%). We discovered that smooth muscle cell fate in experimentally induced advanced lesions is steered via a REST-miR-21-REST feedback signaling pathway. Furthermore, Apoe-/-miR-21-/- mice presented with more pronounced atherosclerotic lesions, greater foam cell formation, and substantially higher levels of arterial macrophage infiltration. Local delivery of a miR-21 mimic using ultrasound-targeted microbubbles into carotid plaques rescued the vulnerable plaque rupture phenotype. In the present study, we identify miR-21 as a key modulator of pathologic processes in advanced atherosclerosis. Targeted, lesion site-specific overexpression of miR-21 can stabilize vulnerable plaques.
Assuntos
Aterosclerose/genética , Aterosclerose/patologia , MicroRNAs/genética , Animais , Apoptose/genética , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Modelos Animais de Doenças , Fibrose , Perfilação da Expressão Gênica , Técnicas de Transferência de Genes , Genótipo , Humanos , Imuno-Histoquímica , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/administração & dosagem , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologiaRESUMO
BACKGROUND: Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis. OBJECTIVES: The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered ß-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS. METHODS: Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated ß-adrenergic signaling and TTS cardiomyocyte function. RESULTS: Enhanced ß-adrenergic signaling in TTS-iPSC-CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate-dependent protein kinase A-mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by ß1-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function. CONCLUSIONS: Enhanced ß-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. (International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621).