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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: 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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Prueba de Esfuerzo/métodos , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/diagnóstico , Imagen por Resonancia Magnética/métodos , Volumen Sistólico/fisiología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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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Envejecimiento Saludable , Rigidez Vascular , Envejecimiento/fisiología , Humanos , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismoRESUMEN
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/complicaciones , Aneurisma/metabolismo , Síndrome de Marfan/complicaciones , Síndrome de Marfan/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Acetofenonas/farmacología , Angiotensina II , Animales , Aorta/metabolismo , Aorta/patología , Modelos Animales de Enfermedad , Fibrilina-1/deficiencia , Fibrilina-1/metabolismo , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , NADPH Oxidasas/metabolismoRESUMEN
RATIONALE: In the search for markers and modulators of vascular disease, microRNAs (miRNAs) have emerged as potent therapeutic targets. OBJECTIVE: To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke. METHODS AND RESULTS: Using patient material from the BiKE (Biobank of Karolinska Endarterectomies), we profiled miRNA expression in patients with stable versus unstable carotid plaque. A polymerase chain reaction-based miRNA array of plasma, sampled at the carotid lesion site, identified 8 deregulated miRNAs (miR-15b, miR-29c, miR-30c/d, miR-150, miR-191, miR-210, and miR-500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser capture microdissection and in situ hybridization revealed a distinct localization of miR-210 in fibrous caps. We confirmed that miR-210 directly targets the tumor suppressor gene APC (adenomatous polyposis coli), thereby affecting Wnt (Wingless-related integration site) signaling and regulating smooth muscle cell survival, as well as differentiation in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in 2 rodent models of vascular remodeling and plaque rupture. Modulating miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease. CONCLUSIONS: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.
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MicroARNs/administración & dosificación , MicroARNs/biosíntesis , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/terapia , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/terapia , Estenosis Carotídea/metabolismo , Estenosis Carotídea/patología , Estenosis Carotídea/terapia , Células Cultivadas , Estudios de Cohortes , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Captura por Microdisección con Láser/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/análisis , Placa Aterosclerótica/patología , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/prevención & controlRESUMEN
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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Conducta Animal , Barrera Hematoencefálica/fisiopatología , Permeabilidad Capilar , Trastornos Cerebrovasculares/terapia , Trastornos del Conocimiento/terapia , Cognición , Terapia Genética/métodos , MicroARNs/genética , Oligonucleótidos Antisentido/administración & dosificación , Regiones no Traducidas 3' , Animales , Sitios de Unión , Barrera Hematoencefálica/metabolismo , Trastornos Cerebrovasculares/genética , Trastornos Cerebrovasculares/fisiopatología , Trastornos Cerebrovasculares/psicología , Claudina-5/genética , Claudina-5/metabolismo , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/psicología , Modelos Animales de Enfermedad , Impedancia Eléctrica , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Ocludina/genética , Ocludina/metabolismo , Oligonucleótidos Antisentido/genética , Uniones Estrechas/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
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 de la Aorta Abdominal/prevención & control , Disección Aórtica/prevención & control , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Vectores Genéticos , Interleucina-10/biosíntesis , Disección Aórtica/inducido químicamente , Disección Aórtica/genética , Disección Aórtica/metabolismo , Angiotensina II , Animales , Aorta Abdominal/inmunología , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/metabolismo , Células Cultivadas , Dilatación Patológica , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Interleucina-10/genética , Interleucina-10/inmunología , Activación de Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Regulación hacia ArribaRESUMEN
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.
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Aterosclerosis/genética , Aterosclerosis/patología , MicroARNs/genética , Animales , Apoptosis/genética , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/patología , Modelos Animales de Enfermedad , Fibrosis , Perfilación de la Expresión Génica , Técnicas de Transferencia de Gen , Genotipo , Humanos , Inmunohistoquímica , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Ratones Noqueados , MicroARNs/administración & dosificación , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologíaRESUMEN
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 Cardíacos/diagnóstico por imagen , Imagen por Resonancia Cinemagnética/métodos , Miocardio/patología , Cardiomiopatía de Takotsubo/diagnóstico , Función Ventricular Izquierda/fisiología , Anciano , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Cardiomiopatía de Takotsubo/fisiopatologíaRESUMEN
The aorta is a blood vessel that provides a low-resistance path for blood flow directed from the heart to peripheral organs and tissues. However, the aorta has another central hemodynamic function, whereby the elastic nature of the aortic wall provides a significant biomechanical buffering capacity complementing the pulsatile cardiac blood flow, and this is often referred to as Windkessel function. Stiffening of the arterial wall leads to fundamental alterations in central hemodynamics, with widespread detrimental implications for organ function. In this Recent Highlights article, we describe recent contributions in ATVB that have highlighted the novel mechanisms and consequences of arterial stiffness and the clinical conditions in which arterial stiffness occurs, with a focus on advancements in the field.
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Aorta/fisiopatología , Enfermedades Cardiovasculares/fisiopatología , Hemodinámica , Rigidez Vascular , Animales , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/terapia , Comorbilidad , Adaptabilidad , Humanos , Estilo de Vida , Pronóstico , Factores de Riesgo , Estrés MecánicoRESUMEN
Chronic kidney disease (CKD) is associated with increased risk and worse prognosis of cardiovascular disease, including peripheral artery disease. An impaired angiogenic response to ischemia may contribute to poor outcomes of peripheral artery disease in patients with CKD. Hypoxia inducible factors (HIF) are master regulators of angiogenesis and therefore represent a promising target for therapeutic intervention. To test this we induced hind-limb ischemia in rats with CKD caused by 5/6 nephrectomy and administered two different treatments known to stabilize HIF protein in vivo: carbon monoxide and a pharmacological inhibitor of prolyl hydroxylation 2-(1-chloro-4- hydroxyisoquinoline-3-carboxamido) acetate (ICA). Expression levels of pro-angiogenic HIF target genes (Vegf, Vegf-r1, Vegf-r2, Ho-1) were measured by qRT-PCR. Capillary density was measured by CD31 immunofluorescence staining and HIF expression was evaluated by immunohistochemistry. Capillary density in ischemic skeletal muscle was significantly lower in CKD animals compared to sham controls. Rats with CKD showed significantly lower expression of HIF and all measured pro-angiogenic HIF target genes, including VEGF. Both HIF stabilizing treatments rescued HIF target gene expression in animals with CKD and led to significantly higher ischemia-induced capillary sprouting compared to untreated controls. ICA was effective regardless of whether it was administered before or after induction of ischemia and led to a HIF expression in skeletal muscle. Thus, impaired ischemia-induced angiogenesis in rats with CKD can be improved by HIF stabilization, even if started after onset of ischemia.
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Capilares/efectos de los fármacos , Monóxido de Carbono/farmacología , Glicina/análogos & derivados , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Isquemia/tratamiento farmacológico , Isoquinolinas/farmacología , Músculo Esquelético/irrigación sanguínea , Neovascularización Fisiológica/efectos de los fármacos , Insuficiencia Renal Crónica/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Capilares/metabolismo , Capilares/fisiopatología , Línea Celular , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Glicina/farmacología , Hemo Oxigenasa (Desciclizante)/genética , Hemo Oxigenasa (Desciclizante)/metabolismo , Miembro Posterior , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Isquemia/genética , Isquemia/metabolismo , Isquemia/fisiopatología , Masculino , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Estabilidad Proteica , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/fisiopatología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
RATIONALE: Accelerated arterial stiffening is a major complication of diabetes mellitus with no specific therapy available to date. OBJECTIVE: The present study investigates the role of the osteogenic transcription factor runt-related transcription factor 2 (Runx2) as a potential mediator and therapeutic target of aortic fibrosis and aortic stiffening in diabetes mellitus. METHODS AND RESULTS: Using a murine model of type 2 diabetes mellitus (db/db mice), we identify progressive structural aortic stiffening that precedes the onset of arterial hypertension. At the same time, Runx2 is aberrantly upregulated in the medial layer of db/db aortae, as well as in thoracic aortic samples from patients with type 2 diabetes mellitus. Vascular smooth muscle cell-specific overexpression of Runx2 in transgenic mice increases expression of its target genes, Col1a1 and Col1a2, leading to medial fibrosis and aortic stiffening. Interestingly, increased Runx2 expression per se is not sufficient to induce aortic calcification. Using in vivo and in vitro approaches, we further demonstrate that expression of Runx2 in diabetes mellitus is regulated via a redox-sensitive pathway that involves a direct interaction of NF-κB with the Runx2 promoter. CONCLUSIONS: In conclusion, this study highlights Runx2 as a previously unrecognized inducer of vascular fibrosis in the setting of diabetes mellitus, promoting arterial stiffness irrespective of calcification.
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Aorta/metabolismo , Aorta/patología , Subunidad alfa 1 del Factor de Unión al Sitio Principal/biosíntesis , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Rigidez Vascular/fisiología , Anciano , Animales , Células Cultivadas , Femenino , Fibrosis , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Factores de Transcripción/biosíntesisRESUMEN
RATIONALE: Tissue engineering approaches may improve survival and functional benefits from human embryonic stem cell-derived cardiomyocyte transplantation, thereby potentially preventing dilative remodeling and progression to heart failure. OBJECTIVE: Assessment of transport stability, long-term survival, structural organization, functional benefits, and teratoma risk of engineered heart muscle (EHM) in a chronic myocardial infarction model. METHODS AND RESULTS: We constructed EHMs from human embryonic stem cell-derived cardiomyocytes and released them for transatlantic shipping following predefined quality control criteria. Two days of shipment did not lead to adverse effects on cell viability or contractile performance of EHMs (n=3, P=0.83, P=0.87). One month after ischemia/reperfusion injury, EHMs were implanted onto immunocompromised rat hearts to simulate chronic ischemia. Bioluminescence imaging showed stable engraftment with no significant cell loss between week 2 and 12 (n=6, P=0.67), preserving ≤25% of the transplanted cells. Despite high engraftment rates and attenuated disease progression (change in ejection fraction for EHMs, -6.7±1.4% versus control, -10.9±1.5%; n>12; P=0.05), we observed no difference between EHMs containing viable and nonviable human cardiomyocytes in this chronic xenotransplantation model (n>12; P=0.41). Grafted cardiomyocytes showed enhanced sarcomere alignment and increased connexin 43 expression at 220 days after transplantation. No teratomas or tumors were found in any of the animals (n=14) used for long-term monitoring. CONCLUSIONS: EHM transplantation led to high engraftment rates, long-term survival, and progressive maturation of human cardiomyocytes. However, cell engraftment was not correlated with functional improvements in this chronic myocardial infarction model. Most importantly, the safety of this approach was demonstrated by the lack of tumor or teratoma formation.
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Células Madre Embrionarias/trasplante , Supervivencia de Injerto , Trasplante de Corazón/métodos , Infarto del Miocardio/cirugía , Miocitos Cardíacos/trasplante , Músculos Papilares/trasplante , Ingeniería de Tejidos/métodos , Animales , Biomarcadores/metabolismo , Diferenciación Celular , Línea Celular , Supervivencia Celular , Conexina 43/metabolismo , Modelos Animales de Enfermedad , Células Madre Embrionarias/inmunología , Células Madre Embrionarias/metabolismo , Trasplante de Corazón/efectos adversos , Xenoinjertos , Humanos , Inmunosupresores/farmacología , Masculino , Contracción Miocárdica , Infarto del Miocardio/inmunología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocitos Cardíacos/inmunología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Músculos Papilares/inmunología , Músculos Papilares/metabolismo , Músculos Papilares/patología , Músculos Papilares/fisiopatología , Ratas Desnudas , Ratas Sprague-Dawley , Volumen Sistólico , Factores de Tiempo , TransfecciónRESUMEN
BACKGROUND: Stiffening of the aortic wall is a phenomenon consistently observed in age and in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined. METHODS AND RESULTS: Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening precedes aneurysm growth. Finite-element analysis reveals that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) wall stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent aortic segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with the reduced segmental stiffness of the AAA-prone aorta (attributable to equalized stiffness in adjacent segments), reduced axial wall stress, decreased production of reactive oxygen species, attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, and attenuated apoptosis within the aortic wall, as well. Cyclic pressurization of segmentally stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening. CONCLUSIONS: The present study introduces the novel concept of segmental aortic stiffening as an early pathomechanism generating aortic wall stress and triggering aneurysmal growth, thereby delineating potential underlying molecular mechanisms and therapeutic targets. In addition, monitoring segmental aortic stiffening may aid the identification of patients at risk for AAA.
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Aneurisma de la Aorta Abdominal/etiología , Rigidez Vascular , Adulto , Anciano , Envejecimiento/patología , Animales , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/diagnóstico por imagen , Aneurisma de la Aorta Abdominal/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Matriz Extracelular/metabolismo , Perfilación de la Expresión Génica , Humanos , Inflamación , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Elastasa Pancreática/toxicidad , Estrés Mecánico , Adhesivos Tisulares , UltrasonografíaRESUMEN
OBJECTIVE: Rupture and dissection of aortic root aneurysms remain the leading causes of death in patients with the Marfan syndrome, a hereditary connective tissue disorder that affects 1 in 5000 individuals worldwide. In the present study, we use a Marfan mouse model (Fbn1(C1039G/+)) to investigate the biological importance of apoptosis during aneurysm development in Marfan syndrome. APPROACH AND RESULTS: Using in vivo single-photon emission computed tomographic-imaging and ex vivo autoradiography for Tc99m-annexin, we discovered increased apoptosis in the Fbn1(C1039G/+) ascending aorta during early aneurysm development peaking at 4 weeks. Immunofluorescence colocalization studies identified smooth muscle cells (SMCs) as the apoptotic cell population. As biological proof of concept that early aortic wall apoptosis plays a role in aneurysm development in Marfan syndrome, Fbn1(C1039G/+) mice were treated daily from 2 to 6 weeks with either (1) a pan-caspase inhibitor, Q-VD-OPh (20 mg/kg), or (2) vehicle control intraperitoneally. Q-VD-OPh treatment led to a significant reduction in aneurysm size and decreased extracellular matrix degradation in the aortic wall compared with control mice. In vitro studies using Fbn1(C1039G/+) ascending SMCs showed that apoptotic SMCs have increased elastolytic potential compared with viable cells, mostly because of caspase activity. Moreover, in vitro (1) cell membrane isolation, (2) immunofluorescence staining, and (3) scanning electron microscopy studies illustrate that caspases are expressed on the exterior cell surface of apoptotic SMCs. CONCLUSIONS: Caspase inhibition attenuates aneurysm development in an Fbn1(C1039G/+) Marfan mouse model. Mechanistically, during apoptosis, caspases are expressed on the cell surface of SMCs and likely contribute to elastin degradation and aneurysm development in Marfan syndrome.
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Aneurisma de la Aorta/etiología , Apoptosis , Caspasas/metabolismo , Membrana Celular/enzimología , Síndrome de Marfan/complicaciones , Músculo Liso Vascular/enzimología , Miocitos del Músculo Liso/enzimología , Remodelación Vascular , Animales , Aorta/enzimología , Aneurisma de la Aorta/diagnóstico , Aneurisma de la Aorta/enzimología , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/prevención & control , Apoptosis/efectos de los fármacos , Autorradiografía , Inhibidores de Caspasas/farmacología , Células Cultivadas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Elastina/metabolismo , Femenino , Fibrilina-1 , Fibrilinas , Técnica del Anticuerpo Fluorescente , Masculino , Síndrome de Marfan/genética , Ratones Endogámicos C57BL , Ratones Mutantes , Proteínas de Microfilamentos/genética , Microscopía Electrónica de Rastreo , Músculo Liso Vascular/diagnóstico por imagen , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/ultraestructura , Mutación , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/ultraestructura , Factores de Tiempo , Tomografía Computarizada de Emisión de Fotón Único , Remodelación Vascular/efectos de los fármacosRESUMEN
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.
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Cardiomiopatías Diabéticas/metabolismo , Estrés Oxidativo , Animales , Cardiomiopatías Diabéticas/tratamiento farmacológico , Cardiomiopatías Diabéticas/patología , Fibrosis , HumanosRESUMEN
Efficient and safe anticoagulation is crucial in patients requiring percutaneous coronary intervention (PCI) or extracorporeal circulation during cardiac surgery. Although new anticoagulant strategies have emerged for PCI as alternatives to the established treatment with heparins, the development of new anticoagulants with an improved efficacy/safety ratio is still necessary. Our study compared the efficacy of the novel, dual-acting, neutralizable FIIa/FXa-inhibitor EP217609C101 (EP) at 2, 1.2, 0.9, and 0.6 µg/ml to unfractionated heparin (UFH), enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis under in vitro conditions. Blood drawn by venepunction from healthy male volunteers (n = 10) pretreated with 500 mg aspirin orally was treated with the anticoagulant to test and continuously circulated through a cardiac catheter for 60 min or until the catheter became blocked by thrombotic debris. Anticoagulant efficacy was assessed by thrombus weight, electron microscopic features of the developing thrombi, and laboratory parameters. Whereas UFH, enoxaparin, EP 2, and EP 1.2 µg/ml secured maximum circulation times, statistically significant premature catheter occlusions were observed for EP 0.9, EP 0.6 µg/ml, and fondaparinux. The UFH group and both high-dose concentrations of EP showed significantly lower thrombus weights than the low-dose concentrations of EP and fondaparinux, (p ≤ 0.05). On electron microscopic analysis of the thrombotic debris no differences were observed in erythrocyte deposition between UFH, enoxaparin, and all EP concentrations tested. A significant reduction in fibrin deposition was achieved by UFH and EP 2 µg/ml but no significant differences in platelet deposition were found, except for a significant reduction for EP 0.6 µg/ml. Our in vitro study showed that EP217609C101 is a promising new drug that is dose-dependently superior to classical (UFH, enoxaparin) and newer (fondaparinux) drugs in preventing heart catheter thrombosis.
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Anticoagulantes/farmacología , Biotina/análogos & derivados , Catéteres Cardíacos/efectos adversos , Enoxaparina/farmacología , Inhibidores del Factor Xa , Heparina/farmacología , Oligosacáridos/farmacología , Polisacáridos/farmacología , Protrombina/antagonistas & inhibidores , Trombosis/prevención & control , Adolescente , Adulto , Biotina/farmacología , Femenino , Fondaparinux , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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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Progresión de la Enfermedad , Insuficiencia Cardíaca , Volumen Sistólico , Rigidez Vascular , Humanos , Rigidez Vascular/fisiología , Femenino , Masculino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/diagnóstico por imagen , Anciano , Volumen Sistólico/fisiología , Animales , Ratones , Estudios Prospectivos , Imagen por Resonancia Cinemagnética/métodos , Ecocardiografía , Imagen por Resonancia Magnética , Análisis de la Onda del PulsoRESUMEN
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 , Insuficiencia Cardíaca , Rigidez Vascular , Humanos , Anciano , Persona de Mediana Edad , Ratones , Animales , Lactante , Neprilisina , Angiotensinas , Tetrazoles/uso terapéutico , Receptores de Angiotensina , Valsartán/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Combinación de Medicamentos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Volumen SistólicoRESUMEN
The contribution of abdominal aortic aneurysm (AAA) disease to human morbidity and mortality has increased in the aging, industrialized world. In response, extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of the diseased aorta. This work aims to develop novel diagnostic and therapeutic strategies to limit AAA expansion and, ultimately, rupture. Contributions from multiple research groups have uncovered a complex transcriptional and post-transcriptional regulatory milieu, which is believed to be essential for maintaining aortic vascular homeostasis. Recently, novel small noncoding RNAs, called microRNAs, have been identified as important transcriptional and post-transcriptional inhibitors of gene expression. MicroRNAs are thought to "fine tune" the translational output of their target messenger RNAs (mRNAs) by promoting mRNA degradation or inhibiting translation. With the discovery that microRNAs act as powerful regulators in the context of a wide variety of diseases, it is only logical that microRNAs be thoroughly explored as potential therapeutic entities. This current review summarizes interesting findings regarding the intriguing roles and benefits of microRNA expression modulation during AAA initiation and propagation. These studies utilize disease-relevant murine models, as well as human tissue from patients undergoing surgical aortic aneurysm repair. Furthermore, we critically examine future therapeutic strategies with regard to their clinical and translational feasibility.