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1.
Cytokine ; 161: 156077, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36356495

RESUMEN

BACKGROUND: Studies have shown that lipoproteins, such as LDL and VLDL, as well as its major protein component ApoE2 impact on macrophage polarization important in atherosclerosis. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a key regulator of lipoprotein receptor expression. The present study investigated the effect of the VLDL/VLDL-receptor (VLDL-R) axis on mononuclear cell polarization, as well as the role of PCSK9 and PCSK9 inhibitors (PCSK9i) within this network. METHODS: Human monocytic THP-1 cells and human monocyte-derived macrophages isolated from peripheral blood mononuclear cells (PBMC) were treated with either LPS/IFN-γ to induce a pro-inflammatory phenotype, or with IL-4/IL-13 to induce an anti-inflammatory phenotype. Cells were then subjected to further treatments by lipoproteins, PCSK9, PCSK9i and lipoprotein receptor blockers. RESULTS: LPS/IFN-γ treatment promoted a pro-inflammatory state with an increased expression of pro-inflammatory mediators such as TNF-α, CD80 and IL-1ß. VLDL co-treatment induced a switch of this pro-inflammatory phenotype to an anti-inflammatory phenotype. In pro-inflammatory cells, VLDL significantly decreased the expression of pro-inflammatory markers e.g., TNF-α, CD80, and IL-1ß. These effects were eliminated by PCSK9 and restored by co-incubation with a specific anti-PCSK9 monoclonal antibody (PCSK9i). Migration assays demonstrated that pro-inflammatory cells displayed a significantly higher invasive capacity when compared to untreated cells or anti-inflammatory cells. Moreover, pro-inflammatory cell chemotaxis was significantly decreased by VLDL-mediated acquisition of the anti-inflammatory phenotype. PCSK9 significantly lessened this VLDL-mediated migration inhibition, which was reversed by the PCSK9i. CONCLUSION: VLDL promotes mononuclear cell differentiation towards an anti-inflammatory phenotype. PCSK9, via its capacity to inhibit VLDL-R expression, reverses the VLDL-mediated anti-inflammatory action, thereby promoting a pro-inflammatory phenotype. Thus, PCSK9 targeting therapies may exert anti-inflammatory properties within the vessel wall.


Asunto(s)
Leucocitos Mononucleares , Proproteína Convertasa 9 , Humanos , Proproteína Convertasa 9/genética , Lipopolisacáridos , Factor de Necrosis Tumoral alfa , Lipoproteínas , Antiinflamatorios
2.
Heart Vessels ; 38(10): 1277-1287, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37418015

RESUMEN

Despite the progress in understanding left atrial substrate and arrhythmogenesis, only little is known about conduction characteristics in atrial fibrillation patients with various stages of fibrotic atrial cardiomyopathy (FACM). This study evaluates left atrial conduction times and conduction velocities based on high-density voltage and activation maps in sinus rhythm (CARTO®3 V7) of 53 patients with persistent atrial fibrillation (LVEF 60% (55-60 IQR), LAVI 39 ml/m2 (31-47 IQR), LApa 24 ± 6 cm2). Measurements were made in low voltage areas (LVA ≤ 0.5 mV) and normal voltage areas (NVA ≥ 1.5 mV) at the left atrial anterior and posterior walls. Maps of 28 FACM and 25 no FACM patients were analyzed (19 FACM I/II, 9 FACM III/IV, LVA 14 ± 11 cm2). Left atrial conduction time averaged to 110 ± 24 ms but was shown to be prolonged in FACM (119 ms, + 17%) when compared to no FACM patients (101 ms, p = 0.005). This finding was pronounced in high-grade FACM (III/IV) (133 ms, + 31.2%, p = 0.001). In addition, the LVA extension correlated significantly with the left atrial conduction time (r = 0.56, p = 0.002). Conduction velocities were overall slower in LVA than in NVA (0.6 ± 0.3 vs. 1.3 ± 0.5 m/s, -51%, p < 0.001). Anterior conduction appeared slower than posterior, which was significant in NVA (1 vs. 1.4 m/s, -29%, p < 0.001) but not in LVA (0.6 vs. 0.8 m/s, p = 0.096). FACM has a significant influence on left atrial conduction characteristics in patients with persistent atrial fibrillation. Left atrial conduction time prolongs with the grade of FACM and the quantitative expanse of LVA up to 31%. LVAs show a 51% conduction velocity reduction compared to NVA. Moreover, regional conduction velocity differences are present in the left atrium when comparing anterior to posterior walls. Our data may influence individualized ablation strategies.


Asunto(s)
Fibrilación Atrial , Cardiomiopatías , Ablación por Catéter , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Sistema de Conducción Cardíaco , Atrios Cardíacos , Frecuencia Cardíaca , Cardiomiopatías/diagnóstico , Fibrosis
3.
Artif Organs ; 46(1): 155-158, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34605037

RESUMEN

A patient was admitted in cardiogenic shock and a constant decrease of pump flow requiring combined inotropic support. To evaluate the cause, echocardiography and a ramp test were performed. The results suggested a LVAD related problem - particularly a suspected outflow graft obstruction. Wether CT scan nor angiography confirmed the assumption. However, a post-mortem LVAD examination revealed an outflow obstruction caused by a fungal thrombus formation invisible for standard imaging procedures.


Asunto(s)
Candida/aislamiento & purificación , Corazón Auxiliar/microbiología , Choque Cardiogénico/etiología , Trombosis/microbiología , Candidiasis/patología , Ecocardiografía , Corazón Auxiliar/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/terapia , Tomografía Computarizada por Rayos X
4.
Biochem Biophys Res Commun ; 485(2): 312-318, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28232185

RESUMEN

Monocyte migration is a key element in atherosclerosis. LDL-C facilitates monocyte migration via induction of CCR2. PCSK9 regulates cell surface expression of the LDL-R and is expressed in vascular smooth muscle cells (VSMCs). The present study was done to investigate the regulation of PCSK9 in VSMCs and its impact on monocyte function. METHODS AND RESULTS: PCSK9 mRNA and protein levels were upregulated in VSMCs by the TLR-4 ligand LPS, whereas TGF-ß or angiotensin II had no effect. Induction of PCSK9 was selectively inhibited by TLR-4 blockade and further downstream by the SAPK/JNK-inhibitor SP600125, whereas inhibitors of ERK1/2, p38 or PI3-kinase pathways had no effect. Incubation of monocytes in conditioned media from LPS-stimulated VSMCs resulted in a significant reduction of LDL-R levels on monocytes, comparable to the effects of recombinant PCSK9. LDL-C increased monocyte CCR2 expression, which augmented monocyte migration towards MCP-1. This LDL-C dependent monocyte chemotaxis was inhibited by supernatants from LPS-stimulated VSMCs, similar to recombinant PCSK9 and a specific LDL-R blocking antibody. CONCLUSION: PCSK9 is regulated in VSMCs by TLR-4 - SAPK/JNK signaling, a pathway important in inflammation and metabolism. VSMC-derived PCSK9 reduces monocyte LDL-R expression, affecting LDL-C/LDL-R-mediated CCR2-expression on monocytes, which is crucial to cell motility and atherogenesis.


Asunto(s)
Monocitos/inmunología , Proproteína Convertasa 9/inmunología , Receptores CCR2/inmunología , Animales , Aterosclerosis/inmunología , Línea Celular , Células Cultivadas , Quimiotaxis de Leucocito , Humanos , Inflamación/inmunología , Lipopolisacáridos/inmunología , Masculino , Monocitos/citología , Músculo Liso Vascular/citología , Músculo Liso Vascular/inmunología , Ratas Sprague-Dawley , Receptores CCR2/análisis , Receptor Toll-Like 4/inmunología
5.
BMC Med Imaging ; 17(1): 51, 2017 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-28835220

RESUMEN

BACKGROUND: Cardiovascular magnetic resonance feature tracking (CMR-FT) is a novel tissue tracking technique developed for noninvasive assessment of myocardial motion and deformation. This preliminary study aimed to evaluate the observer's reproducibility of CMR-FT in a small animal (mouse) model and define sample size calculation for future trials. METHODS: Six C57BL/6 J mice were selected from the ongoing experimental mouse model onsite and underwent CMR with a 3 Tesla small animal MRI scanner. Myocardial deformation was analyzed using dedicated software (TomTec, Germany) by two observers. Left ventricular (LV) longitudinal, circumferential and radial strain (EllLAX, EccSAX and ErrSAX) were calculated. To assess intra-observer agreement data analysis was repeated after 4 weeks. The sample size required to detect a relative change in strain was calculated. RESULTS: In general, EccSAX and EllLAX demonstrated highest inter-observer reproducibility (ICC 0.79 (0.46-0.91) and 0.73 (0.56-0.83) EccSAX and EllLAX respectively). In contrast, at the intra-observer level EllLAX was more reproducible than EccSAX (ICC 0.83 (0.73-0.90) and 0.74 (0.49-0.87) EllLAX and EccSAX respectively). The reproducibility of ErrSAX was weak at both observer levels. Preliminary sample size calculation showed that a small study sample (e.g. ten animals to detect a relative 10% change in EccSAX) could be sufficient to detect changes if parameter variability is low. CONCLUSIONS: This pilot study demonstrates good to excellent inter- and intra-observer reproducibility of CMR-FT technique in small animal model. The most reproducible measures are global circumferential and global longitudinal strain, whereas reproducibility of radial strain is weak. Furthermore, sample size calculation demonstrates that a small number of animals could be sufficient for future trials.


Asunto(s)
Ventrículos Cardíacos/diagnóstico por imagen , Imagen por Resonancia Cinemagnética/métodos , Animales , Tamaño Corporal , Ratones , Ratones Endogámicos C57BL , Variaciones Dependientes del Observador , Proyectos Piloto , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Tamaño de la Muestra , Programas Informáticos
6.
Nephrol Dial Transplant ; 31(5): 789-97, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26333546

RESUMEN

BACKGROUND: The matrix metalloproteinases (MMP) MMP-2 and MMP-9 are physiological regulators of vascular remodelling. Their dysregulation could contribute to vascular calcification. We examined the role of the MMP-2 and MMP-9 in uraemic vascular calcification in vivo and in vitro. METHODS: The impact of pharmacological MMP inhibition on the development of media calcifications was explored in an aggressive animal model of uraemic calcification. In addition, the selective effects of addition and inhibition, respectively, of MMP-2 and MMP-9 on calcium-/phosphate-induced calcifications were studied in a murine cell line of vascular smooth muscle cells (VSMCs). RESULTS: High-dose calcitriol treatment of uraemic rats given a high phosphate diet induced massive calcifications, apoptosis and increased gene expressions of MMP-2, MMP-9 and of osteogenic transcription factors and proteins in aortic VSMC. The MMP inhibitor doxycycline prevented the VSMC transdifferentiation to osteoblastic cells, suppressed transcription of mediators of matrix remodelling and almost completely blocked aortic calcifications while further increasing apoptosis. Similarly, specific inhibitors of either MMP-2 or -9, or of both gelatinases (Ro28-2653) and a selective knockdown of MMP-2/-9 mRNA expression blocked calcification of murine VSMC induced by calcification medium (CM). In contrast to MMP inhibition, recombinant MMP-2 or MMP-9 enhanced CM-induced calcifications and the secretion of gelatinases. CONCLUSIONS: These data indicate that both gelatinases provide essential signals for phenotypic VSMC conversion, matrix remodelling and the initiation of vascular calcification. Their inhibition seems a promising strategy in the prevention of vascular calcifications.


Asunto(s)
Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Uremia/fisiopatología , Calcificación Vascular/fisiopatología , Animales , Apoptosis/efectos de los fármacos , Transdiferenciación Celular/efectos de los fármacos , Células Cultivadas , Masculino , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 9 de la Matriz/química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Osteogénesis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley
8.
Curr Opin Lipidol ; 26(4): 338-44, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26103607

RESUMEN

PURPOSE OF REVIEW: The proprotein convertases subtilisin/kexin (PCSKs) are endoproteases identified as activators of precursors from hormones and peptides. On the basis of the variety of substrates and regulation in disease, they have been recognized as mediators in atherogenesis. The discovery of PCSK9, which regulates low-density lipoprotein receptor cell membrane availability, has led to a resurgence of interest in these enzymes and their function in cardiovascular diseases. RECENT FINDINGS: Recent data demonstrate that PCSKs are expressed in human atheroma and are regulated in animal models of atherosclerosis. In animal models, inhibition of PCSKs, such as PCSK3, affects cell proliferation and migration as well as inflammation, reducing atherosclerosis. In addition, targeting PCSK9 lowers cholesterol levels and has now been demonstrated to lessen vascular lesion formation in mice. Experimentally investigated novel anti-PCSK9 strategies include genome editing and vaccination. Furthermore, studies show that PCSKs contribute to the initiation and progression of cardiometabolic risk factors, such as insulin resistance and obesity. SUMMARY: PCSKs affect cardiovascular diseases on multiple levels, including atherosclerotic lesion formation as well as their contribution to cardiometabolic risk factors. PCSK9 is a key regulator of plasma cholesterol levels, thereby potentially affecting atherosclerosis and has rapidly emerged as a pharmacological target.


Asunto(s)
Aterosclerosis/enzimología , Proproteína Convertasas/metabolismo , Animales , Insuficiencia Cardíaca/enzimología , Humanos , Síndrome Metabólico/enzimología
9.
Eur Heart J ; 35(33): 2224-31b, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-24603307

RESUMEN

AIMS: Sympathetic stimulation induces left ventricular hypertrophy and is associated with increased cardiovascular risk. Catheter-based renal denervation (RDN) has been shown to reduce sympathetic outflow and blood pressure (BP). The present multi-centre study aimed to investigate the effect of RDN on anatomic and functional myocardial parameters, assessed by cardiac magnetic resonance (CMR), in patients with resistant hypertension. METHODS AND RESULTS: Cardiac magnetic resonance was performed in 72 patients (mean age 66 ± 10 years) with resistant hypertension (55 patients underwent RDN, 17 served as controls) at baseline and after 6 months. Clinical data and CMR results were analysed blindly. Renal denervation significantly reduced systolic and diastolic BP by 22/8 mm Hg and left ventricular mass index (LVMI) by 7.1% (46.3 ± 13.6 g/m(1.7) vs. 43.0 ± 12.6 g/m(1.7), P < 0.001) without changes in the control group (41.9 ± 10.8 g/m(1.7) vs. 42.0 ± 9.7 g/m(1.7), P = 0.653). Ejection fraction (LVEF) in patients with impaired LVEF at baseline (<50%) significantly increased after RDN (43% vs. 50%, P < 0.001). Left ventricular circumferential strain as a surrogate of diastolic function in the subgroup of patients with reduced strain at baseline increased by 21% only in the RDN group (-14.8 vs. -17.9; P = 0.001) and not in control patients (-15.5 vs. -16.4, P = 0.508). CONCLUSIONS: Catheter-based RDN significantly reduced BP and LVMI and improved EF and circumferential strain in patients with resistant hypertension, occurring partly BP independently.


Asunto(s)
Hipertensión/cirugía , Simpatectomía/métodos , Anciano , Análisis de Varianza , Antihipertensivos/uso terapéutico , Presión Sanguínea/fisiología , Ablación por Catéter , Resistencia a Medicamentos , Femenino , Atrios Cardíacos , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Angiografía por Resonancia Magnética , Masculino , Estrés Fisiológico/fisiología , Función Ventricular Izquierda/fisiología
10.
Circ Res ; 110(3): 394-405, 2012 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-22207709

RESUMEN

RATIONALE: The nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of gene transcription in vascular cells and mediates the vascular protection observed with antidiabetic glitazones. OBJECTIVE: To determine the molecular mechanism of ligand-dependent transrepression in vascular smooth muscle cells and their impact on the vascular protective actions of PPARγ. METHODS AND RESULTS: Here, we report a molecular pathway in vascular smooth muscle cells by which ligand-activated PPARγ represses transcriptional activation of the matrix-degrading matrix metalloproteinase-9 (MMP-9) gene, a crucial mediator of vascular injury. PPARγ-mediated transrepression of the MMP-9 gene was dependent on the presence of the high-mobility group A1 (HMGA1) protein, a gene highly expressed in vascular smooth muscle cells, newly identified by oligonucleotide array expression analysis. Transrepression of MMP-9 by PPARγ and regulation by HMGA1 required PPARγ SUMOylation at K367. This process was associated with formation of a complex between PPARγ, HMGA1, and the SUMO E2 ligase Ubc9 (ubiquitin-like protein SUMO-1 conjugating enzyme). After PPARγ ligand stimulation, HMGA1 and PPARγ were recruited to the MMP-9 promoter, which facilitated binding of SMRT (silencing mediator of retinoic acid and thyroid hormone receptor), a nuclear corepressor involved in transrepression. The relevance of HMGA1 for vascular PPARγ signaling was underlined by the complete absence of vascular protection through a PPARγ ligand in HMGA1(-/-) mice after arterial wire injury. CONCLUSIONS: The present data suggest that ligand-dependent formation of HMGA1-Ubc9-PPARγ complexes facilitates PPARγ SUMOylation, which results in the prevention of SMRT corepressor clearance and induction of MMP-9 transrepression. These data provide new information on PPARγ-dependent vascular transcriptional regulation and help us to understand the molecular consequences of therapeutic interventions with PPARγ ligands in the vasculature.


Asunto(s)
Proteína HMGA1a/metabolismo , Músculo Liso Vascular/metabolismo , PPAR gamma/metabolismo , Transducción de Señal/fisiología , Transcripción Genética/fisiología , Animales , Endotelina-1/metabolismo , Arteria Femoral/efectos de los fármacos , Arteria Femoral/lesiones , Arteria Femoral/metabolismo , Proteína HMGA1a/deficiencia , Proteína HMGA1a/genética , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Noqueados , Modelos Animales , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/lesiones , FN-kappa B/metabolismo , Tiazolidinedionas/farmacología , Enzimas Ubiquitina-Conjugadoras/metabolismo
11.
PLoS One ; 19(5): e0303540, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38820336

RESUMEN

INTRODUCTION: Microvascular dysfunction (MVD) is a hallmark feature of chronic graft dysfunction in patients that underwent orthotopic heart transplantation (OHT) and is the main contributor to impaired long-term graft survival. The aim of this study was to determine the effect of MVD on functional and structural properties of cardiomyocytes isolated from ventricular biopsies of OHT patients. METHODS: We included 14 patients post-OHT, who had been transplanted for 8.1 years [5.0; 15.7 years]. Mean age was 49.6 ± 14.3 years; 64% were male. Coronary microvasculature was assessed using guidewire-based coronary flow reserve(CFR)/index of microvascular resistance (IMR) measurements. Ventricular myocardial biopsies were obtained and cardiomyocytes were isolated using enzymatic digestion. Cells were electrically stimulated and subcellular Ca2+ signalling as well as mitochondrial density were measured using confocal imaging. RESULTS: MVD measured by IMR was present in 6 of 14 patients with a mean IMR of 53±10 vs. 12±2 in MVD vs. controls (CTRL), respectively. CFR did not differ between MVD and CTRL. Ca2+ transients during excitation-contraction coupling in isolated ventricular cardiomyocytes from a subset of patients showed unaltered amplitudes. In addition, Ca2+ release and Ca2+ removal were not significantly different between MVD and CTRL. However, mitochondrial density was significantly increased in MVD vs. CTRL (34±1 vs. 29±2%), indicating subcellular changes associated with MVD. CONCLUSION: In-vivo ventricular microvascular dysfunction post OHT is associated with preserved excitation-contraction coupling in-vitro, potentially owing to compensatory changes on the mitochondrial level or due to the potentially reversible cause of the disease.


Asunto(s)
Trasplante de Corazón , Miocitos Cardíacos , Humanos , Masculino , Trasplante de Corazón/efectos adversos , Persona de Mediana Edad , Femenino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Adulto , Acoplamiento Excitación-Contracción , Microvasos/patología , Microvasos/fisiopatología , Calcio/metabolismo , Mitocondrias Cardíacas/metabolismo , Señalización del Calcio
12.
Cell Commun Signal ; 11: 49, 2013 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-23889985

RESUMEN

BACKGROUND: Insulin signaling is tightly controlled by tyrosine dephosphorylation of the insulin receptor through protein-tyrosine-phosphatases (PTPs). DEP-1 is a PTP dephosphorylating tyrosine residues in a variety of receptor tyrosine kinases. Here, we analyzed whether DEP-1 activity is differentially regulated in liver, skeletal muscle and adipose tissue under high-fat diet (HFD), examined the role of DEP-1 in insulin resistance in vivo, and its function in insulin signaling. RESULTS: Mice were fed an HFD for 10 weeks to induce obesity-associated insulin resistance. Thereafter, HFD mice were subjected to systemic administration of specific antisense oligonucleotides (ASOs), highly accumulating in hepatic tissue, against DEP-1 or control ASOs. Targeting DEP-1 led to improvement of insulin sensitivity, reduced basal glucose level, and significant reduction of body weight. This was accompanied by lower insulin and leptin serum levels. Suppression of DEP-1 in vivo also induced hyperphosphorylation in the insulin signaling cascade of the liver. Moreover, DEP-1 physically associated with the insulin receptor in situ, and recombinant DEP-1 dephosphorylated the insulin receptor in vitro. CONCLUSIONS: These results indicate that DEP-1 acts as an endogenous antagonist of the insulin receptor, and downregulation of DEP-1 results in an improvement of insulin sensitivity. DEP-1 may therefore represent a novel target for attenuation of metabolic diseases.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Obesidad/metabolismo , Oligonucleótidos Antisentido/farmacología , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores/metabolismo , Tejido Adiposo/metabolismo , Animales , Línea Celular , Insulina/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Músculo Esquelético/metabolismo , Obesidad/etiología , Especificidad de Órganos , Fenotipo , Fosforilación , Receptor de Insulina/metabolismo , Transducción de Señal , Tirosina/metabolismo
13.
Circ Res ; 109(5): 524-33, 2011 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-21719759

RESUMEN

RATIONALE: Positive outward remodeling of pre-existing collateral arteries into functional conductance arteries, arteriogenesis, is a major endogenous rescue mechanism to prevent cardiovascular ischemia. Collateral arterial growth is accompanied by expression of kinin precursor. However, the role of kinin signaling via the kinin receptors (B1R and B2R) in arteriogenesis is unclear. OBJECTIVE: The purpose of this study was to elucidate the functional role and mechanism of bradykinin receptor signaling in arteriogenesis. METHODS AND RESULTS: Bradykinin receptors positively affected arteriogenesis, with the contribution of B1R being more pronounced than B2R. In mice, arteriogenesis upon femoral artery occlusion was significantly reduced in B1R mutant mice as evidenced by reduced microspheres and laser Doppler flow perfusion measurements. Transplantation of wild-type bone marrow cells into irradiated B1R mutant mice restored arteriogenesis, whereas bone marrow chimeric mice generated by reconstituting wild-type mice with B1R mutant bone marrow showed reduced arteriogenesis after femoral artery occlusion. In the rat brain 3-vessel occlusion arteriogenesis model, pharmacological blockade of B1R inhibited arteriogenesis and stimulation of B1R enhanced arteriogenesis. In the rat, femoral artery ligation combined with arterial venous shunt model resulted in flow-driven arteriogenesis, and treatment with B1R antagonist R715 decreased vascular remodeling and leukocyte invasion (monocytes) into the perivascular tissue. In monocyte migration assays, in vitro B1R agonists enhanced migration of monocytes. CONCLUSIONS: Kinin receptors act as positive modulators of arteriogenesis in mice and rats. B1R can be blocked or therapeutically stimulated by B1R antagonists or agonists, respectively, involving a contribution of peripheral immune cells (monocytes) linking hemodynamic conditions with inflammatory pathways.


Asunto(s)
Arterias/crecimiento & desarrollo , Receptor de Bradiquinina B1/fisiología , Receptor de Bradiquinina B2/fisiología , Transducción de Señal/fisiología , Animales , Arteriopatías Oclusivas/metabolismo , Arteriopatías Oclusivas/fisiopatología , Arterias/fisiopatología , Arterias Cerebrales/crecimiento & desarrollo , Arteria Femoral/crecimiento & desarrollo , Miembro Posterior/irrigación sanguínea , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Patológica/fisiopatología , Ratas , Ratas Sprague-Dawley
14.
ASAIO J ; 69(9): 827-834, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37146602

RESUMEN

Lysis therapy is an established treatment option for intra-pump thrombosis of left ventricular assist devices (LVADs). In clinical routine, we observed repeated cases of acute outflow graft occlusions (OGO) associated with lysis therapy with need for urgent intervention. The aim of this investigation was to gain understanding of this observation. We screened data of 962 HeartWare ventricular assist device (HVAD) patients. One hundred twenty (13.8%) had intra-pump thromboses; 58 were treated with recombinant tissue-type plasminogen activator (rtPA). Mean age was 53.0 ± 11.1 years; 84.9% were male. In 13 (24.5%) patients, OGO occurred following rtPA-lysis. These patients showed an increase in left ventricular function (18.45% ± 12.62% to 27.73% ± 10.57%; p = 0.056), more frequent 1:1 aortic valve opening (OGO+: +36.4%; OGO-: +7.4%; p = 0.026), a decrease in LVAD pulsatility within 12 months prior intra-pump thrombosis (OGO+: -0.8 L/min [interquartile range {IQR}, -1.4 to -0.4 L/min]; OGO-: -0.3 L/min [IQR, -0.9 to 0.1 L/min]; p = 0.038) and lower HVAD flows at admission (OGO+: 6.7 L/min [IQR, 6.1-7.4 L/min]; OGO-: 8.3 L/min [IQR, 6.9-9.3 L/min]; p = 0.013), indicating a subclinical OGO prior intra-pump thrombosis. There were no differences in implantation techniques, blood parameters, and lysis strategy. Subclinical OGO represented a major risk factor for acute OGO following rtPA lysis therapy. We here propose an algorithm for risk stratification and dealing with patients presenting this first-described complication. Further research is required to confirm our results and decipher the underlying pathomechanism. http://links.lww.com/ASAIO/B97.


Asunto(s)
Insuficiencia Cardíaca , Corazón Auxiliar , Trombosis , Humanos , Masculino , Adulto , Persona de Mediana Edad , Femenino , Corazón Auxiliar/efectos adversos , Insuficiencia Cardíaca/terapia , Resultado del Tratamiento , Estudios Retrospectivos , Trombosis/etiología , Trombosis/terapia
15.
J Cardiovasc Dev Dis ; 10(8)2023 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-37623329

RESUMEN

BACKGROUND: Cardiac magnetic resonance (CMR) imaging with gadolinium-based contrast agents offers unique non-invasive insights into cardiac tissue composition. Myocardial extracellular volume (ECV) has evolved as an objective and robust parameter with broad diagnostic and prognostic implications. For the gadolinium compound gadobutrol, the recommended dose for cardiac imaging, including ECV measurements, is 0.1 mmol/kg (single dose). This dose was optimized for late enhancement imaging, a measure of focal fibrosis. Whether a lower dose is sufficient for ECV measurements is unknown. We aim to evaluate the accuracy of ECV measurements using a half dose of 0.05 mmol/kg gadobutrol compared to the standard single dose of 0.1 mmol/kg. METHODS AND RESULTS: From a contemporary trial (NCT04747366, registered 10 February 2021), a total of 25 examinations with available T1 mapping before and after 0.05 and 0.1 mmol/kg gadobutrol were analyzed. ECV values were calculated automatically from pre- and post-contrast T1 relaxation times. T1 and ECV Measurements were performed in the midventricular septum. ECV values after 0.05 and 0.1 mmol/kg gadobutrol were correlated (R2 = 0.920, p < 0.001). ECV values after 0.05 mmol/kg had a bias of +0.9% (95%-CI [0.4; 1.4], p = 0.002) compared to 0.1 mmol/kg gadobutrol, with limits of agreement from -1.5 to 3.3%. CONCLUSIONS: CMR with a half dose of 0.05 mmol/kg gadobutrol overestimated ECV by 0.9% compared with a full dose of 0.1 mmol/kg, necessitating adjustment of normal values when using half-dose ECV imaging.

16.
Eur Heart J Imaging Methods Pract ; 1(2): qyad022, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39045067

RESUMEN

Aims: Cardiac magnetic resonance (CMR) T1 relaxation time mapping is an established technique primarily used to identify diffuse interstitial fibrosis and oedema. The myocardial extracellular volume (ECV) can be calculated from pre- and post-contrast T1 relaxation times and is a reproducible parametric index of the proportion of volume occupied by non-cardiomyocyte components in myocardial tissue. The conventional calculation of the ECV requires blood sampling to measure the haematocrit (HCT). Given the high variability of the HCT, the blood collection is recommended within 24 h of the CMR scan, limiting its applicability and posing a barrier to the clinical routine use of ECV measurements. In recent years, several research groups have proposed a method to determine the ECV by CMR without blood sampling. This is based on the inverse relationship between the T1 relaxation rate (R1) of blood and the HCT. Consequently, a 'synthetic' HCT could be estimated from the native blood R1, avoiding blood sampling. Methods and results: We performed a review and meta-analysis of published studies on synthetic ECV, as well as a secondary analysis of previously published data to examine the effect of the chosen regression modell on bias. While, overall, a good correlation and little bias between synthetic and conventional ECV were found in these studies, questions regarding its accuracy remain. Conclusion: Synthetic HCT and ECV can provide a 'non-invasive' quantitative measurement of the myocardium's extracellular space when timely HCT measurements are not available and large alterations in ECV are expected, such as in cardiac amyloidosis. Due to the dependency of T1 relaxation times on the local setup, calculation of local formulas using linear regression is recommended, which can be easily performed using available data.

17.
Eur Heart J Imaging Methods Pract ; 1(1): qyad015, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-39044796

RESUMEN

Aims: This study aims to evaluate the success of the cardiovascular magnetic resonance (CMR) imaging Academy Berlin's transition from in-person to online CMR imaging training during the global pandemic 2020 and to gather recommendations for future courses. Methods and results: We conducted an online survey targeting CMR course participants from both the pre-pandemic, in-person era and the pandemic, online era of the CMR Academy Berlin. The survey primarily used Likert-type questions to assess participants' experiences and preferences.A total of 61 out of 158 invited participants (38.61%) completed the survey, with 31 (50.82%) being in-person alumni and 30 (49.18%) being online alumni. Both in-person [83.87% (26/31)] and online [83.33% (25/30)] participants rated the course as either 'very good' or 'excellent', and both groups found the course either 'extremely helpful' or 'very helpful'. However, a higher percentage of in-person participants [96.77% (30/31)] felt comfortable asking questions compared to online participants [83.33% (25/30); P = 0.025]. The majority in both groups preferred a written exam [total: 75.41% (46/61); in-person alumni: 77.42% (24/31); online alumni 73.33% (22/30)]. In terms of course format preferences, in-person courses were preferred by both in-person alumni [38.71% (12/31)] and online alumni [60% (18/30)], almost as much as a hybrid format combining in-person and online elements [in-person alumni: 41.94% (13/31), online alumni: 30% (9/30)]. Conclusion: The transition from in-person to online CMR training at the CMR Academy Berlin was successful in maintaining overall satisfaction. However, there is room for improvement in terms of increased interaction, particularly for online participants. Future CMR- and potentially also cardiac computer tomography-courses should consider adopting a hybrid format to accommodate participants' preferences and enhance their learning experience, especially to gain level II competency, whereas level I virtual only might be sufficient.


The COVID-19 pandemic has greatly changed the landscape of medical education, necessitating the shift from traditional in-person learning to online platforms. This study evaluated how well an online training programme for cardiovascular magnetic resonance imaging (CMR) was received by doctors who attended the CMR Academy in Berlin, Germany. We asked both in-person and online course participants about their experiences and preferences for future courses. A total of 61 out of 158 participants (38.61%) responded to our survey. Both in-person and online attendees rated the course as either 'very good' or 'excellent'. However, more in-person attendees felt comfortable asking questions during the course compared to online attendees. In terms of future courses, most of the participants preferred a blend of in-person and online learning, known as a hybrid format. They felt that online learning had some benefits, such as increased access, especially during a pandemic. However, they missed the interaction and engagement that in-person learning provides. They also preferred written exams to be conducted online. This study emphasizes the need for future CMR training to be more flexible and include both online and in-person elements. This would not only accommodate the participants' preferences but also enhance their learning experience. It also stresses the importance of interaction during the learning process, which needs to be improved in online platforms. The findings can potentially inform the development of educational frameworks in other areas of medical imaging, like cardiac computer tomography (CT).

18.
Cerebrovasc Dis ; 33(5): 419-29, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22456527

RESUMEN

BACKGROUND AND PURPOSE: Restoration of cerebrovascular reserve capacity (CVRC) depends on the recruitment and positive outward remodeling of preexistent collaterals (arteriogenesis). With this study, we provide functional evidence that granulocyte colony-stimulating factor (G-CSF) augments therapeutic arteriogenesis in two animal models of cerebral hypoperfusion. We identified an effective dosing regimen that improved CVRC and stimulated collateral growth, thereby improving the outcome after experimentally induced stroke. METHODS: We used two established animal models of (a) cerebral hypoperfusion (mouse, common carotid artery ligation) and (b) cerebral arteriogenesis (rat, 3-vessel occlusion). Following therapeutic dose determination, both models received either G-CSF, 40 µg/kg every other day, or vehicle for 1 week. Collateral vessel diameters were measured following latex angiography. Cerebrovascular reserve capacities were assessed after acetazolamide stimulation. Mice with left common carotid artery occlusion (CCAO) were additionally subjected to middle cerebral artery occlusion, and stroke volumes were assessed after triphenyltetrazolium chloride staining. Given the vital role of monocytes in arteriogenesis, we assessed (a) the influence of G-CSF on monocyte migration in vitro and (b) monocyte counts in the adventitial tissues of the growing collaterals in vivo. RESULTS: CVRC was impaired in both animal models 1 week after induction of hypoperfusion. While G-CSF, 40 µg/kg every other day, significantly augmented cerebral arteriogenesis in the rat model, 50 or 150 µg/kg every day did not show any noticeable therapeutic impact. G-CSF restored CVRC in mice (5 ± 2 to 12 ± 6%) and rats (3 ± 4 to 19 ± 12%). Vessel diameters changed accordingly: in rats, the diameters of posterior cerebral arteries (ipsilateral: 209 ± 7-271 ± 57 µm; contralateral: 208 ± 11-252 ± 28 µm) and in mice the diameter of anterior cerebral arteries (185 ± 15-222 ± 12 µm) significantly increased in the G-CSF groups compared to controls. Stroke volume in mice (10 ± 2%) was diminished following CCAO (7 ± 4%) and G-CSF treatment (4 ± 2%). G-CSF significantly increased monocyte migration in vitro and perivascular monocyte numbers in vivo. CONCLUSION: G-CSF augments cerebral collateral artery growth, increases CVRC and protects from experimentally induced ischemic stroke. When comparing three different dosing regimens, a relatively low dosage of G-CSF was most effective, indicating that the common side effects of this cytokine might be significantly reduced or possibly even avoided in this indication.


Asunto(s)
Circulación Cerebrovascular/efectos de los fármacos , Trastornos Cerebrovasculares/tratamiento farmacológico , Círculo Arterial Cerebral/crecimiento & desarrollo , Circulación Colateral/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Animales , Arteriopatías Oclusivas/patología , Estenosis Carotídea/patología , Movimiento Celular/efectos de los fármacos , Trastornos Cerebrovasculares/patología , Círculo Arterial Cerebral/efectos de los fármacos , Interpretación Estadística de Datos , Hemodinámica/efectos de los fármacos , Infarto de la Arteria Cerebral Media/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/uso terapéutico , Recuperación de la Función
19.
ASAIO J ; 68(11): 1332-1338, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-35184090

RESUMEN

As patients on long-term left ventricular assist device (LVAD) face a substantial risk for open cardiac reoperation, interventional treatment approaches are becoming increasingly important in this population. We evaluated data of 871 patients who were on LVAD support between January 1, 2016 and December 1, 2020. Interventional treatments for LVAD-associated complications were performed in 76 patients. Seventeen patients underwent transcatheter aortic valve replacements (TAVR) and 61 patients underwent outflow graft interventions (OGI). TAVR improved symptoms in patients with severe symptomatic aortic regurgitation. Postinterventional complications included aggravation of preexisting right heart failure (RHF), third-degree atrioventricular block, and intrapump thrombosis (in 3 [16.7%], 2 [11.1%], and 1 [5.6%] patients, respectively). In outflow graft obstructions, OGI led to recovery of LVAD flow ( p < 0.001), unloading of the left ventricle ( p = 0.004), decrease of aortic valve opening time ( p = 0.010), and improvement of right heart function ( p < 0.001). Complications included bleeding, RHF, and others (in 9 [10.8%], 5 [6.0%], and 5 [6.0%] patients, respectively). Eight (9.6%) patients died within the hospital stay after OGI, including mortality secondary to prolonged cardiogenic shock. In conclusion, interventional procedures are a feasible and safe treatment modality for LVAD-associated complications.


Asunto(s)
Insuficiencia de la Válvula Aórtica , Insuficiencia Cardíaca , Corazón Auxiliar , Humanos , Corazón Auxiliar/efectos adversos , Resultado del Tratamiento , Insuficiencia de la Válvula Aórtica/etiología , Insuficiencia de la Válvula Aórtica/cirugía , Insuficiencia Cardíaca/cirugía , Insuficiencia Cardíaca/diagnóstico , Válvula Aórtica , Estudios Retrospectivos
20.
Am J Physiol Heart Circ Physiol ; 301(1): H115-22, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21478409

RESUMEN

Exercise-induced cardiac hypertrophy has been recently identified to be regulated in a sex-specific manner. In parallel, women exhibit enhanced exercise-mediated lipolysis compared with men, which might be linked to cardiac responses. The aim of the present study was to assess if previously reported sex-dependent differences in the cardiac hypertrophic response during exercise are associated with differences in cardiac energy substrate availability/utilization. Female and male C57BL/6J mice were challenged with active treadmill running for 1.5 h/day (0.25 m/s) over 4 wk. Mice underwent cardiac and metabolic phenotyping including echocardiography, small-animal PET, peri-exercise indirect calorimetry, and analysis of adipose tissue (AT) lipolysis and cardiac gene expression. Female mice exhibited increased cardiac hypertrophic responses to exercise compared with male mice, measured by echocardiography [percent increase in left ventricular mass (LVM): female: 22.2 ± 0.8%, male: 9.0 ± 0.2%; P < 0.05]. This was associated with increased plasma free fatty acid (FFA) levels and augmented AT lipolysis in female mice after training, whereas FFA levels from male mice decreased. The respiratory quotient during exercise was significantly lower in female mice indicative for preferential utilization of fatty acids. In parallel, myocardial glucose uptake was reduced in female mice after exercise, analyzed by PET {injection dose (ID)/LVM [%ID/g]: 36.8 ± 3.5 female sedentary vs. 28.3 ± 4.3 female training; P < 0.05}, whereas cardiac glucose uptake was unaltered after exercise in male counterparts. Cardiac genes involved in fatty acid uptake/oxidation in females were increased compared with male mice. Collectively, our data demonstrate that sex differences in exercise-induced cardiac hypertrophy are associated with changes in cardiac substrate availability and utilization.


Asunto(s)
Cardiomegalia/fisiopatología , Metabolismo Energético/fisiología , Condicionamiento Físico Animal/fisiología , Tejido Adiposo/metabolismo , Animales , Western Blotting , Calorimetría , Cardiomegalia/diagnóstico por imagen , Ecocardiografía , Femenino , Fluorodesoxiglucosa F18 , Glucosa/metabolismo , Glucógeno/metabolismo , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Ácido Láctico/metabolismo , Lipólisis/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Tomografía de Emisión de Positrones , ARN/biosíntesis , ARN/genética , Radiofármacos , Carrera/fisiología , Caracteres Sexuales
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