Dataset Information

Dynamics and implications of circulating anti-angiogenic VEGF-A₁₆₅b isoform in patients with ST-elevation myocardial infarction.

ABSTRACT: Angiogenesis is crucial to restore microvascular perfusion in the jeopardized myocardium in the weeks following reperfused ST-segment elevation myocardial infarction (STEMI). (VEGF)-A₁₆₅b, an anti-angiogenic factor, has been identified as a regulator of vascularization; however, it has not been previously implicated in acute myocardial infarction. We sought to investigate the dynamics of circulating VEGF-A₁₆₅b and its association with cardiac magnetic resonance-derived infarct size and left ventricular ejection fraction (LVEF). 50 STEMI patients and 23 controls were included. Compared with control individuals, serum VEGF-A₁₆₅b was elevated in STEMI patients prior to primary percutaneous coronary intervention (PCI). Following PCI, serum VEGF-A₁₆₅b increased further, reaching a maximum level at 24?h and decreased one month after reperfusion. VEGF-A₁₆₅b levels at 24?h were associated with a large infarct size and inversely related to LVEF. VEGF-A₁₆₅b expression was increased in myocardial infarct areas from patients with previous history of AMI. An ex vivo assay using serum from STEMI patients showed that neutralization of VEGF-A₁₆₅b increased tubulogenesis. Overall, the study suggests that VEGF-A₁₆₅b might play a deleterious role after AMI as an inhibitor of angiogenesis in the myocardium. Accordingly, neutralization of VEGF-A₁₆₅b could represent a novel pro-angiogenic therapy for reperfusion of myocardium in STEMI.

SUBMITTER: Hueso L

PROVIDER: S-EPMC5577291 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Dynamics and implications of circulating anti-angiogenic VEGF-A165b isoform in patients with ST-elevation myocardial infarction.

Hueso Luisa L Rios-Navarro Cesar C Ruiz-Sauri Amparo A Chorro Francisco Javier FJ Nunez Julio J Sanz Maria Jesus MJ Bodi Vicente V Piqueras Laura L

Scientific reports 20170830 1

Angiogenesis is crucial to restore microvascular perfusion in the jeopardized myocardium in the weeks following reperfused ST-segment elevation myocardial infarction (STEMI). (VEGF)-A165b, an anti-angiogenic factor, has been identified as a regulator of vascularization; however, it has not been previously implicated in acute myocardial infarction. We sought to investigate the dynamics of circulating VEGF-A165b and its association with cardiac magnetic resonance-derived infa ...[more]

PMID: 28855597

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Project description:Vascular endothelial growth factor 165 (VEGF165) is an important extracellular protein involved in pathological angiogenesis in diseases such as cancer, wet age-related macular degeneration (wet-AMD) and retinitis pigmentosa. VEGF165 exists in two different isoforms: the angiogenic VEGF165a, and the anti-angiogenic VEGF165b. In some angiogenic diseases the proportion of VEGF165b may be equal to or higher than that of VEGF165a. Therefore, developing therapeutics that inhibit VEGF165a and not VEGF165b may result in greater anti-angiogenic activity and therapeutic benefit. To this end, we report the selective binding properties of sulfated hyaluronic acid (s-HA). Selective biopolymers offer several advantages over antibodies or aptamers including cost effective and simple synthesis, and the ability to make nanoparticles or hydrogels for drug delivery applications or VEGF165a sequestration. Limiting sulfation to the C-6 hydroxyl (C-6 OH) in the N-acetyl-glucosamine repeat unit of hyaluronic acid (HA) resulted in a polymer with strong affinity for VEGF165a but not VEGF165b. Increased sulfation beyond the C-6 OH (i.e. greater than 1 sulfate group per HA repeat unit) resulted in s-HA polymers that bound both VEGF165a and VEGF165b. The C-6 OH sulfated HA (Mw 150 kDa) showed strong binding properties to VEGF165a with a fast association rate constant (Ka; 2.8 × 10(6) M(-1) s(-1)), slow dissociation rate constant (Kd; 2.8 × 10(-3) s(-1)) and strong equilibrium binding constant (KD; ?1.0 nM)), which is comparable to the non-selective VEGF165 binding properties of the commercialized therapeutic anti-VEGF antibody (Avastin(®)). The C-6 OH sulfated HA also inhibited human umbilical vein endothelial cell (HUVEC) survival and proliferation and human dermal microvascular endothelial cell (HMVEC) tube formation. These results demonstrate that the semi-synthetic natural polymer, C-6 OH sulfated HA, may be a promising biomaterial for the treatment of angiogenesis-related disease.

Project description:ImportanceChallenges to improving ST-segment elevation myocardial infarction (STEMI) care are formidable in low- to middle-income countries because of several system-level factors.ObjectiveTo examine access to reperfusion and percutaneous coronary intervention (PCI) during STEMI using a hub-and-spoke model.Design, setting, and participantsThis multicenter, prospective, observational study of a quality improvement program studied 2420 patients 20 years or older with symptoms or signs consistent with STEMI at primary care clinics, small hospitals, and PCI hospitals in the southern state of Tamil Nadu in India. Data were collected from the 4 clusters before implementation of the program (preimplementation data). We required a minimum of 12 weeks for the preimplementation data with the period extending from August 7, 2012, through January 5, 2013. The program was then implemented in a sequential manner across the 4 clusters, and data were collected in the same manner (postimplementation data) from June 12, 2013, through June 24, 2014, for a mean 32-week period.ExposuresCreation of an integrated, regional quality improvement program that linked the 35 spoke health care centers to the 4 large PCI hub hospitals and leveraged recent developments in public health insurance schemes, emergency medical services, and health information technology.Main outcomes and measuresPrimary outcomes focused on the proportion of patients undergoing reperfusion, timely reperfusion, and postfibrinolysis angiography and PCI. Secondary outcomes were in-hospital and 1-year mortality.ResultsA total of 2420 patients with STEMI (2034 men [84.0%] and 386 women [16.0%]; mean [SD] age, 54.7 [12.2] years) (898 in the preimplementation phase and 1522 in the postimplementation phase) were enrolled, with 1053 patients (43.5%) from the spoke health care centers. Missing data were common for systolic blood pressure (213 [8.8%]), heart rate (223 [9.2%]), and anterior MI location (279 [11.5%]). Overall reperfusion use and times to reperfusion were similar (795 [88.5%] vs 1372 [90.1%]; P = .21). Coronary angiography (314 [35.0%] vs 925 [60.8%]; P < .001) and PCI (265 [29.5%] vs 707 [46.5%]; P < .001) were more commonly performed during the postimplementation phase. In-hospital mortality was not different (52 [5.8%] vs 85 [5.6%]; P = .83), but 1-year mortality was lower in the postimplementation phase (134 [17.6%] vs 179 [14.2%]; P = .04), and this difference remained consistent after multivariable adjustment (adjusted odds ratio, 0.76; 95% CI, 0.58-0.98; P = .04).Conclusions and relevanceA hub-and-spoke model in South India improved STEMI care through greater use of PCI and may improve 1-year mortality. This model may serve as an example for developing STEMI systems of care in other low- to middle-income countries.

Dataset Information

Dynamics and implications of circulating anti-angiogenic VEGF-A₁₆₅b isoform in patients with ST-elevation myocardial infarction.

Publications

Dynamics and implications of circulating anti-angiogenic VEGF-A<sub>165</sub>b isoform in patients with ST-elevation myocardial infarction.

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