ABSTRACT
Ocular pulse amplitude (OPA) is defined as the difference between maximum and minimum intraocular pressure (IOP) during a cardiac cycle. Average values of OPA range from 1 to 4 mmHg. The purpose of this investigation is to determine the source of an irregular IOP waveform with elevated OPA in a 48-year-old male. Ocular pressure waveforms had an unusual shape consistent with early ventricular contraction. With a normal IOP, OPA was 9 mmHg, which is extraordinarily high. The subject was examined by a cardiologist and was determined to be in ventricular bigeminy. In addition, he had bounding carotid pulses and echocardiogram confirmed aortic insufficiency. After replacement of the aortic valve, the bigeminy resolved and the ocular pulse waveform became regular in appearance with an OPA of 1.6-2.0 mmHg. The ocular pressure waveform is a direct reflection of hemodynamics. Evaluating this waveform may provide an additional opportunity for screening subjects for cardiovascular anomalies and arrhythmias.
Subject(s)
Aortic Valve Insufficiency/physiopathology , Glaucoma, Open-Angle/physiopathology , Heart Ventricles/physiopathology , Intraocular Pressure/physiology , Myocardial Contraction/physiology , Ventricular Function/physiology , Aortic Valve Insufficiency/complications , Aortic Valve Insufficiency/diagnostic imaging , Echocardiography , Glaucoma, Open-Angle/complications , Heart Ventricles/diagnostic imaging , Humans , Male , Middle AgedABSTRACT
Increased cellular production of vascular endothelial growth factor (VEGF) is responsible for the development and progression of multiple cancers and other neovascular conditions, and therapies targeting post-translational VEGF products are used in the treatment of these diseases. Development of methods to control and modify the transcription of the VEGF gene is an alternative approach that may have therapeutic potential. We have previously shown that isoforms of the transcriptional enhancer factor 1-related (TEAD4) protein can enhance the production of VEGF. In this study we describe a new TEAD4 isoform, TEAD4(216), which represses VEGF promoter activity. The TEAD4(216) isoform inhibits human VEGF promoter activity and does not require the presence of the hypoxia responsive element (HRE), which is the sequence critical to hypoxia inducible factor (HIF)-mediated effects. The TEAD4(216) protein is localized to the cytoplasm, whereas the enhancer isoforms are found within the nucleus. The TEAD4(216) isoform can competitively repress the stimulatory activity of the TEAD4(434) and TEAD4(148) enhancers. Synthesis of the native VEGF(165) protein and cellular proliferation is suppressed by the TEAD4(216) isoform. Mutational analysis indicates that nuclear or cytoplasmic localization of any isoform determines whether it acts as an enhancer or repressor, respectively. The TEAD4(216) isoform appears to inhibit VEGF production independently of the HRE required activity by HIF, suggesting that this alternatively spliced isoform of TEAD4 may provide a novel approach to treat VEGF-dependent diseases.
