Unbiased plasma proteomics for novel diagnostic biomarkers in cardiovascular disease: identification of quiescin Q6 as a candidate biomarker of acutely decompensated heart failure

Aims Biochemical marker testing has improved the evaluation and management of patients with cardiovascular diseases over the past decade. Natriuretic peptides (NPs), used in clinical practice to assess cardiac dysfunction, exhibit many limitations, however. We used an unbiased proteomics approach for the discovery of novel diagnostic plasma biomarkers of heart failure (HF). Methods and results A proteomics pipeline adapted for very low-abundant plasma proteins was applied to clinical samples from patients admitted with acute decompensated HF (ADHF). Quiescin Q6 (QSOX1), a protein involved in the formation of disulfide bridges, emerged as the best performing marker for ADHF (with an area under the receiver operator characteristic curve of 0.86, 95% confidence interval: 0.79-0.92), and novel isoforms of NPs were also identified. Diagnostic performance of QSOX1 for ADHF was confirmed in 267 prospectively collected subjects of whom 76 had ADHF. Combining QSOX1 to B-type NP (BNP) significantly improved diagnostic accuracy for ADHF by particularly improving specificity. Using thoracic aortic constriction in rats, QSOX1 was specifically induced within both left atria and ventricles at the time of HF onset. Conclusion The novel biomarker QSOX1 accurately identifies ADHF, particularly when combined with BNP. Through both clinical and experimental studies we provide lines of evidence for a link between ADHF and cardiovascular production of QSOX1.     

Stroke and Death Due to Spontaneous Intracranial Hypotension

Background

Spontaneous intracranial hypotension has become a well-recognized cause of headaches and a wide variety of other manifestations have been reported. Recently, several patients with asymptomatic spontaneous intracranial hypotension were reported. I now report two patients with spontaneous intracranial hypotension who developed multiple arterial strokes associated with death in one patient, illustrating the spectrum of disease severity in spontaneous intracranial hypotension.

Methods

Medical records and radiologic imaging of the two patients were reviewed.

Results

Case 1. A 45-year-old man presented with an orthostatic headache. Neurologic examination was normal. MRI showed bilateral subdural fluid collections, brain sagging, and pachymeningeal enhancement. At lumbar puncture, the opening pressure was too low to record. He underwent two epidural blood patches with transient improvement of symptoms. His headaches progressed and a CT-myelogram showed a lower cervical CSF leak. Subsequently, periodic lethargy and confusion was noted and he then rapidly deteriorated. Examination showed coma (GCS: 4 [E1, M2, V1]), a fixed and dilated right pupil, and decerebrate posturing. Bilateral craniotomies were performed for the evacuation of chronic subdural hematomas. Immediate postoperative CT showed bilateral posterior cerebral artery infarcts and a recurrent right subdural hematoma, requiring re-evacuation. Postoperative examination was consistent with brain death and support was withdrawn.  Case 2. A 42-year-old man presented with a non-positional headache. Neurologic examination was normal. CT showed bilateral acute on chronic subdural hematomas and effacement of the basilar cisterns. MRI showed brain sagging, bilateral subdural hematomas, and pachymeningeal enhancement. Bilateral craniotomies were performed and subdural hematomas were evacuated. Postoperatively, the patient became progressively lethargic (GCS: 8 [E2, M4, V2]) and variable degrees of pupillary asymmetry and quadriparesis were noted. MRI now also showed multiple areas of restricted diffusion in the pons and midbrain, consistent with multiple infarcts. CT showed worsening subdural fluid collections with midline shift and increased effacement of the basilar cisterns. Repeat bilateral craniotomies were performed for evacuation of the subdural fluid collections. Neurologic examination was then noted to be fluctuating but clearly improved when lying flat (GCS: 10T [E4, M6, VT]). CT-myelography demonstrated an extensive cervico-thoracic CSF leak. An epidural blood patch was performed. The patient made a good, but incomplete, recovery with residual quadriparesis and dysphagia.

Conclusions

Arterial cerebral infarcts are rare, but potentially life-threatening complications of spontaneous intracranial hypotension. The strokes are due to downward displacement of the brain and can be precipitated by craniotomy for evacuation of associated subdural hematomas.     

Aspiration thrombectomy during primary percutaneous coronary intervention as adjunctive therapy to early (in-ambulance) abciximab administration in patients with acute ST elevation myocardial infarction: an analysis from Leiden MISSION! acute myocardial infarction treatment optimization program

Background: The benefits of early abciximab administration and thrombus aspiration in ST elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI) have previously been elaborated. However, whether there is an adjunctive effect of thrombus aspiration among STEMI patients, with angiographic evidence of thrombus, receiving early prehospital abciximab remains unclear. Methods: In the context of a fixed protocol for PPCI, 158 consecutive patients with STEMI were enrolled, in whom abciximab was started early before hospital arrival (in‐ambulance); 79 patients who had PPCI with thrombus aspiration (thrombectomy‐facilitated PCI group), were compared to 79 who had PPCI without thrombus aspiration (conventional PCI group) in a prospective nonrandomized study. The primary end‐point was complete ST‐segment resolution within 90 minutes. Secondary end points included distal embolization, enzymatic infarct size as well as left ventricular ejection fraction (LVEF) assessed by gated single‐photon emission computed tomography. Major adverse cardiac events (MACEs) were evaluated up to 12 months. Results: Both groups were comparable for baseline characteristics. ST‐segment resolution was significantly higher in the thrombectomy‐facilitated group (P = 0.002), and multivariate analysis identified thrombectomy as an independent predictor of ST‐segment resolution (OR = 9.4, 95% CI = 2.6–33.5, P = 0.001). Distal embolization was higher in the conventional PCI group among patients with higher thrombus grades. No difference was observed between both groups in infarct size assessed by peak creatine kinase (p = 0.689) and peak Tn‐T levels (P = 0.435). Also, the LVEF at 3 months was similar (P = 0.957). At 12 month clinical follow‐up, thrombus aspiration was, however, associated with reduced all‐cause mortality (log‐rank p = 0.032). Conclusion: Among STEMI patients treated with PPCI and in‐ambulance abciximab, it appears that a selective strategy of thrombus aspiration still has additive benefit. (J Interven Cardiol 2012;25:1–9)     

Affective Decision-Making Is Predictive of Three-Month Relapse in Polysubstance-Dependent Alcoholics

Background/Aims: Common and long-lasting deficits in decision-making in polysubstance-dependent alcoholics (PSA) reflect neurobiological alterations that define the chronic nature of addiction. These deficits affect goal-directed behavior and might be critical risk factors predicting relapse in PSA. Methods: The Delay Discounting Task (DDT) and the Iowa Gambling Task (IGT) assessed the delay-discounting and decision-making skills among 37 abstinent PSA. Results: The findings indicated that IGT but not DDT performances were associated with 3-month abstinence, irrespective of the influence of personality traits and coexistent medications. Conclusion: The results show that the IGT, which assesses processes that are important in the latter stages of addiction, is ecologically more valid compared to the DDT, which assesses processes important in the early stages. They underline the importance of using neurocognitive measures to identify high relapse risk patients and emphasize the relevance of promoting new treatments.