Intracerebral hemorrhage (ICH) is a devastating form of stroke with high morbidity and mortality. This review article focuses on the epidemiology, cause, mechanisms of injury, current treatment strategies, and future research directions of ICH. Incidence of hemorrhagic stroke has increased worldwide over the past 40 years, with shifts in the cause over time as hypertension management has improved and anticoagulant use has increased. Preclinical and clinical trials have elucidated the underlying ICH cause and mechanisms of injury from ICH including the complex interaction between edema, inflammation, iron-induced injury, and oxidative stress. Several trials have investigated optimal medical and surgical management of ICH without clear improvement in survival and functional outcomes. Ongoing research into novel approaches for ICH management provide hope for reducing the devastating effect of this disease in the future. Areas of promise in ICH therapy include prognostic biomarkers and primary prevention based on disease pathobiology, ultra-early hemostatic therapy, minimally invasive surgery, and perihematomal protection against inflammatory brain injury.

Background— Alternative mRNA splicing is an important mechanism for regulation of gene expression. Altered mRNA splicing occurs in association with several types of cancer, and a small number of disease-associated changes in splicing have been reported in heart disease. However, genome-wide approaches have not been used to study splicing changes in heart disease. We hypothesized that mRNA splicing is different in diseased hearts compared with control hearts. Methods and Results— We used the Affymetrix Exon array to globally evaluate mRNA splicing in left ventricular myocardial RNA from controls (n=15) and patients with ischemic cardiomyopathy (n=15). We observed a broad and significant decrease in mRNA splicing efficiency in heart failure, which affected some introns to a greater extent than others. The profile of mRNA splicing separately clustered ischemic cardiomyopathy and control samples, suggesting distinct changes in mRNA splicing between groups. Reverse transcription–polymerase chain reaction validated 9 previously unreported alternative splicing events. Furthermore, we demonstrated that splicing of 4 key sarcomere genes, cardiac troponin T ( TNNT2 ), cardiac troponin I ( TNNI3 ), myosin heavy chain 7 ( MYH7 ), and filamin C, gamma ( FLNC ), was significantly altered in ischemic cardiomyopathy and in dilated cardiomyopathy and aortic stenosis. In aortic stenosis samples, these differences preceded the onset of heart failure. Remarkably, the ratio of minor to major splice variants of TNNT2 , MYH7 , and FLNC classified independent test samples as control or disease with >98% accuracy. Conclusions— Our data indicate that mRNA splicing is broadly altered in human heart disease and that patterns of aberrant RNA splicing accurately assign samples to control or disease classes.

BACKGROUND: Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr). OBJECTIVE: To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes. METHODS: Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial. RESULTS: Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation. CONCLUSION: This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal.

Cavernous angioma (CA) is also known as cavernoma, cavernous hemangioma, and cerebral cavernous malformation (CCM) (National Library of Medicine Medical Subject heading unique ID D006392). In its sporadic form, CA occurs as a solitary hemorrhagic vascular lesion or as clustered lesions associated with a developmental venous anomaly. In its autosomal dominant familial form (Online Mendelian Inheritance in Man #116860), CA is caused by a heterozygous germline loss-of-function mutation in one of three genes—CCM1/KRIT1, CCM2/Malcavernin, and CCM3/PDCD10—causing multifocal lesions throughout the brain and spinal cord.In this paper, the authors review the cardinal features of CA’s disease pathology and clinical radiological features. They summarize key aspects of CA’s natural history and broad elements of evidence-based management guidelines, including surgery. The authors also discuss evidence of similar genetic defects in sporadic and familial lesions, consequences of CCM gene loss in different tissues at various stages of development, and implications regarding the pathobiology of CAs.The concept of CA with symptomatic hemorrhage (CASH) is presented as well as its relevance to clinical care and research in the field. Pathobiological mechanisms related to CA include inflammation and immune-mediated processes, angiogenesis and vascular permeability, microbiome driven factors, and lesional anticoagulant domains. These mechanisms have motivated the development of imaging and plasma biomarkers of relevant disease behavior and promising therapeutic targets.The spectrum of discoveries about CA and their implications endorse CA as a paradigm for deconstructing a neurosurgical disease.

Aims A novel combination therapy consisting of a left ventricular assist device (LVAD) combined with pharmacologic therapy including the selective β₂-agonist, clenbuterol, has shown promise in restoring ventricular function in patients with heart failure. The aim of this study was to identify common genes and signalling pathways whose expression was associated with reversal of heart failure and restoration of ventricular function. Methods and results Microarray analysis was performed on six paired human heart samples harvested at the time of LVAD implant and at the time of LVAD explant for recovery of ventricular function (post). Follow-up data shows that the improvements in ventricular function have been maintained for an average of 3.8 years post-explant. Analysis of the gene expression data revealed: (i) a significant association of integrin pathway signalling with recovery and (ii) the identification of several novel targets including, EPAC2, in the well-described cAMP pathway whose expression was down-regulated with recovery, and was associated with improvements in cardiac contractility, metabolism, and function. Conclusion This data set represents the first description of signalling pathways associated with the functional recovery of end-stage human heart failure and the identification of new targets in the human heart that are modified by this combination therapy.