2 Minute Medicine Rewind July 26 – August 2, 2015

Clinical Implications of Changes in Individual Platelet Reactivity to Aspirin Over Time in Acute Ischemic Stroke

There is variability in the pharmacodynamic response to aspirin, especially in patients post-acute ischemic stroke. Measuring platelet function at a single time point may not be sufficient to determine platelet reactivity in individual patients with acute ischemic stroke. In this single-centered, prospective, observational study the authors sought to evaluate the individual variability in platelet reactivity in 349 patients on aspirin during the acute stage after suffering an ischemic stroke and to determine the clinical implications of this variability in platelet reactivity. Aspirin activity was measured after 3 hours of aspirin loading, with higher values indicating increased platelet reactivity. Subsequent activity was measured on the 5^th day of consecutive aspirin intake. The numeric difference between these two values was calculated. Clinical outcomes were determined by early neurological deterioration. The authors found early neurological deterioration in 72 patients (20.6%), and changes in platelet reactivity over time were approximated by a Gaussian distribution. The difference between aspirin activity at 3 hours compared to the 5^th day was independently associated with early neurological deterioration (odds ratio, 3.19; 95% CI, 1.43-7.10; p = 0.005). Therefore the results show that increase in platelet reactivity to aspirin over time is independently associated with early neurological deterioration in patients who suffered an acute ischemic stroke. Analysis in the acute setting of serial platelet reactivity assays may be more useful than a single assay for identifying the clinical implications of aspirin platelet reactivity after ischemic stroke.

Association Between Social Integration and Suicide Among Women in the United States

Over the past decade suicide rates among middle-aged women in the United States have increased by more than 20%, making it the demographic group with the highest age-adjusted rate of suicide in the United States. Most research in this area emphasizes the psychiatric, psychological or biological determinants of suicide, with little emphasis on the social determinants. In this study, authors used data from the US Nurses’ Health Study, an ongoing nationwide prospective cohort study to estimate the association between social integration and suicide among women over 18 years of follow-up. Social integration was measured with a 7-item index that included marital status, social network size, frequency of contact with social ties, and participation in religious or other social groups. The authors found the incidence of suicide decreased with increasing social integration. More specifically, suicide was lowest among participants in the highest category of social integration (adjusted hazard ratio, 0.23 [95% CI, 0.09-0.58]). Poor mental health and serious physical illness were accounted for with the sensitivity analysis. This large nationwide study adds convincing evidence that women who are socially well integrated had a more than 3-fold lower risk for suicide.

Lanosterol reverses protein aggregation in cataracts

Cataracts are the most common cause of blindness worldwide. The current gold-standard treatment of the opacified lens is surgical removal. The pathophysiology of cataracts relates to protein aggregation and the human lens is comprised of highly ordered crystalline proteins needed for transparency and refraction. Any disruption of these proteins exposes hydrophobic surfaces leading to protein aggregation and cataract formation. Factors that lead to protein aggregation include mutations in crystallin proteins, which are known to cause congenital cataracts, or oxidative stress, which in turn contributes to age-related cataracts. Lanosterol, an amphipathic molecule synthesized by lanosterol synthase (LSS), is enriched in the lens. Two distinct homozygous LSS missense mutations (W581R and G588S) affect highly conserved amino acid residues and impair key catalytic functions of LSS. The authors found that engineered wildtype LSS prevents intracellular protein aggregation. However, mutant LSS did not prevent protein aggregation. Lansosterol treatment significantly decreased preformed protein aggregates in both in vitro and in cell-transfection experiments. Using dissected rabbit cataractous lenses in vitro and in vivo in dogs, the authors showed that lanosterol treatment reduced cataract severity and increased transparency. Therefore the authors identified a key molecule in the prevention of protein aggregation and is a innovative approach to cataract prevention and future treatment.

Response to endovascular reperfusion is not time-dependent in patients with salvageable tissue

Recent endovascular trials demonstrate that benefit from endovascular therapy post-stroke is time dependent for patients, with lack of benefit seen beyond seven hours. However this may be patient dependent because time to save brain tissue may depend on degree to which cerebral blood flow is reduced and availability of good collateral arteries.The authors hypothesize that tissue that can be salvageable is best determined by the mismatch between the magnetic resonance perfusion (MRP) lesion and the diffusion-weighted imaging (DWI) lesion. The MRP-DWI mismatch hypothesis states that patients with mismatch benefit from reperfusion regardless of the time at which reperfusion occurs. The authors conducted a prospective multicenter cohort study from 2008 to 2011 to test this theory in patients treated with endovascular reperfusion therapy up to 12 hours after symptom onset.  Good functional outcomes was defined as a modified Rankin Scale score <=2 at day 90. The authors found that in 78 patients with a MRP-DWI mismatch, reperfusion was associated with increased odds of good functional outcomes (adjusted odds ratio 3.7, 95% CI 1.2-12, p = 0.03) and attenuation of lesion growth (p = 0.02). Time to treatment did not modify these effects. Therefore, the association between endovascular reperfusion and improved functional and radiologic outcomes is not time-dependent in patients with a perfusion-diffusion mismatch. Follow-up with a randomized placebo-controlled trial is the next step following the results from this study.

Left Ventricular Dilatation Increases the Risk of Ventricular Arrhythmias in Patients With Reduced Systolic Function

Identification of risk factors for ventricular arrhythmias is important given that ICD placement is associated with risk from broth the initial placement and associated long-term risks such as device malfunction or infection. One risk factor for ventricular arrhythmias is left ventricle dilation reflecting adverse ventricular remodeling. The goal of this prospective multicenter observational study was to determine the ability of left ventricle (LV) diameter and mass to predict the risk of ventricular arrhythmias in a cohort of 930 heart failure patients with severely depressed ejection fraction. The LV mass was divided into normal, mild, moderate and severe. The authors found that severe LV end-diastolic diameter had worse shock-free survival than normal and mild LV end-diastolic diameter (p = 0.0002 and 0.0063, respectively) and freedom from death, transplant, or ventricular assist device compared with normal and moderate LV end-diastolic diameter (p < 0.0001 and 0.04441, respectively). Compared to LV end-diastolic diameter, severe LV mass had worse shock-free survival than normal and mild LV mass (p = 0.0370 and 0.0280, respectively) but no association with death, transplant, or ventricular assist device (p = 0.1319). Therefore the results show that only LV dilation and not LV mass was associated with increased ICD shocks and the end point of death and transplant. LV dilation can be easily assessed during routine clinical practice and may provide a useful clinical tool for risk stratification for sudden cardiac death in heart failure patients.

Image: PD

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