Amy Sarma

Developmental Dynamics of Piriform Cortex

The piriform cortex (PCX) is a trilaminar paleocortex that is of interest for its role in odor coding and as a model for studying general principles of cortical sensory processing. While the structure of the mature PCX has been well characterized, its development is poorly understood. Notably, the kinetics as well as the cellular and morphological basis of the postnatal events that shape the PCX remain unknown. We followed the cellular fates of early- versus late-born cells in layer II of the anterior PCX, with a focus on the molecular maturation of pyramidal cells and the kinetics of their differentiation. We showed that: 1) early-born pyramidal cells differentiate more rapidly than late-born cells and 2) the position of pyramidal cells within the thickness of layer II determines the kinetics of their molecular maturation. We then examined the postnatal development of cortical lamination and showed that the establishment of inhibitory networks in the PCX proceeds through an increase in the density of inhibitory synapses despite a decrease in the number of interneurons. Together, our results provide a more comprehensive view of the postnatal development of the anterior PCX and reveal both similarities and differences in the development of this paleocortex versus the neocortex.

Biomarkers in ACS and Heart Failure: Should Men and Women Be Interpreted Differently?

BACKGROUND Sex-based differences exist in the circulating concentrations of certain novel and established biomarkers in patients with acute coronary syndromes (ACS) and heart failure (HF). However, to date, few studies have compared the diagnostic and prognostic utility of these markers in men vs women. CONTENT This mini-review contains a discussion of the published reports of studies that have explored whether differences in biomarker concentrations exist between men and women with ACS or HF. It also examines those studies that have compared the utility of biomarkers for diagnosis or risk stratification in women vs men. Because biomarkers are often used to make therapeutic and triage decisions in patient care, the potential clinical implications for any observed differences in biomarker reference limits for men and women is discussed. SUMMARY Although the concentration distributions may differ between men and women for certain biomarkers in clinical use, the clinical implications of these observations remain unclear. Because elements of the pathophysiology of ACS and HF may differ between the sexes, further research is needed to better evaluate the diagnostic and prognostic utility of biomarkers in men vs women.

Sex Differences in Faculty Rank Among Academic Cardiologists in the United StatesClinical Perspective

Background: Studies demonstrate that women physicians are less likely than men to be full professors. Comprehensive evidence examining whether sex differences in faculty rank exist in academic cardiology, adjusting for experience and research productivity, is lacking. Therefore, we evaluated for sex differences in faculty rank among a comprehensive, contemporary cohort of US cardiologists after adjustment for several factors that impact academic advancement, including measures of clinical experience and research productivity. Methods: We identified all US cardiologists with medical school faculty appointments in 2014 by using the American Association of Medical Colleges faculty roster and linked this list to a comprehensive physician database from Doximity, a professional networking website for doctors. Data on physician age, sex, years since residency, cardiology subspecialty, publications, National Institutes of Health grants, and registered clinical trials were available for all academic cardiologists. We estimated sex differences in full professorship, adjusting for these factors and medical school–specific fixed effects in a multivariable regression model. Results: Among 3810 cardiologists with faculty appointments in 2014 (13.3% of all US cardiologists), 630 (16.5%) were women. Women faculty were younger than men (mean age, 48.3 years versus 53.5 years, P<0.001), had fewer total publications (mean number: 16.5 publications versus 25.2 publications; P<0.001), were similarly likely to have National Institutes of Health funding (proportion with at least 1 National Institutes of Health award, 10.8% versus 10.4%; P=0.77), and were less likely to have a registered clinical trial (percentage with at least 1 clinical trial, 8.9% versus 11.1%; P=0.10). Among 3180 men, 973 (30.6%) were full professors in comparison with 100 (15.9%) of 630 women. In adjusted analyses, women were less likely to be full professors than men (adjusted odds ratio, 0.63; 95% confidence interval, 0.43–0.94; P=0.02; adjusted proportions, 22.7% versus 26.7%; absolute difference, –4.0%; 95% confidence interval, –7.5% to –0.7%). Conclusions: Among cardiology faculty at US medical schools, women were less likely than men to be full professors after accounting for several factors known to influence faculty rank.

The Incidence of Kidney Injury for Patients Treated With a High‐Potency Versus Moderate‐Potency Statin Regimen After an Acute Coronary Syndrome

Background Observational studies have raised concerns that high‐potency statins increase the risk of acute kidney injury. We therefore examined the incidence of kidney injury across 2 randomized trials of statin therapy. Methods and Results PROVE IT‐TIMI 22 enrolled 4162 subjects after an acute coronary syndrome (ACS) and randomized them to atorvastatin 80 mg/day versus pravastatin 40 mg/day. A‐to‐Z enrolled 4497 subjects after ACS and randomized them to a high‐potency (simvastatin 40 mg/day×1 months, then simvastatin 80 mg/day) versus a delayed moderate‐potency statin strategy (placebo×4 months, then simvastatin 20 mg/day). Serum creatinine was assessed centrally at serial time points. Adverse events (AEs) relating to kidney injury were identified through database review. Across both trials, mean serum creatinine was similar between treatment arms at baseline and throughout follow‐up. In A‐to‐Z, the incidence of a 1.5‐fold or ≥0.3 mg/dL rise in serum creatinine was 11.4% for subjects randomized to a high‐potency statin regimen versus 12.4% for those on a delayed moderate‐potency regimen (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.76 to 1.10; P=0.33). In PROVE IT‐TIMI 22, the incidence was 9.4% for subjects randomized to atorvastatin 80 mg/day and 10.6% for subjects randomized to pravastatin 40 mg/day (OR, 0.88; 95% CI, 0.71 to 1.09; P=0.25). Consistent results were observed for different kidney injury thresholds and in individuals with diabetes mellitus or with moderate renal dysfunction. The incidence of kidney injury‐related adverse events (AEs) was not statistically different for patients on a high‐potency versus moderate‐potency statin regimen (OR, 1.06; 95% CI, 0.68 to 1.67; P=0.78). Conclusions For patients enrolled in 2 large randomized trials of statin therapy after ACS, the use of a high‐potency statin regimen did not increase the risk of kidney injury.

Assessing and Modifying Coronary Artery Disease Risk in Women

Opinion statementDespite continued advances in the field, cardiovascular disease remains the leading cause of death in women in the USA with an annual mortality rate that has remained higher for women as compared to men. The factors leading to this sex difference remain incompletely understood. Likely contributors include atypical symptoms at presentation and lack of recognition of cardiovascular risk by women and their providers alike. In addition, women have a higher burden of comorbidities at the time of disease diagnosis and can have differential pathophysiological mechanisms of their acute events. Women also can develop unique cardiovascular risk factors such as preeclampsia and hypertensive disorders of pregnancy. As a result, when women present with symptoms, even atypical, healthcare providers should increase their index level of suspicion for cardiovascular disease. Even after diagnosis, women are less likely to receive guideline-directed medical therapies and be referred for coronary angiography or cardiac rehabilitation. Thus, greater awareness of and research into the aspects of coronary disease that remain unique to women is critical, as women presenting with coronary disease continue to receive disparate care as compared to men. Improvements in awareness and care and new research avenues may reduce the incidence and complications of cardiovascular disease among women.

The Role of Cardiac Biomarkers in Pregnancy

Opinion statementCardiovascular disease (CVD) is the leading cause of pregnancy-associated mortality, with an increasingly complex pregnant population. While our understanding of CVD in pregnancy continues to evolve, there remains a need to develop widely accessible tools to follow pregnant women both with and without preexisting disease with respect to cardiovascular risk, particularly for those presenting with symptoms suggestive of cardiovascular pathology. Thus, research is emerging with respect to the potential role of novel and established cardiac biomarkers in diagnosing and following CVD in pregnancy. Here, we review the normal hemodynamics of pregnancy and the behavior of various biomarkers in both normal and complicated pregnancies.

Aspirin Use in Women: Current Perspectives and Future Directions.

Purpose of ReviewThis review examines the recent literature on the use of low-dose aspirin (LDA) for primary and secondary prevention of cardiovascular disease in women, use of LDA for pre-eclampsia prevention in pregnancy, and the underutilization of aspirin therapy in women as compared to men.Recent FindingsWhile men and women should not differ with respect to aspirin use for secondary prevention, its role in primary prevention remains unclear for both sexes, with particular uncertainty in women. Reflective of this are conflicting recommendations in current guidelines for primary prevention and thus investigations of primary prevention aspirin use are ongoing and will play an important role in elucidating its efficacy. While there is significant heterogeneity in studies to date of LDA for pre-eclampsia prevention, based on recent meta-analyses suggesting promising results, guidelines now recommend initiation in high risk women after the 12th week of gestation. Finally, studies consistently reveal that aspirin therapy is underutilized in women as compared to men, suggesting a need to better educate physicians and the general public about its use in women.SummaryFurther research is needed to better elucidate the role of aspirin in women for primary prevention of cardiovascular disease and for pre-eclampsia in high risk pregnant women. In addition, further investigation into the factors that lead to the current underutilization of aspirin in women are required in order to ensure that patients of both sexes are optimally treated, with the goal of improving cardiovascular outcomes in all patients.

Current and developing strategies for monitoring and reversing direct oral anticoagulants in patients with non-valvular atrial fibrillation

Abstract Objective: In light of the increasing clinical utilization of the direct oral anticoagulants (DOACs) among patients with non-valvular atrial fibrillation, this review evaluates strategies for monitoring and reversing the anticoagulant effect of these agents. Methods: We summarize the data currently available for laboratory monitoring and reversal of DOACs. Relevant literature was identified using search terms pertaining to oral anticoagulants, reversal agents, and laboratory monitoring using Pubmed, clinicaltrials.gov, and abstracts from recent major cardiovascular meetings. Results: Significant user appeal for the DOACs stems from the reliable pharmacokinetics of these agents, which render routine laboratory monitoring unnecessary for general use, as well as lower rates of bleeding as compared to warfarin. However, readily available laboratory tests have not been clinically validated for use with these agents. The ability to measure the anticoagulant effect of a DOAC in selected situations (e.g. serious bleeding, overanticoagulation, emergent procedures, and compliance monitoring) remains an unmet clinical need. Further, there is a paucity of data to guide treatment in patients receiving DOACs who experience a serious hemorrhage. Conclusion: While evidence-based recommendations cannot be definitively provided for management of DOAC-related bleeding events at present, several targeted reversal agents are currently in development, and hold promise for solving this important clinical problem.

Dabigatran Excess: Case Report and Review of the Literature

IntroductionNovel oral anticoagulants are increasingly used for stroke prophylaxis in patients with non-valvular atrial fibrillation. While these agents offer a more predictable pharmacokinetic profile, the lack of readily available laboratory tests to monitor the level of anticoagulation and absence of an antidote or established therapies to reverse the anticoagulant effect make management of cases of over-anticoagulation challenging.Case ReportIn this case report an 87-year-old man with a history of atrial fibrillation presented with dabigatran excess in the setting of life-threatening, acute renal and hepatic failure. The authors review the use of dabigatran in elderly patients, the available data on management of patients with excess anticoagulation, and the potential options for reversal of the anticoagulation effect.ConclusionFurther investigation into reliable means of monitoring and reversing the anticoagulant effect of dabigatran is crucial to the management of such patients.

Pregnancy Among Survivors of Childhood Cancer: Cardiovascular Considerations

Purpose of reviewTo educate clinicians on cardiovascular considerations and management strategies surrounding pregnancy in childhood cancer survivors.Recent findingsWith advances in oncologic treatment, growing numbers of childhood cancer survivors are now able to consider pregnancy. A significant proportion of survivors have received cardiotoxic therapy, particularly anthracyclines, and/or chest radiation. Cardiomyopathy is the most common cardiac complication of cancer-directed therapy; pericardial disease, valvular disease, premature coronary artery disease, and conduction abnormalities are other potential sequelae. In female survivors of childhood malignancy, cardiac evaluation should be performed prior to pregnancy as subclinical disease has the potential to be unmasked by the hemodynamic stress of pregnancy. However, limited data exist on pregnancy outcomes after cancer survivorship.SummaryWith appropriate management, maternal and fetal outcomes in pregnancy following childhood cancer are generally favorable. Further research is needed to understand the incidence of cardiac complications among childhood cancer survivors, strategies to prevent these complications, optimal cardiovascular management during pregnancy and the postpartum period, and on the impact of pregnancy itself on the natural history of treatment-related cardiotoxicity.