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Here the authors propose an RNA interference-based switch for dynamic control of AAV transgene expression. In this approach, transgene expression may be silenced by RNAi and subsequently recovered using REVERSIR oligonucleotides.

BackgroundCoronary microvascular dysfunction (CMD) has differences in prevalence and presentation between women and men; however, we have limited understanding about underlying contributors to sex differences in CMD. Myocardial perfusion reserve index (MPRI), as semi-quantitative measure of myocardial perfusion derived from cardiac magnetic resonance (CMR) imaging has been validated as a measure of CMD. We sought to understand the sex differences in the relations between the MPRI and traditional measures of cardiovascular disease by CMR.MethodsA retrospective analysis of a single-center cohort of patients receiving clinical stress CMR from 2015 to 2022 was performed. Patients with calculated MPRI and no visible perfusion defects consistent with obstructive epicardial coronary disease were included. We compared associations between MPRI versus traditional cardiovascular risk factors and markers of cardiac structure/function in sex-stratified populations using univariable and multivariable regression models.ResultsA total of 229 patients [193 female, 36 male, median age 57 (47–67) years] were included in the analysis. In the female population, no traditional cardiovascular risk factors were associated with MPRI, whereas in the male population, diabetes (β: −0.80, p = 0.03) and hyperlipidemia (β: −0.76, p = 0.006) were both associated with reduced MPRI in multivariable models. Multivariable models revealed significant associations between reduced MPRI and increased ascending aortic diameter (β: −0.42, p = 0.005) and T1 times (β: −0.0056, p = 0.03) in the male population, and increased T1 times (β: −0.0037, p = 0.006) and LVMI (β: −0.022, p = 0.0003) in the female population.ConclusionThe findings suggest different underlying pathophysiology of CMD in men versus women, with lower MPRI in male patients fitting a more “traditional” atherosclerotic profile.

Objective: Coronary artery calcium score (CAC) is a validated tool to predict and reclassify cardiovascular risk. Additional metrics such as regional distribution and extent of CAC over Agatston CAC score may allow further risk stratification. In this study, we evaluate the prognostic significance of proximal CAC involvement in asymptomatic population from the prospective EISNER (Early-Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) registry, focusing on patients with mild CAC (score 1-99). Methods: This study included a total of 2,047 adult asymptomatic subject who underwent baseline CAC scan and 14-year follow-up for MACE, defined as myocardial infarction, late revascularization, or cardiac death. Proximal involvement was defined as presence of CAC in the LM, proximal LAD, LCX or RCA. CAC was categorized as 0, 1-99, and ≥100. Results: 1,090 (53.2%) subjects had no CAC, 576 (28.1%) had CAC 1-99, and 381 (18.7%) had CAC ≥100. Proximal involvement was seen in 67.2% of subjects with CAC 1-99 and 97.3% of subjects with CAC ≥100. In the CAC 1-99 category, the presence of proximal CAC was associated with increased MACE risk after adjustment for CAC score, CAC extent and conventional risk factors compared to those without proximal CAC (HR: 2.84 95% CI: 1.29-6.25, p=0.009). Conclusion: In asymptomatic subjects with CAC scores of 1-99, the presence and extent of proximal CAC plaques provides strong independent prognostic information in predicting MACE

Abstract Background In women with evidence of ischemia and no obstructive coronary artery disease the underlying mechanism is most often attributed to coronary microvascular dysfunction. Higher rates of adverse cardiovascular events, specifically heart failure with preserved ejection fraction, are present in women with coronary microvascular dysfunction, leading to the hypothesis that coronary microvascular dysfunction may contribute to the progression of heart failure with preserved ejection fraction. Case summary A 55-year-old, Caucasian woman with a past medical history of chest pain and shortness of breath was referred to our tertiary care center and diagnosed as having coronary microvascular dysfunction by invasive coronary reactivity testing. After 10 years of follow-up care for coronary microvascular dysfunction, she presented to an emergency room in acute heart failure and was diagnosed as having heart failure with preserved ejection fraction. Discussion The current case report provides a specific example in support of existing studies that demonstrate that coronary microvascular dysfunction may be a precursor of heart failure with preserved ejection fraction. Further research is needed to establish causality and management. Trial registration Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02582021.

Abstract Background Ischemia, in the absence of obstructive coronary artery disease, is prevalent in women, and associated with increased risk for major cardiovascular events. Coronary microvascular dysfunction is prevalent in these patients, and associated with impaired diastolic function. Despite our general understanding, however, optimal treatment of this cohort remains elusive. Methods To address this knowledge gap, we performed an open-label treatment trial to assess whether phosphodiesterase type 5 inhibition improves coronary microvascular perfusion and diastolic function in women with signs and symptoms of ischemia but no evidence of obstructive coronary artery disease. Left ventricular morphology and function, along with myocardial perfusion reserve index, were assessed by contrast-enhanced cardiac magnetic resonance imaging. Results A total of five women enrolled of which four completed the trial, while one was withdrawn by the investigators after developing dyspnea 1 week after treatment. Her symptoms resolved after cessation of the study medication. In contrast to our hypothesis, phosphodiesterase type 5 inhibition reduced the rate of circumferential strain in diastole in all four women who completed the trial (that is, diastolic dysfunction). This impairment could not be explained by changes in heart rate, contractility, blood pressure, or preload, and was not associated with a change in myocardial perfusion reserve index. Frequency of angina also tended to increase with treatment, with the greatest increase occurring in the patient with the greatest impairment in diastolic strain. Conclusions Taken together, these data question the efficacy of phosphodiesterase type 5 inhibition to treat women with ischemic heart disease, and highlight the need for further investigation.

In complex real-world scenes, image content is conveyed by a large collection of intertwined visual features. The visual system disentangles these features in order to extract information about image content. Here, we investigate the role of one integral component: the content of spatial frequencies in an image. Specifically, we measure the amount of image content carried by low versus high spatial frequencies for the representation of real-world scenes in scene-selective regions of human visual cortex. To this end, we attempted to decode scene categories from the brain activity patterns of participants viewing scene images that contained the full spatial frequency spectrum, only low spatial frequencies, or only high spatial frequencies, all carefully controlled for contrast and luminance. Contrary to the findings from numerous behavioral studies and computational models that have highlighted how low spatial frequencies preferentially encode image content, decoding of scene categories from the scene-selective brain regions, including the parahippocampal place area (PPA), was significantly more accurate for high than low spatial frequency images. In fact, decoding accuracy was just as high for high spatial frequency images as for images containing the full spatial frequency spectrum in scene-selective areas PPA, RSC, OPA and object selective area LOC. We also found an interesting dissociation between the posterior and anterior subdivisions of PPA: categories were decodable from both high and low spatial frequency scenes in posterior PPA but only from high spatial frequency scenes in anterior PPA; and spatial frequency was explicitly decodable from posterior but not anterior PPA. Our results are consistent with recent findings that line drawings, which consist almost entirely of high spatial frequencies, elicit a neural representation of scene categories that is equivalent to that of full-spectrum color photographs. Collectively, these findings demonstrate the importance of high spatial frequencies for conveying the content of complex real-world scenes.