Mark Gajjar

Architecture of a serine recombinase-DNA regulatory complex

Summary An essential feature of many site-specific recombination systems is their ability to regulate the direction and topology of recombination. Resolvases from the serine recombinase family assemble an interwound synaptic complex that harnesses negative supercoiling to drive the forward reaction and promote recombination between properly oriented sites. To better understand the interplay of catalytic and regulatory functions within these synaptic complexes, we have solved the structure of the regulatory site synapse in the Sin resolvase system. It reveals an unexpected synaptic interface between helix-turn-helix DNA-binding domains that is also highlighted in a screen for synapsis mutants. The tetramer defined by this interface provides the foundation for a robust model of the synaptic complex, assembled entirely from available crystal structures, that gives insight into how the catalytic activity of Sin and other serine recombinases may be regulated.

Coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction

There are multiple proposed mechanisms for the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). We hypothesized that coronary microvascular dysfunction is common in these patients. In a prospective, observational study, patients undergoing cardiac catheterization with HFpEF [left ventricular (LV) ejection fraction ≥ 50% and with clinical HF] were compared with similar patients without HFpEF. Patients with ≥50% stenosis were excluded, and coronary flow reserve (CFR) and the index of microvascular resistance (IMR) were measured after adenosine administration using a guidewire, with CFR ≤ 2 and IMR ≥ 23 being abnormal. Baseline characteristics and CFR and IMR were compared in 30 HFpEF patients and 14 control subjects. Compared with control subjects, HFpEF patients were older (65.4 ± 9.6 vs. 55.1 ± 3.1 yr, P < 0.01), had higher numbers of comorbidities (4.4 ± 1.5 vs. 2.6 ± 1.9, P = 0.002), had higher median B-type natriuretic peptide [161 (interquartile range: 75-511) pg/dl vs. 37 (interquartile range: 18.5-111) pg/dl, P < 0.01], and had higher LV end-diastolic pressure (17.8 ± 4.2 vs. 8.4 ± 4.2, P < 0.01). HFpEF patients had lower CFR (2.55 ± 1.60 vs. 3.84 ± 1.89, P = 0.024) and higher IMR (26.7 ± 10.3 vs. 19.7 ± 9.7 units, P = 0.037) than control subjects. Most (71.4%) control subjects had normal coronary physiology, whereas 36.7% of HFpEF patients had both abnormal CFR and IMR and another 36.7% had either abnormal CFR or IMR. In conclusion, this is the first study that has reported invasively determined CFR and IMR in HFpEF patients. We demonstrated the presence of four distinct coronary physiology groups in HFpEF patients. Investigation into the potential mechanisms for these findings is needed. NEW & NOTEWORTHY In this prospective observational study of patients with heart failure with preserved ejection fraction (HFpEF), we found that patients with HFpEF had more abnormalities of coronary flow and resistance than asymptomatic control patients, indicating that coronary microvascular dysfunction may play a role in the HFpEF disease process.

Real-Time Continuous Left Atrial Pressure Monitoring During Mitral Valve Repair Using the MitraClip NT System: A Feasibility Study

Transcatheter mitral valve repair with the Abbott MitraClip device (Abbott Park, Illinois) is indicated for patients with symptomatic, degenerative mitral regurgitation (MR) of 3+ or greater severity with prohibitive surgical risk [(1)][1]. The mainstay for procedural success is the use of

Letter to the EditorResearch LetterReal-Time Continuous Left Atrial Pressure Monitoring During Mitral Valve Repair Using the MitraClip NT System: A Feasibility Study

Transcatheter mitral valve repair with the Abbott MitraClip device (Abbott Park, Illinois) is indicated for patients with symptomatic, degenerative mitral regurgitation (MR) of 3+ or greater severity with prohibitive surgical risk [(1)][1]. The mainstay for procedural success is the use of

Global longitudinal strain from resting echocardiogram is associated with long-term adverse cardiac outcomes in patients with suspected coronary artery disease

Purpose: Measuring myocardial strain using two-dimensional speckle tracking echocardiography has emerged as a new tool to identify subclinical ventricular dysfunction. Abnormal strain has been shown to have superior sensitivity compared with dobutamine stress echocardiography for viability assessment; however, there is a paucity of data regarding the prediction of long-term major adverse cardiac events. We compared the prognostic ability of both global longitudinal strain (GLS) from resting echocardiograms to regional wall motion score index (WMSI) from stress echocardiograms in their ability to predict long-term major adverse cardiac events. Methods: Patients referred for stress echocardiography, who also underwent coronary angiography within 3 months of stress echo (n=122), were enrolled. Patients with reduced ejection fractions (<40%) were excluded. Patients were followed for a median of 3.4 years for major adverse cardiac events, readmissions and repeat cardiac testing. Results: Patients with abnormal GLS (GLS <16.8%) from the resting echocardiogram obtained as part of the exercise echocardiogram experienced a significantly shorter time to major adverse cardiac events (p=0.026), first cardiovascular hospitalization and repeat cardiac testing (p=0.0011) compared to those with normal GLS. Abnormal GLS appears to be a better predictor than abnormal WMSI in predicting major adverse cardiac events (p=0.174) and time to first cardiovascular hospitalization or repeat cardiac testing (p=0.0093). Conclusion: GLS may be a better predictor of long-term major adverse cardiac events, readmissions and repeat cardiac testing than WMSI in patients undergoing stress echocardiography.

MYOCARDIAL FIBROSIS FOLLOWING ISCHEMIA AND INFARCTION IS GREATER AMONG PERSONS WITH HUMAN IMMUNODEFICIENCY VIRUS THAN UNINFECTED CONTROLS

Persons with human immunodeficiency virus (HIV) have greater risks for myocardial infarction and sudden cardiac death (SCD) than the general population. Associations between coronary artery disease (CAD) and myocardial fibrosis - a mediator of SCD - in the setting of HIV are unknown. We hypothesized

MACHINE LEARNING OF STS AND ECHO DERIVED FUNCTIONAL PARAMETERS PREDICTS AORTIC STENOSIS MORTALITY BETTER THAN THE STS MORTALITY SCORE ALONE

Background: The Society of Thoracic Surgeons Predicted Risk of Mortality (STS) score was designed to predict operable patient mortality. Recently, it has been used to select inoperable patients for transcatheter aortic valve replacement. Statistical machine learning algorithms (MLA) improve the accuracy of predictive models. We determined if 6 different MLA combining STS and transthoracic echocardiographic (TTE) parameters would improve sensitivity of the STS score alone in predicting mortality in inoperable aortic stenosis (AS) patients.

TCT-305 Correlation Between Predicted to Observed Coronary Drug-Eluting Stent (DES) Expansion as Determined by Intravascular Ultrasound (IVUS): Variance Between Stent Platforms and Impact of Lesion Characteristics

Manufacturer-predicted stent expansion is based on in-vitro testing. Actual expansion is related to stent architecture, lesion characteristics, etc. We evaluated the relationships between these variables on coronary DES expansion via IVUS. 1,652 IVUS frames were acquired and blindly analyzed in 56