Abstract Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca 2+ signal. Promisingly, our smartly formulated Ca 2+ -sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failure, expression of TnC L48Q before the MI preserves cardiac function and performance. Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. We demonstrate engineering TnC can specifically and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease.
ABSTRACT Background There is a paucity of data regarding the optimal timing of left atrial appendage closure (LAAC) and whether scheduling delays increase the risk for adverse outcomes. Objectives This study sought to assess the incidence and predictors of adverse events among patients awaiting LAAC. Methods This single‐center retrospective study assessed all patients who underwent LAAC from January 2017 to March 2020. The primary study endpoints were the rate and characteristics of adverse events occurring from the time of initial shared decision to pursue LAAC until the time of LAAC. Adverse events were defined as clinically significant bleeding or anemia, thromboembolic complications, or death. Patients were censored after successful closure or the first adverse event. Results Two hundred and sixty‐five patients underwent LAAC with demographics notable for age 73.5 ± 8.1 years, 98 (37%) females, left ventricular ejection fraction 52.3% ± 10.4%, CHA 2 DS 2 ‐VASc 4.8 ± 1.4, and HAS‐BLED 3.2 ± 1.2. Median time from shared decision to insurance approval and insurance approval to LAAC were 18 (IQR 28) and 44 (IQR 40) days, respectively. Seventeen (6%) patients suffered an adverse event, including 15 (88%) cases of bleeding or anemia and 2 (12%) cases of thromboembolism. Multivariate analysis demonstrated that increased time to LAAC (odds ratio [OR] 1.31, 95% confidence interval [CI] [1.15, 1.50], p < 0.001) and higher HAS‐BLED score (OR 1.67, CI [1.11, 2.59], p = 0.017) were associated with significantly increased risk for adverse events. Conclusion Prolonged time to LAAC and higher HAS‐BLED score portend an increased risk for adverse events while awaiting LAAC. Expedited closure is warranted in high‐risk patients.
The use of detection to activate protected left-turn phasing has developed primarily through empirical trial and error and has been instituted without the supporting scientific theory. This study compared the performance of left-turn phasing to provide quantifiable benefits of one phasing over another. Permitted, protected, and protected/permitted (P/P) phasing are analyzed for a range of left-turn volumes and opposing through traffic in order to develop relational curves. The measure of left, through and overall intersection delay is used to compare the different phasing performances. Specific consideration is given to determining the optimal location of the queue detector for P/P phasing. From the analysis, guidelines are developed for determining the type of left-turn phasing based on left-turn volume, opposing through volume and lane geometry. The analysis indicates that P/P phasing provides the best method of left-turn phasing signal control. The P/P phasing allows for a wide range of control and is better able to accommodate the changing volumes throughout the day. The optimal queue detector location for P/P varies based on opposing volume and geometry. The Utah Department of Transportation (UDOT) typically has placed the queue detector location at the third vehicle. This is based on permitted phasing to accommodate two sneakers per cycle. Therefore the third vehicle location triggers the protected phasing so that all left-turning vehicles can be accommodated. However, this assumes that no gaps exist in the oncoming traffic to provide capacity for left turns and that the opposing traffic is operating near capacity. Based on this assumption, delay comparisons indicate that geometry and queue locations are related. For a single lane geometry, the third vehicle location is appropriate. However, as the geometry is increased to two or three lanes, the opposing through volume increases and the overall intersection delay is reduced when the detector location is moved to the fourth vehicle location.
Although sinoatrial node (SAN) dysfunction is a hallmark of human heart failure (HF), the underlying mechanisms remain poorly understood. We aimed to examine the role of adenosine in SAN dysfunction and tachy-brady arrhythmias in chronic HF.We applied multiple approaches to characterize SAN structure, SAN function, and adenosine A1 receptor expression in control (n=17) and 4-month tachypacing-induced chronic HF (n=18) dogs. Novel intramural optical mapping of coronary-perfused right atrial preparations revealed that adenosine (10 μmol/L) markedly prolonged postpacing SAN conduction time in HF by 206 ± 99 milliseconds (versus 66 ± 21 milliseconds in controls; P=0.02). Adenosine induced SAN intranodal conduction block or microreentry in 6 of 8 dogs with HF versus 0 of 7 controls (P=0.007). Adenosine-induced SAN conduction abnormalities and automaticity depression caused postpacing atrial pauses in HF versus control dogs (17.1 ± 28.9 versus 1.5 ± 1.3 seconds; P<0.001). Furthermore, 10 μmol/L adenosine shortened atrial repolarization and led to pacing-induced atrial fibrillation in 6 of 7 HF versus 0 of 7 control dogs (P=0.002). Adenosine-induced SAN dysfunction and atrial fibrillation were abolished or prevented by adenosine A1 receptor antagonists (50 μmol/L theophylline/1 μmol/L 8-cyclopentyl-1,3-dipropylxanthine). Adenosine A1 receptor protein expression was significantly upregulated during HF in the SAN (by 47 ± 19%) and surrounding atrial myocardium (by 90 ± 40%). Interstitial fibrosis was significantly increased within the SAN in HF versus control dogs (38 ± 4% versus 23 ± 4%; P<0.001).In chronic HF, adenosine A1 receptor upregulation in SAN pacemaker and atrial cardiomyocytes may increase cardiac sensitivity to adenosine. This effect may exacerbate conduction abnormalities in the structurally impaired SAN, leading to SAN dysfunction, and potentiate atrial repolarization shortening, thereby facilitating atrial fibrillation. Atrial fibrillation may further depress SAN function and lead to tachy-brady arrhythmias in HF.
AimsThe complex architecture of the human atria may create physical substrates for sustained re-entry to drive atrial fibrillation (AF). The existence of sustained, anatomically defined AF drivers in humans has been challenged partly due to the lack of simultaneous endocardial–epicardial (Endo–Epi) mapping coupled with high-resolution 3D structural imaging.
Background: A mechanism of AF maintenance has been suggested to be a limited number of patient-specific AF drivers seen by optical mapping in animals and now Focal Impulse and Rotor Mapping (FIRM) in patients. The higher resolution optical mapping can only be performed ex vivo and, thus, these two different mapping approaches have never been evaluated simultaneously in human hearts. Methods: Coronary-perfused explanted human atria (n=5, 19-57 y.o.) were optically mapped using voltage sensitive near-infrared di-4-ANBDQBS with 2-4 high resolution CMOS cameras (100x100 pixels with 330-1000μM resolution) simultaneously with a 64-electrode basket catheter or a 64-electrode custom flat catheter from either the endocardium or epicardium. AF (>10 min, 6.8±2.1Hz) was induced by perfusion of adenosine (10-100μM) and/or isoproterenol (10-100nM). AF drivers were defined as localized stable reentrant activity in areas of highest dominant frequency for optical mapping, while unipolar signals from the catheters were analyzed using experienced FIRM user interpretation and RAP, a signal analysis tool that highlights driver regions on commercially available systems. Results: Optical mapping identified reentrant AF drivers in 7/8 episodes of AF in both the left and right atria. Interestingly, one episode of AF was driven by two competing reentrant drivers. Six AF drivers seen by optical mapping were also seen with the same location and rotation by FIRM, while FIRM identified an AF driver in an 8th episode from an endocardial basket that was unseen by optical mapping from the epicardium. In one episode, the intramural AF driver was only defined by dual sided optical mapping and unseen by endocardial FIRM. Conclusions: Our study demonstrates that most localized reentrant AF drivers in ex vivo human hearts have similar spatiotemporal characteristics whether identified by high resolution optical mapping or FIRM and may represent the clinical phenomena seen in AF patients.
Introduction: Dense fibrous connective tissue is inherently found in the human sinoatrial node (hSAN), which further increases in heart failure (HF) leading to sinoatrial node dysfunction (SND). While several factors contribute to cardiac fibrosis, it is unknown if long non-coding RNAs (lncRNA), a novel class of RNA known to affect cardiac fibrosis, are involved in increasing fibrotic content in hSAN in non-failing (nHF) vs HF hearts. Objective: To identify unique lncRNA profiles and pro-fibrotic lncRNAs in isolated SAN and right atrial (RA) fibroblasts (FBs), in HF vs nHF human hearts. Methods: FBs isolated from pure SAN and RA tissues, from HF (n=6; 35-68yo) and nHF (n=4; 26-64yo) cardioplegically arrested human hearts, were cultured with/without transforming growth factor β1 (TGFβ1; 5ng; 48hrs) to activate myofibroblast (myoFB) transition. Frozen FBs and myoFBs were subjected to high throughput Next Generation RNA Sequencing analyses of the whole transcriptome. Results: Averages of total counts across all samples revealed that majority of the genes detected were protein coding 14415(63%), 5876 (26%) lncRNA, 1254 (5%) miscellaneous RNA, 677(3%) miRNA and 577 (3%) other types of RNA (Figure A). Preliminary analyses show that coding mRNA and non-coding lncRNA are differentially expressed in nHF hSAN and RA fibroblasts and TGFβ1 treated myoFBs. Furthermore, these expression patterns were also different in FBs and myoFBs isolated from failing hearts. Conclusions: Our findings show for the first time that lncRNA expression in cultured hSAN Fbs and myoFBs are unique and differentially altered in HF. Ongoing analyses of sequenced transcriptome will identify FB and myoFB lncRNAs associated with intrinsic higher levels of hSAN fibrotic content as well as in HF. We will also determine if they can modify pro-fibrotic activity in HF SAN FBs and myoFBs, which may be beneficial to develop novel molecular approaches to decrease HF-associated SAN fibrosis and associated SND.
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