A feasibility study of [18F]F-AraG positron emission tomography (PET) for cardiac imaging - myocardial viability in ischemia-reperfusion injury model.

Purpose: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, 18F-labeled 2'-deoxy-2'-18F-fluoro-9-ß-d-arabinofuranosylguanine ([18F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI. Procedure: To test whether the myocardial [18F]-F-AraG signal is coming from cardiomyocytes or immune infiltrates, we compared cardiac signal in wild-type (WT) mice with that of T cell deficient Rag1 knockout (Rag1 KO) mice. We assessed the effect of dietary nucleotides on myocardial [18F]F-AraG uptake in normal heart by comparing [18F]F-AraG signals between mice fed with purified diet and those fed with purified diet supplemented with nucleotides. The myocardial viability was investigated in rodent model by imaging rat with [18F]F-AraG and 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) before and after MI. All PET signals were quantified in terms of the percent injected dose per cc (%ID/cc). We also explored [18F]FDG signal variability and potential T cell infiltration into fibrotic area in the affected myocardium with H&E analysis. Results: The difference in %ID/cc for Rag1 KO and WT mice was not significant (p = ns) indicating that the [18F]F-AraG signal in the myocardium was primarily coming from cardiomyocytes. No difference in myocardial uptake was observed between [18F]F-AraG signals in mice fed with purified diet and with purified diet supplemented with nucleotides (p = ns). The [18F]FDG signals showed wider variability at different time points. Noticeable [18F]F-AraG signals were observed in the affected MI regions. There were T cells in the fibrotic area in the H&E analysis, but they did not constitute the predominant infiltrates. Conclusions: Our preliminary preclinical data show that [18F]F-AraG accumulates in cardiomyocytes indicating that it may be suitable for cardiac imaging and to evaluate the myocardial viability after MI.

Local decorin delivery via hyaluronic acid microrods improves cardiac performance, ventricular remodeling after myocardial infarction.

Heart failure (HF) remains a global public health burden and often results following myocardial infarction (MI). Following injury, cardiac fibrosis forms in the myocardium which greatly hinders cellular function, survival, and recruitment, thus severely limits tissue regeneration. Here, we leverage biophysical microstructural cues made of hyaluronic acid (HA) loaded with the anti-fibrotic proteoglycan decorin to more robustly attenuate cardiac fibrosis after acute myocardial injury. Microrods showed decorin incorporation throughout the entirety of the hydrogel structures and exhibited first-order release kinetics in vitro. Intramyocardial injections of saline (n = 5), microrods (n = 7), decorin microrods (n = 10), and free decorin (n = 4) were performed in male rat models of ischemia-reperfusion MI to evaluate therapeutic effects on cardiac remodeling and function. Echocardiographic analysis demonstrated that rats treated with decorin microrods (5.21% ± 4.29%) exhibited significantly increased change in ejection fraction (EF) at 8 weeks post-MI compared to rats treated with saline (-4.18% ± 2.78%, p < 0.001) and free decorin (-3.42% ± 1.86%, p < 0.01). Trends in reduced end diastolic volume were also identified in decorin microrod-treated groups compared to those treated with saline, microrods, and free decorin, indicating favorable ventricular remodeling. Quantitative analysis of histology and immunofluorescence staining showed that treatment with decorin microrods reduced cardiac fibrosis (p < 0.05) and cardiomyocyte hypertrophy (p < 0.05) at 8 weeks post-MI compared to saline control. Together, this work aims to contribute important knowledge to guide rationally designed biomaterial development that may be used to successfully treat cardiovascular diseases.

Stroke in mitral valve prolapse: risk factors and left atrial function in cryptogenic versus non-cryptogenic ischemic subtypes.

Background and purpose: Mitral valve prolapse (MVP) has been associated with an increased risk of ischemic stroke. Older age, thicker mitral leaflets, and significant mitral regurgitation (MR) leading to atrial fibrillation have been traditionally considered risk factors for ischemic stroke in MVP. However, specific risk factors for MVP-stroke subtypes are not well defined. The aim of this study is to evaluate clinical and echocardiographic parameters, including left atrial (LA) function, in MVP with cryptogenic (C) vs. non-cryptogenic (NC) stroke. Methods: In this case-control matched study, MVPs were identified in consecutive echocardiograms obtained after a stroke from January 2013 to December2016 at the University of California, San Francisco. MVP was defined as leaflet displacement ≥2 mm in the parasternal long-axis view at end-systole. Age/gender matched MVPs without stroke and healthy controls without MVP were also identified. We analyzed LA end-systolic/diastolic volume index, emptying fraction (LAEF), function index (LAFI), and global longitudinal strain in all MVPs and controls. We also measured left ventricular (LV) volume indexes, mass index, ejection fraction (EF), degree of MR and leaflet thickness. Results: We identified a total of 30 MVPs (age 70 ± 12, 50% females) with stroke (11 with C- and 19 with NC-stroke), 20 age/gender matched MVPs without a stroke and 16 controls. MVPs without stroke had lower BMI, less hypertension but more MR (≥moderate in 45% vs. 17%), more abnormal LA function (lower LAEF, LAFI) and larger LV volumes/mass (all p < 0.05) when compared to MVPs with stroke. Leaflet thickness was overall mild (<3 mm) and similar in the 2 groups. Within the MVP stroke group, NC-stroke had higher BMI, more hypertension and more atrial fibrillation compared to C-stroke. In the variables tested, patients with C-stroke did not differ from controls. Conclusions: MVP-related MR may be protective against stroke despite abnormal LA function. Risk of NC-stroke in MVP is related to common stroke risk factors rather than mitral valve leaflet thickness. The etiology of C-stroke in MVP warrants further studies.

Local delivery of decorin via hyaluronic acid microrods improves cardiac performance and ventricular remodeling after myocardial infarction.

Heart failure (HF) is a global public health burden and associated with significant morbidity and mortality. HF can result as a complication following myocardial infarction (MI), with cardiac fibrosis forming in the myocardium as a response to injury. The dense, avascular scar tissue that develops in the myocardium after injury following MI creates an inhospitable microenvironment that hinders cellular function, survival, and recruitment, thus severely limiting tissue regeneration. We have previously demonstrated the ability of hyaluronic acid (HA) polymer microrods to modulate fibroblast phenotype using discrete biophysical cues and to improve cardiac outcomes after implantation in rodent models of ischemia-reperfusion MI injury. Here, we developed a dual-pronged biochemical and biophysical therapeutic strategy leveraging bioactive microrods to more robustly attenuate cardiac fibrosis after acute myocardial injury. Incorporation of the anti-fibrotic proteoglycan decorin within microrods led to sustained release of decorin over one month in vitro and after implantation, resulted in marked improvement in cardiac function and ventricular remodeling, along with decreased fibrosis and cardiomyocyte hypertrophy. Together, this body of work aims to contribute important knowledge to help develop rationally designed engineered biomaterials that may be used to successfully treat cardiovascular diseases.

Association of Systemic Vascular Resistance Analog and Cardiovascular Outcomes: The Heart and Soul Study.

Background Systemic vascular resistance (SVR) is an integral component of the hemodynamic profile. Previous studies have demonstrated a close correlation between an estimated SVR analog (eSVR) based on echocardiographic methods and SVR by direct hemodynamic measurement. However, the prognostic impact of eSVR remains unestablished. Methods and Results Study participants with established coronary artery disease from the Heart and Soul Study formed this study cohort. We defined Doppler-derived eSVR as the ratio of systolic blood pressure to left ventricular outflow tract velocity time integral. Study participants were separated based on baseline eSVR tertile: <5.6, 5.6 to <6.9, and ≧6.9. An elevated eSVR was defined as an eSVR in the third tertile (≧6.9). Follow-up eSVR was calculated at the fifth year of checkup. Cardiovascular outcomes included heart failure, major cardiovascular events, and all-cause death. Among the 984 participants (67±11 years old, 82% men), subjects with the highest baseline eSVR tertile were the oldest, with the highest systolic blood pressure and lowest left ventricular outflow tract velocity time integral. A higher eSVR was associated with increased risk of heart failure, major cardiovascular events, and death. The hazard ratio for major cardiovascular events was 1.38 (95% CI, 1.02-1.86, P=0.03) for subjects with the highest eSVR tertile compared with the lowest. In addition, those with a persistently elevated eSVR during follow-up had the most adverse outcomes. Conclusions An elevated eSVR, derived by the ratio of systolic blood pressure and left ventricular outflow tract velocity time integral, was more closely correlated with cardiovascular events than systolic blood pressure alone. Repeatedly elevated eSVR was associated with more adverse outcomes.

Interrater reproducibility of the 2016 American society of echocardiography left ventricular diastolic function guidelines.

BACKGROUND: Little data exist regarding interreader variability of diastolic measurements and their application by the 2016 American Society of Echocardiography left ventricular (LV) diastolic function guidelines. METHODS: Volunteers (n = 49) were recruited from an outpatient cardiology practice. The presence and grade of diastology dysfunction (DD) was determined by the 2016 LV diastology guideline algorithm. We determined the mean, standard deviation, coefficient of variation, and intraclass correlation coefficient (ICC) for each measurement and Fleiss K-statistic to define differences in grading DD. We determined predictors associated with disagreement of DD grade using odds ratios. RESULTS: The mean LVEF was 56%, LAVI 32 ml/m2 , and peak TR velocity was 2.3 m/s. The ICC for mitral inflow and tissue Doppler velocities were >.90, for LV volumes were .80-.86, and for LA volume was .56. The Fleiss K-value for the agreement of the presence of DD was .68 and for DD grade was .59. Variables with increased odds of disagreement were (1) at least one reader considering a TR signal uninterpretable (OR 12.0; 95% CI 1.3-109.6), (2) at least one reader assessing both LVEF 50%-55% and LAVI 29-39 ml/m2 (OR 9.3; 95% CI 1.0-87), and (3) at least one reader assessing LVEF 50-55% (OR 3.8; 95% CI 1.1-13.4). CONCLUSIONS: Using the 2016 ASE/EACVI diastology guidelines, we found excellent interrater reliability of Doppler measurements, moderate-good interrater reliability of volumetric measurements, and moderate-good but not excellent agreement for diastology grade.

Left ventricular end-systolic volume response post-stress echocardiography: Dilation as a marker of multi-vessel coronary artery disease.

BACKGROUND: Transient ischemic dilation of the left ventricle (LV) during stress echocardiography indicates extensive myocardial ischemia. It remains unclear whether the change of LV end-systolic volume (ESV) or end-diastolic volume (EDV) better correlated with significant coronary artery disease (CAD). Meanwhile, the clinical significance of the extent of the volumetric change post-stress has not been investigated. METHODS: One hundred and five individuals (62 ± 12 years and 75% men) who underwent coronary angiography following exercise treadmill echocardiography were enrolled retrospectively. An additional 30 age- and sex-matched healthy subjects were included for comparison. LV dilation was defined as any increase in LV volume from rest to peak exercise. Patients who had at least two coronary arteries with significant stenosis were considered as having multi-vessel CAD. RESULTS: Thirty-four patients had ESV dilation during exercise echocardiography. On the contrary, ESV decreased at peak exercise in all healthy subjects. Forty-one patients had multi-vessel CAD, and its prevalence was higher in patients with ESV dilation (65% vs 27%, p = 0.001). The extent of ESV increase correlated with CAD severity. ESV dilation is associated with multi-vessel CAD (Odds ratio [OR] 5.02, 95% confidence interval [CI] 2.09 - 12.07, p < 0.001). After adjustment for EDV increase, clinical, electrocardiographic, and echocardiographic variables, the association remained significant (adjusted OR 5.57, 95% CI 1.37-22.64; p = 0.02). CONCLUSIONS: ESV dilation independently correlated with multi-vessel CAD, whereas EDV dilation did not. The amount of ESV increase correlated with the severity of CAD. Our findings provide a rationale for incorporating volume measurements into stress echocardiography practice.

Exercise physiology of the left atrium: quantity and timing of contribution to cardiac output.

Although the phases of left atrial (LA) function at rest have been studied, the physiological response of the LA to exercise is undefined. This study defines the exercise behavior of the normal left atrium by quantitating its volumetric response to graded effort. Healthy subjects (n = 131) were enrolled from the Health eHeart cohort. Echocardiograms were obtained at baseline and during ramped supine bicycle exercise. Left ventricular volume index, stroke volume index (LVSVI), left atrial end-systolic volume index (LAESVI), left atrial end-diastolic volume index (LAEDVI), and left atrial emptying fraction (LAEF), reservoir fraction, and conduit fraction were analyzed. The LVSVI increased with low exercise but did not increase further with peak exercise; cardiac output increased through the agency of heart rate. The LAESVI and LAEDVI decreased and the LAEF increased with exercise. As a result, the LA reservoir volume index was static throughout exercise. The reservoir fraction decreased from 46% at rest to 40% with low exercise (P < 0.001) in association with increased LVSVI and remained similar at peak exercise. The conduit volume index increased from 20 mL/m2 at rest to 24 mL/m2 at low exercise and stayed the same at peak exercise. Similarly, the conduit fraction increased from 54% at rest to 60% at low exercise (P < 0.001) and did not change further with peak exercise. Although atrial function increased with exercise, the major contribution to the augmentation of LV stroke volume is LA conduit fraction, a marker of active ventricular relaxation. Furthermore, the major determinant of raising cardiac output during high-level exercise is heart rate.NEW & NOTEWORTHY Diseases of the left atrium (LA) are major sources of disability (e.g., strokes and fatigue), but its exercise physiology has been unstudied. Such knowledge may allow early recognition of disease and suggest therapies. We show that in normal subjects, low-level exercise decreases LA volume and increases its ejection fraction. However, these changes offset each other volumetrically, and the contribution to LV filling from a full to an empty LA (reservoir function) is static. Higher levels of exercise do not change LA reservoir contribution. Blood flowing directly from the pulmonary vein to LV (conduit flow) impelled by augmented LV active relaxation (suction) is the major source of a modest increase in LV stroke volume. The major source of increased cardiac output with exercise is heart rate. During all stages of exercise, the LA works hard but only to keep up. We believe that our findings provide an additional set of benchmarks through which to quantitate LA pathology and gauge its progression.

Subxiphoid Hybrid Epicardial-Endocardial Atrial Fibrillation Ablation and LAA Ligation: Initial Sub-X Hybrid MAZE Registry Results.

OBJECTIVES: The aim of this study was to assess the safety and efficacy of a new subxiphoid hybrid epicardial-endocardial atrial fibrillation (AF) ablation and left atrial appendage (LAA) ligation approach for the treatment of persistent AF. BACKGROUND: Surgical hybrid ablation procedures have shown promise for maintaining sinus rhythm versus catheter ablation but are associated with increased periprocedural adverse events. METHODS: Patients with symptomatic persistent AF (n = 33, mean age 64 ± 9 years, 25 men) who had antiarrhythmic drug therapy or prior catheter ablation was unsuccessful were referred for hybrid epicardial-endocardial AF ablation and LAA exclusion. LAA closure was confirmed by transesophageal echocardiographic Doppler flow and/or computed tomographic angiography 1 to 3 months post-ligation. The incidence of atrial tachycardia or AF recurrence, LAA closure, thromboembolic events, and post-operative complications were assessed. RESULTS: All 33 patients underwent successful LAA ligation with epicardial ablation of the posterior left atrial wall, as well as endocardial pulmonary vein isolation and cavotricuspid isthmus ablation. Freedom from atrial tachycardia or AF was 91% (20 of 22 patients) at 6 months, 90% (18 of 20 patients) at 12 months, 92% (11 of 12 patients) at 18 months, and 92% (11 of 12) at 24 months. There were no acute periprocedural complications (<7 days). Thirty-day adverse events included 2 patients with pericardial effusion requiring pericardiocentesis and 1 incisional hernia repair. There were no long-term complications, strokes, or deaths. LAA ligation was complete in 27 of 33 subjects (82%), with 6 subjects having leaks of <5 mm. CONCLUSIONS: Subxiphoid hybrid epicardial-endocardial ablation with LAA ligation is feasible, safe, and effective. Future prospective studies are needed to validate these initial findings.

Dyssynchrony and Fibrosis Persist After Resolution of Cardiomyopathy in a Swine Premature Ventricular Contraction Model.

OBJECTIVES: This study sought to prospectively study the development and then regression of premature ventricular contraction (PVC)-induced cardiomyopathy, with the hypothesis that structural left ventricular (LV) changes that are of potential clinical significance may endure beyond the period of exposure to PVCs. BACKGROUND: Recovery of LV function after eradication of PVCs in PVC-induced cardiomyopathy is incompletely defined. METHODS: Fifteen swine were exposed to: 1) 50% paced PVCs from the LV lateral epicardium for 12 weeks (LV PVC, n = 5); 2) no pacing for 12 weeks (Control, n = 5); or 3) 50% paced LV PVCs for 12 weeks followed by pacing cessation for 4 weeks (Recovery, n = 5). LV function was quantified biweekly in sinus rhythm with echocardiography. Dyssynchrony was measured from pressure-volume loops at baseline and terminal studies. LV fibrosis was quantified after sacrifice. RESULTS: LV ejection fraction during sinus rhythm fell between baseline and terminal studies in the LV PVC group (65.8 ± 3.0 to 39.3 ± 3.2; p < 0.05), whereas there was no significant change in the Control group (69.6 ± 3.0 to 72.2 ± 3.0; p = NS) or after Recovery (64.5 ± 3.4% to 61.4 ± 3.4%; p = NS) groups. There was a significant increase in LV dyssynchrony measured during sinus rhythm between baseline and terminal studies in the LV PVC group (4.0 ± 1.5% to 9.0 ± 1.5%; p < 0.05); there was a similar increase in dyssynchrony that persisted 4 weeks after PVC cessation in the Recovery group (4.4 ± 1.7% to 12.8 ± 1.7%; p < 0.05). After sacrifice, percent fibrosis was higher in the LV PVC group compared with Control (5.7 ± 0.3% vs. 3.0 ± 0.3%; p < 0.05) and remained elevated in Recovery (4.1 ± 0.3% vs. 3.0 ± 0.3%; p < 0.05) despite return to baseline LV ejection fraction. CONCLUSIONS: In a swine model of PVC-induced cardiomyopathy, cessation of PVCs for 4 weeks leads to normalization of LV systolic function but significant changes in myocardial fibrosis and LV dyssynchrony during sinus rhythm persist.

Left atrial mass: relationship between gross anatomy and quantitative echocardiography.

BACKGROUND: Left atrial (LA) enlargement is associated with increased risk of adverse cardiovascular outcomes. Unlike the left ventricular mass, LA mass has not been described. We sought to define the anatomic mass of the LA using anatomic specimens from autopsy. We hypothesized that LA mass could be estimated by echocardiography. METHODS AND RESULTS: Using anatomic specimens of 22 subjects who died and underwent post mortem examination as well as echocardiogram, we defined normal LA mass by weighing anatomic specimens of those with normal LA volume on echocardiogram. Using 17 subjects with normal LA volume on echocardiogram, we found their LA mass on anatomic specimens to be 25.5 ± 6.3 grams (14.4 ± 3.2 g/m2). We developed an echocardiographic measure of LA mass and validated this measurement with paired LA anatomic specimens. We found the normal LA mass on echocardiogram to be 25.4 ± 6.3 g (14.4 ± 2.8 g/m2) which correlated well with anatomic specimens (ß = 0.99; Confidence interval CI 0.6-1.4, P < .0001; Pearson correlation coefficient r = 0.83). Furthermore, we defined the normal LA volume to mass ratio as 1.38 ± 0.45. CONCLUSIONS: LA mass is an additional parameter with which may contribute to the study of LA morphology.

Endurance exercise in seniors: Tonic, toxin or neither?

INTRODUCTION: Cardiac adaptation to sustained exercise in the athletes is established. However, exercise-associated effect on the cardiac function of the elderly has to be elucidated. The aim of this study was to analyse left (LV) and right ventricular (RV) characteristics at different levels of chronic exercise in the senior heart. MATERIALS AND METHODS: We studied 178 participants in the World Senior Games (mean age 68 ± 8 years, 86 were men; 48%). Three groups were defined based on the type and intensity of sports: low-, moderate- and high-intensity level. Exclusion criteria were coronary artery disease, atrial fibrillation, valvular heart disease or uncontrolled hypertension. LV and RV size and function were evaluated with an echocardiogram. RESULTS: LV trans-mitral inflow deceleration time decreased in parallel to the intensity of chronic exercise: 242 ± 54 ms in low-, 221 ± 52 ms in moderate- and 215 ± 58 ms in high-intensity level, p = .03. Left atrial volume index (LAVI) was larger in high-intensity group, p = .001. The LAVI remained significantly larger when adjusting for age, gender, heart rate, hypertension and diabetes (p = .002). LV and RV sizes were larger in the high-intensity group. LV ejection fraction and RV systolic function evaluated by tissue Doppler velocity, atrioventricular plane displacement and strain did not differ between groups. CONCLUSION: Left ventricular diastolic filling is not only preserved, but may also be enhanced in long-term, top-level senior athletes. Moreover, LV and RV systolic function remain unchanged at different levels of exercise. This supports the beneficial effects of endurance exercise participation in senior hearts.

Left Atrial End-Diastolic Volume Index as a Predictor of Cardiovascular Outcomes: The Heart and Soul Study.

BACKGROUND: The left atrial end-systolic volume index (LAESVI) is a predictor of cardiovascular outcomes and is the recommended measurement of left atrial size. The left atrial end-diastolic volume index (LAEDVI), representing the minimum or residual left atrial volume, has not been fully evaluated as a predictor of cardiovascular events. This study evaluated the predictive power of LAEDVI compared with LAESVI for heart failure (HF) hospitalizations, a composite of HF hospitalizations, myocardial infarction, stroke, and heart disease death, and all-cause mortality. METHODS: We measured LAESVI and LAEDVI in subjects without atrial fibrillation or flutter or significant mitral valve disease. Using Cox proportional-hazard models, the association of LAESVI and LAEDVI with the stated outcomes was examined. RESULTS: After a mean of 7.3±2.6 years of follow-up, there were 147 HF hospitalizations, 118 myocardial infarctions, 45 strokes, 96 heart disease deaths, and 351 deaths from all causes in 938 subjects. When comparing the highest and the lowest quartiles of LAEDVI, there was a near 6-fold increase in the hazard ratio (HR) for HF hospitalization (HR, 5.96; P<0.001). This was higher than what was seen with LAESVI (HR, 4.85; P<0.001). Similar associations were noted for the composite cardiovascular outcome (HR for LAEDVI, 2.97; P<0.001) and for all-cause mortality (HR for LAEDVI, 2.08; P<0.001). In adjusted models, LAEDVI demonstrated equal or better predictive power than LAESVI for HF hospitalization and the composite cardiovascular outcome. CONCLUSIONS: LAEDVI is a strong predictor of cardiovascular events in ambulatory patients with stable coronary heart disease and may merit routine use.

A collective European experience with left atrial appendage suture ligation using the LARIAT+ device.

AIMS: We report the collective European experience of percutaneous left atrial appendage (LAA) suture ligation using the recent generation LARIAT+ suture delivery device. METHODS AND RESULTS: A total of 141 patients with non-valvular atrial fibrillation and contraindication to oral anticoagulation (OAC), thrombo-embolic events despite OAC or electrical LAA isolation were enrolled at seven European hospitals to undergo LAA ligation. Patients were followed up by clinical visits and transoesophageal echocardiography (TOE) following LAA closure. Left atrial appendage ligation was completed in 138/141 patients (97.8%). Three patients did not undergo attempted deployment of the LARIAT device due to pericardial adhesion after previous epicardial ventricular tachycardia ablation (n = 1), a pericardial access-related complication (n = 1), and multiple posterior LAA lobes (n = 1). Serious 30-day procedural adverse events occurred in 4/141 patients (2.8%). There were two device-related LAA perforations (1.4%) not resulting in any corrective intervention as the LAA was completely sealed with the LARIAT. Minor adverse events occurred in 19 patients (13.5%), including two pericardial effusions due to procedure-related pericarditis requiring pericardiocentesis. Transoesophageal echocardiography was performed after LAA ligation in 103/138 patients (74.6%) after a mean of 181 ± 72 days. Complete LAA closure was documented in 100 patients (97.1%). Two patients (1.8% of patients with follow-up) experienced a transient ischaemic attack at 4 and 7 months follow-up, although there was no leak observed with TOE. There were two deaths during long-term follow-up which were both not device related. CONCLUSION: Initial experience with the LARIAT+ device demonstrates feasibility of LAA exclusion. Further larger prospective studies with longer follow-up are warranted.

Association of Machine Learning-Derived Phenogroupings of Echocardiographic Variables with Heart Failure in Stable Coronary Artery Disease: The Heart and Soul Study.

BACKGROUND: Many individual echocardiographic variables have been associated with heart failure (HF) in patients with stable coronary artery disease (CAD), but their combined utility for prediction has not been well studied. METHODS: Unsupervised model-based cluster analysis was performed by researchers blinded to the study outcome in 1,000 patients with stable CAD on 15 transthoracic echocardiographic variables. We evaluated associations of cluster membership with HF hospitalization using Cox proportional hazards regression analysis. RESULTS: The echo-derived clusters partitioned subjects into four phenogroupings: phenogroup 1 (n = 85) had the highest levels, phenogroups 2 (n = 314) and 3 (n = 205) displayed intermediate levels, and phenogroup 4 (n = 396) had the lowest levels of cardiopulmonary structural and functional abnormalities. Over 7.1 ± 3.2 years of follow-up, there were 198 HF hospitalizations. After multivariable adjustment for traditional cardiovascular risk factors, phenogroup 1 was associated with a nearly fivefold increased risk (hazard ratio [HR] = 4.8; 95% CI, 2.4-9.5), phenogroup 2 was associated with a nearly threefold increased risk (HR = 2.7; 95% CI, 1.4-5.0), and phenogroup 3 was associated with a nearly twofold increased risk (HR = 1.9; 95% CI, 1.0-3.8) of HF hospitalization, relative to phenogroup 4. CONCLUSIONS: Transthoracic echocardiographic variables can be used to classify stable CAD patients into separate phenogroupings that differentiate cardiopulmonary structural and functional abnormalities and can predict HF hospitalization, independent of traditional cardiovascular risk factors.

Association of Longitudinal Change in High-Sensitivity Troponin with All-Cause Mortality in Coronary Artery Disease: The Heart and Soul Study.

BACKGROUND: Serial increases in high-sensitivity cardiac troponin (hs-cTnT) have been associated with death in community-dwelling adults, but the association remains uninvestigated in those with coronary artery disease (CAD). METHODS: We measured hs-cTnT at baseline and after 5 years in 635 ambulatory Heart and Soul Study patients with CAD. We also performed echocardiography at rest and after treadmill exercise at baseline and after 5 years. Participants were subsequently followed for the outcome of death. We used a multivariable-adjusted Cox proportional hazards model to evaluate the association between 5-year change in hs-cTnT and subsequent all-cause mortality. RESULTS: Of the 635 subjects, there were 386 participants (61%) who had an increase in hs-cTnT levels between baseline and year 5 measurements (median increase 5.6 pg/mL, IQR 3.2-9.9 pg/mL). There were 182 deaths after a mean 4.2-year follow-up after the year 5 visit. After adjusting for clinical variables, a >50% increase in hs-cTnT between baseline and year 5 was associated with a nearly 2-fold increased risk of death from any cause (hazard ratio 1.7, 95% confidence interval 1.1-2.7). When addition of year 5 hs-cTnT was compared to a model including clinical variables and baseline hs-cTnT, there was a modest but statistically significant increase in C-statistic from 0.82 to 0.83 (p = 0.04). CONCLUSION: In ambulatory patients with CAD, serial increases in hs-cTnT over time are associated with an increased risk of death.

Injectable Drug-Releasing Microporous Annealed Particle Scaffolds for Treating Myocardial Infarction.

Intramyocardial injection of hydrogels offers great potential for treating myocardial infarction (MI) in a minimally invasive manner. However, traditional bulk hydrogels generally lack microporous structures to support rapid tissue ingrowth and biochemical signals to prevent fibrotic remodeling toward heart failure. To address such challenges, a novel drug-releasing microporous annealed particle (drugMAP) system is developed by encapsulating hydrophobic drug-loaded nanoparticles into microgel building blocks via microfluidic manufacturing. By modulating nanoparticle hydrophilicity and pregel solution viscosity, drugMAP building blocks are generated with consistent and homogeneous encapsulation of nanoparticles. In addition, the complementary effects of forskolin (F) and Repsox (R) on the functional modulations of cardiomyocytes, fibroblasts, and endothelial cells in vitro are demonstrated. After that, both hydrophobic drugs (F and R) are loaded into drugMAP to generate FR/drugMAP for MI therapy in a rat model. The intramyocardial injection of MAP gel improves left ventricular functions, which are further enhanced by FR/drugMAP treatment with increased angiogenesis and reduced fibrosis and inflammatory response. This drugMAP platform represents a new generation of microgel particles for MI therapy and will have broad applications in regenerative medicine and disease therapy.

Development of Injectable Amniotic Membrane Matrix for Postmyocardial Infarction Tissue Repair.

Ischemic heart disease represents the leading cause of death worldwide. Heart failure following myocardial infarction (MI) is associated with severe fibrosis formation and cardiac remodeling. Recently, injectable hydrogels have emerged as a promising approach to repair the infarcted heart and improve heart function through minimally invasive administration. Here, a novel injectable human amniotic membrane (hAM) matrix is developed to enhance cardiac regeneration following MI. Human amniotic membrane is isolated from human placenta and engineered to be a thermoresponsive, injectable gel around body temperature. Ultrasound-guided injection of hAM matrix into rat MI hearts significantly improves cardiac contractility, as measured by ejection fraction (EF), and decrease fibrosis. The results of this study demonstrate the feasibility of engineering as an injectable hAM matrix and its efficacy in attenuating degenerative changes in cardiac function following MI, which may have broad applications in tissue regeneration.

Who is young at heart and when? Diastolic Doppler data from the mind your heart study.

To further define the age-related distribution of diastolic function as defined by E/A ratio, in healthy male adults. The age-sensitive ratio of mitral inflow E-wave to A-wave (E/A) velocity is often considered in the evaluation of diastolic function. To appropriately direct a comprehensive evaluation of diastolic function, we sought to improve the characterization of the influence of age on E/A ratio. We analyzed echocardiographic data from the Mind Your heart Study, a cohort of outpatients recruited from two San Francisco Veterans centers to examine the effect of mental health on cardiovascular outcomes. Individuals with a history of heart disease or hypertension were excluded, leaving 313 veterans for analysis. We examined E/A by 5-year increments and performed linear and logistic regression analysis to predict trends in E/A and E dominance. Within the age ranges of population (54.9 ± 11.5), there is a steady gradual decline in absolute E/A ratio (beta coefficient/year- 0.018, P < .001) and the odds of E dominance similarly declines with age (odds ratio/year = 0.89, P < .001). Despite this decline, 90% of individuals below the age of 50 years maintain E dominance. Beyond age 50, 55% maintain E dominance, and beyond age 70, only 28% have E dominance. In this adequately healthy population, age-related progression of delayed relaxation appears to be a state of normality rather than diastolic dysfunction. Careful attention to specific cutoff points in age and E/A ratio could avoid misinterpretation or inappropriate management.

Embolic Stroke of Undetermined Source: A Population with Left Atrial Dysfunction.

BACKGROUND: Cryptogenic stroke, now defined as embolic stroke of undetermined source (ESUS), represents about a quarter of all ischemic strokes and the reoccurrence is high. Understanding this stroke subtype better would likely guide treatment recommendations. In this study, we tested the hypothesis that left atrial (LA) shape and function at rest, as well as with exercise, are abnormal compared to matched normal controls. METHODS: The study design was prospective enrollment of ESUS subjects who underwent measurement of LA function at rest and exercise by 2D and 3D echocardiograms. The exercise portion of the study was conducted using a ramped supine bicycle protocol during which LA function was measured. Stroke subjects were matched with normal subjects by age, gender, and body surface area. RESULTS: Over a 1-year enrollment period, 18 ESUS patients met inclusionary criteria and were studied. Their average age was 58 years old and 44% were female. ESUS subjects have larger LA end-diastolic volume at rest (14 versus 11 mL/m2, P = .04) and with exercise (11 versus 6 mL/m2, P = .001) compared to normal controls. In ESUS, there was a lack of response to maximal exercise of LA function as measured by the LA ejection fraction (61% versus 73% P = .001) and the LA function index (.68 versus .82, P = .02). The 3D analysis showed spherical remodeling of the LA in ESUS. This remodeling was documented by the sphericity index, which was increased in both diastole (.40 versus .32, P = .02) and systole (.63 versus .71 P = .03). CONCLUSIONS: In support of our hypothesis, we found that ESUS subjects have LA dysfunction and remodeling at rest and exercise in comparison to healthy, matched controls. Evaluation of the left atrium in this high-risk stroke subtype has potential to inform stroke prevention strategies and to suggest pathways for research.