Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Identifies Abnormal Calf Muscle-Specific Energetics in Peripheral Artery Disease.

BACKGROUND: Peripheral artery disease (PAD) results in exercise-induced ischemia in leg muscles. 31Phosphorus (P) magnetic resonance spectroscopy demonstrates prolonged phosphocreatine recovery time constant after exercise in PAD but has low signal to noise, low spatial resolution, and requires multinuclear hardware. Chemical exchange saturation transfer (CEST) is a quantitative magnetic resonance imaging method for imaging substrate (CEST asymmetry [CESTasym]) concentration by muscle group. We hypothesized that kinetics measured by CEST could distinguish between patients with PAD and controls. METHODS: Patients with PAD and age-matched normal subjects were imaged at 3T with a transmit-receive coil around the calf. Four CEST mages were acquired over 24-second intervals. The subjects then performed plantar flexion exercise on a magnetic resonance imaging-compatible ergometer until calf exhaustion. Twenty-five CEST images were obtained at end exercise. Regions of interest were drawn around individual muscle groups, and (CESTasym) decay times were fitted by exponential curve to CEST values. In 10 patients and 11 controls, 31P spectra were obtained 20 minutes later after repeat exercise. Five patients and 5 controls returned at a mean of 1±1 days later for repeat CEST studies. RESULTS: Thirty-five patients with PAD (31 male, age 66±8 years) and 29 controls (11 male, age 63±8 years) were imaged with CEST. The CESTasym decay times for the whole calf (341±332 versus 153±72 seconds; P<0.03) as well as for the gastrocnemius and posterior tibialis were longer in patients with PAD. Agreement between CESTasym decay and phosphocreatine recovery time constant was good. CONCLUSIONS: CEST is a magnetic resonance imaging method that can distinguish energetics in patients with PAD from age-matched normal subjects on a per muscle group basis. CEST agrees reasonably well with the gold standard 31P magnetic resonance spectroscopy. Moreover, CEST has higher spatial resolution, creates an image, and does not require multinuclear hardware and thus may be more suitable for clinical studies in PAD.

Utility of Ischemia Testing Prior to Ablation for Sustained Monomorphic Ventricular Tachycardia.

The aim of this study was to determine the relationship between ischemia testing prior to ablation for sustained monomorphic ventricular tachycardia (VT) (SMVT) and post-ablation mortality and VT recurrence. As SMVT is generally caused by myocardial scar and not active ischemia, the utility of ischemia testing prior to SMVT ablation is unclear. Patients who underwent ablation for SMVT at 2 tertiary care centers between January 2016 and July 2018 were included in a retrospective study. A Kaplan-Meier survival analysis was performed, stratifying patients by pre-ablation ischemia testing for the endpoints of mortality and VT recurrence. A Cox multivariable regression analysis was performed to identify predictors of post-ablation VT recurrence. A total of 163 patients were included, with 46 (28%) patients undergoing ischemia testing prior to ablation. Only 5 of the 46 patients (11%) received revascularization pre-ablation. After a median follow-up period of 625 days (interquartile range, 292-982 days) following ablation, 97 of 163 patients (60%) had VT recurrence, and 32 patients (20%) had died. There was no difference in mortality or VT recurrence between patients who did or did not experience ischemia testing or revascularization. In the multivariable regression analysis, predictors of VT recurrence were the number of anti-arrhythmics failed, non-ischemic cardiomyopathy, sex, and cardiac magnetic resonance imaging pre-ablation. Neither ischemia testing nor revascularization was a significant predictor of VT recurrence in univariable or multivariable regression analysis. In conclusion, ischemia testing is frequently ordered prior to SMVT ablation but infrequently leads to revascularization and is not associated with post-ablation outcomes. The findings support adopting an individualized approach rather than performing routine ischemia testing.

Cardiac Magnetic Resonance Assessment of Response to Cardiac Resynchronization Therapy and Programming Strategies.

OBJECTIVES: The objective was to determine the feasibility and effectiveness of cardiac magnetic resonance (CMR) cine and strain imaging before and after cardiac resynchronization therapy (CRT) for assessment of response and the optimal resynchronization pacing strategy. BACKGROUND: CMR with cardiac implantable electronic devices can safely provide high-quality right ventricular/left ventricular (LV) ejection fraction (RVEF/LVEF) assessments and strain. METHODS: CMR with cine imaging, displacement encoding with stimulated echoes for the circumferential uniformity ratio estimate with singular value decomposition (CURE-SVD) dyssynchrony parameter, and scar assessment was performed before and after CRT. Whereas the pre-CRT scan constituted a single "imaging set" with complete volumetric, strain, and scar imaging, multiple imaging sets with complete strain and volumetric data were obtained during the post-CRT scan for biventricular pacing (BIVP), LV pacing (LVP), and asynchronous atrial pacing modes by reprogramming the device outside the scanner between imaging sets. RESULTS: 100 CMRs with a total of 162 imaging sets were performed in 50 patients (median age 70 years [IQR: 50-86 years]; 48% female). Reduction in LV end-diastolic volumes (P = 0.002) independent of CRT pacing were more prominent than corresponding reductions in right ventricular end-diastolic volumes (P = 0.16). A clear dependence of the optimal CRT pacing mode (BIVP vs LVP) on the PR interval (P = 0.0006) was demonstrated. The LVEF and RVEF improved more with BIVP than LVP with PR intervals ≥240 milliseconds (P = 0.025 and P = 0.002, respectively); the optimal mode (BIVP vs LVP) was variable with PR intervals <240 milliseconds. A lower pre-CRT displacement encoding with stimulated echoes (DENSE) CURE-SVD was associated with greater improvements in the post-CRT CURE-SVD (r = -0.69; P < 0.001), LV end-systolic volume (r = -0.58; P < 0.001), and LVEF (r = -0.52; P < 0.001). CONCLUSIONS: CMR evaluation with assessment of multiple pacing modes during a single scan after CRT is feasible and provides useful information for patient care with respect to response and the optimal pacing strategy.

Functional and Economic Impact of INOCA and Influence of Coronary Microvascular Dysfunction.

OBJECTIVES: This study sought to better characterize the quality of life and economic impact in patients with symptoms of ischemia and no obstructive coronary disease (INOCA) and to identify the influence of coronary microvascular dysfunction (CMD). BACKGROUND: Patients with INOCA have a high symptom burden and an increased incidence of major adverse cardiac events. CMD is a frequent cause of INOCA. The morbidity associated with INOCA and CMD has not been well-characterized. METHODS: Sixty-six patients with INOCA underwent stress cardiac magnetic resonance with calculation of myocardial perfusion reserve (MPR); MPR 2.0 to 2.4 was considered borderline-reduced (possible CMD) and MPR <2.0 was defined as reduced (definite CMD). Subjects completed quality of life questionnaires to assess the morbidity and economic impact of INOCA. Questionnaire results were compared between INOCA patients with and without CMD. In addition, logistic regression was used to determine the predictors of CMD within the INOCA population. RESULTS: The prevalence of definite CMD was 24%. Definite or borderline CMD was present in 59% (MPR ≤2.4). Patients with INOCA reported greater physical limitation, angina frequency, and reduced quality of life compared to referent stable coronary artery disease and acute myocardial infarction populations. In addition, Patients with INOCA reported frequent time missed from work and work limitations, suggesting a substantial economic impact. No difference was observed in reported symptoms between INOCA patients with and without CMD. Glomerular filtration rate and body-mass index were significant predictors of CMD in multivariable regression analysis. CONCLUSIONS: INOCA is associated with high morbidity similar to other high-risk cardiac populations, and work limitations reported by Patients with INOCA suggest a substantial economic impact. CMD is a common cause of INOCA but is not associated with increased morbidity. These results suggest that there is significant symptom burden in the INOCA population regardless of etiology.

Off-label Use of Direct Oral Anticoagulants Compared With Warfarin for Left Ventricular Thrombi.

Importance: Left ventricular (LV) thrombi can arise in patients with ischemic and nonischemic cardiomyopathies. Anticoagulation is thought to reduce the risk of stroke or systemic embolism (SSE), but there are no high-quality data on the effectiveness of direct oral anticoagulants (DOACs) for this indication. Objective: To compare the outcomes associated with DOAC use and warfarin use for the treatment of LV thrombi. Design, Setting, and Participants: A cohort study was performed at 3 tertiary care academic medical centers among 514 eligible patients with echocardiographically diagnosed LV thrombi between October 1, 2013, and March 31, 2019. Follow-up was performed through the end of the study period. Exposures: Type and duration of anticoagulant use. Main Outcomes and Measures: Clinically apparent SSE. Results: A total of 514 patients (379 men; mean [SD] age, 58.4 [14.8] years) with LV thrombi were identified, including 300 who received warfarin and 185 who received a DOAC (64 patients switched treatment between these groups). The median follow-up across the patient cohort was 351 days (interquartile range, 51-866 days). On unadjusted analysis, DOAC treatment vs warfarin use (hazard ratio [HR], 2.71; 95% CI, 1.31-5.57; P = .01) and prior SSE (HR, 2.13; 95% CI, 1.22-3.72; P = .01) were associated with SSE. On multivariable analysis, anticoagulation with DOAC vs warfarin (HR, 2.64; 95% CI, 1.28-5.43; P = .01) and prior SSE (HR, 2.07; 95% CI, 1.17-3.66; P = .01) remained significantly associated with SSE. Conclusions and Relevance: In this multicenter cohort study of anticoagulation strategies for LV thrombi, DOAC treatment was associated with a higher risk of SSE compared with warfarin use, even after adjustment for other factors. These results challenge the assumption of DOAC equivalence with warfarin for LV thrombi and highlight the need for prospective randomized clinical trials to determine the most effective treatment strategies for LV thrombi.

Adherence to Pulmonary Rehabilitation in COPD: A QUALITATIVE EXPLORATION OF PATIENT PERSPECTIVES ON BARRIERS AND FACILITATORS.

PURPOSE: Adherence to pulmonary rehabilitation (PR) is low. This qualitative study used the PRECEDE model to identify predisposing (intrapersonal), reinforcing (interpersonal), and enabling (structural) factors acting as barriers or facilitators of adherence to PR, and elicit recommendations for solutions from patients with chronic obstructive pulmonary disease (COPD). METHODS: Focus groups with COPD patients who had attended PR in the past year were conducted. Sessions were recorded, transcribed verbatim, and coded independently by 2 coders, who then jointly decided on the final coding scheme. Data were summarized across groups, and analysis was used a thematic approach with constant comparative method to generate categories. RESULTS: Five focus groups with 24 participants each were conducted. Participants (mean age 62 yr) were 54% male, and 67% black. More than half had annual income less than $20 000, 17% were current smokers, and 54% had low adherence (less than 35% of prescribed PR sessions). The most prominent barriers included physical ailments and lack of motivation (intrapersonal), no support system (interpersonal), transportation difficulties, and financial burden (structural). The most prominent facilitators included health improvement, personal determination (intrapersonal), support from peers, family, and friends (interpersonal), and program features such as friendly staff and educational component of sessions (structural). Proposed solutions included incentives to maintain motivation, tobacco cessation support (intrapersonal), educating the entire family (interpersonal), transportation assistance, flexible program scheduling, and financial assistance (structural). CONCLUSION: Health limitations, social support, transportation and financial difficulties, and program features impact ability of patients to attend PR. Interventions addressing these interpersonal, intrapersonal, and structural barriers are needed to facilitate adherence to PR.

Recent Advances in Imaging of Hypertensive Heart Disease.

PURPOSE OF REVIEW: To review recent advances in the imaging of hypertensive heart disease (HHD) with an emphasis on developments in the imaging of diffuse myocardial fibrosis using cardiac magnetic resonance (CMR). RECENT FINDINGS: HHD results from long-standing hypertension and is characterized by the development of left ventricular hypertrophy and diffuse interstitial fibrosis. Diffuse fibrosis traditionally required endomyocardial biopsy to diagnose, but recent developments using T1 mapping in CMR allow for noninvasive assessment. Studies using T1 mapping have shown an increase in extracellular volume fraction (ECV) in patients with HHD compared to normal controls, suggesting ECV can be used as a noninvasive marker for fibrosis in HHD. In addition to T1 mapping, other recent advances in HHD imaging include improvements in three-dimensional echocardiography, allowing for accurate real-time volumetric measurements, and the use of speckle tracking echocardiography to detect subclinical systolic dysfunction. Measurement of ECV using T1 mapping in CMR can be used as a noninvasive marker of diffuse myocardial fibrosis in HHD. While further studies are needed to validate this approach with larger patient cohorts, ECV can potentially be used to both monitor disease progression and assess therapeutic interventions in HHD.

Social Determinants of Adherence to Pulmonary Rehabilitation for Chronic Obstructive Pulmonary Disease.

Adherence to pulmonary rehabilitation (PR) is low. Previous studies have focused on clinical predictors of PR completion. We aimed to identify social determinants of adherence to PR. A cross-sectional analysis of a database of COPD patients (N = 455) in an outpatient PR program was performed. Adherence, a ratio of attended-to-prescribed sessions, was coded as low (<35%), moderate (35-85%), and high (>85%). Individual-level measures included age, sex, race, BMI, smoking status, pack-years, baseline 6-minute walk distance (6MWD: <150, 150-249, ≥250), co-morbidities, depression, and prescribed PR sessions (≤20, 21-30, >30). Fifteen area-level measures aggregated to Census tracts were obtained from the U.S. Census after geocoding patients' addresses. Using exploratory factor analysis, a neighborhood socioeconomic disadvantage index was constructed, which included variables with factor loading >0.5: poverty, public assistance, households without vehicles, cost burden, unemployment, and minority population. Multivariate regression models were adjusted for clustering on Census tracts. Twenty-six percent of patients had low adherence, 23% were moderately adherent, 51% were highly adherent. In the best fitted full model, each decile increase in neighborhood socioeconomic disadvantage increased the risk of moderate vs high adherence by 14% (p < 0.01). Smoking tripled the relative risk of low adherence (p < 0.01), while each increase in 6MWD category decreased that risk by 72% (p < 0.01) and 84% (p < 0.001), respectively. These findings show that, relative to high adherence, low adherence is associated with limited functional capacity and current smoking, while moderate adherence is associated with socioeconomic disadvantage. The distinction highlights different pathways to suboptimal adherence and calls for tailored intervention approaches.

Pulmonary Rehabilitation Improves Outcomes in Chronic Obstructive Pulmonary Disease Independent of Disease Burden.

RATIONALE: Current practice guidelines recommend pulmonary rehabilitation as an adjunct to standard pharmacologic therapy for individuals with moderate to severe chronic obstructive pulmonary disease (COPD). Whether pulmonary rehabilitation benefits all subjects with COPD independent of baseline disease burden is not known. OBJECTIVES: To test whether pulmonary rehabilitation benefits patients with COPD independent of baseline exercise capacity, dyspnea, and lung function. METHODS: Data from a prospectively maintained database of participants with COPD enrolled in pulmonary rehabilitation at the University of Alabama at Birmingham from 1996 to 2013 were retrospectively analyzed. Subjects were divided into four quartiles based on their baseline level of dyspnea as assessed by the San Diego Shortness of Breath Questionnaire at the initial visit. Similar quartiles were assessed for FEV1 percent predicted as well as the 6-minute-walk distance (6MWD). The primary outcome was the change in quality of life as measured by the 36-item Short Form Health Survey (SF-36). Secondary outcomes were change in dyspnea, 6MWD, and depression scores assessed using the Beck Depression Inventory-II. Differences between baseline and final scores were compared using paired t tests and across quartiles using analysis of variance. MEASUREMENTS AND MAIN RESULTS: A total of 229 subjects were included. Their mean age was 66.5 (SD, 9) years. Ninety-one (40%) were female, and 42 (18%) were African American. The mean FEV1 percent predicted was 46.3% (20.0%). On completion of pulmonary rehabilitation, clinically significant improvements were seen in most components of SF-36: physical function, 11.5 (95% confidence interval [CI], 7.4-15.5; P < 0.001); health perception, 2.1 (95% CI, -0.7 to 4.8; P = 0.12); physical role, 16.7 (95% CI, 10.3-23.1; P < 0.001); emotional role, 14.7 (95% CI, 7.1-22.3; P < 0.001); social function, 16.4 (95% CI, 11.3-21.5; P < 0.001); mental health, 5.4 (95% CI, 2.6-8.3; P < 0.001); pain, 5 (95% CI, 1-9.1; P = 0.02); vitality, 12.4 (95% CI, 8.8-16.1; P < 0.001); and depression, 0.01 (95% CI, -0.11 to 0.07; P = 0.54). There was no difference in improvement in SF-36 across quartiles of San Diego Shortness of Breath Questionnaire, 6MWD, and FEV1 percent predicted. CONCLUSIONS: Pulmonary rehabilitation results in significant improvement in quality of life, dyspnea, and functional capacity independent of baseline disease burden.

Treatment of Non-ST Elevation Myocardial Infarction: A Process Analysis of Patient and Program Factors in a Teaching Hospital.

As part of a quality improvement project, we performed a process analysis to evaluate how patients presenting with type 1 non-ST elevation myocardial infarction (STEMI) are diagnosed and managed early after the diagnosis has been made. We performed a retrospective chart review and collected detailed information regarding the timing of the first 12-lead electrocardiogram, troponin order entry and first positive troponin result, administration of anticoagulation and antiplatelet medications, and referral for coronary angiography to identify areas of treatment variability and delay. A total of 242 patients with type 1 non-STEMI were included. The majority of patients received aspirin early after presentation to the emergency department; however, there was significant variability in the time from presentation to administration of other medications, including anticoagulation and P2Y12 therapy, even after an elevated troponin level was documented in the chart. Lack of a standardized non-STEMI admission order set, inconsistency regarding whether the emergency department physician or the cardiology admitting team order these medications after the diagnosis is made, and per current protocol, the initial call regarding the patient made to the cardiology fellow, not the admitting house staff, were identified as possible contributors to the delay. Patients who presented during "nighttime" hours had higher rates of atypical symptoms (P = 0.036) and longer delays to coronary angiography (46.5 versus 24 hours, P < 0.001) even in those deemed intermediate to high risk. A process analysis revealed considerable variation in non-STEMI treatment in our teaching hospital and identified specific areas for quality improvement measures.

Determinants of successful completion of pulmonary rehabilitation in COPD.

BACKGROUND: Despite known benefits, a significant proportion of patients with COPD do not complete pulmonary rehabilitation (PR). Little is known regarding which factors promote successful completion of PR. METHODS: We analyzed data from a prospectively maintained database of subjects with COPD who attended a PR program at the University of Alabama at Birmingham, from 1996 to 2013. Subjects were categorized as either completers or non-completers, based on successful completion of at least 8 weeks of PR. Demographics and comorbidities were recorded. Short Form 36 Health Survey, Beck Depression Inventory-II, and San Diego Shortness of Breath Questionnaire were administered to all participants at baseline and on completion of PR to assess participants' perception of their health status, severity of depression, and dyspnea with performance of activities of daily living. Univariate and multivariable analyses were performed to identify predictors of successful completion of PR. RESULTS: Four hundred and forty subjects were included, of whom 229 completed PR. Forty-one percent were female, and 17% were African American. Compared with non-completers, completers had greater Short Form 36 Health Survey pain score, lower forced expiratory volume in the first second, and lower Beck Depression Inventory score, and included a lower percentage of current smokers. On multivariate analysis, cigarette smoking at enrollment was associated with lower likelihood of completion of PR (adjusted odds ratio 0.38, 95% confidence interval 0.16-0.90; P=0.02). CONCLUSION: Cigarette smoking was the sole independent predictor of PR dropout, and smoking cessation may warrant greater emphasis prior to enrollment.

Benefits of completing pulmonary rehabilitation in patients with asthma.

BACKGROUND: Asthma affects 30 million Americans and results in reduced productivity and quality of life. Pulmonary rehabilitation (PR) is known to improve physical conditioning and exercise performance in chronic lung diseases such as COPD, however, few studies have examined its benefits in patients with asthma. We aimed to determine the benefits of PR in this population as well as the predictors of completion of therapy. METHODS: We performed a retrospective review of data from patients with a diagnosis of asthma who participated in PR at our institution from 1996 to 2013. Nine hundred and nineteen patients participated in the program of whom 75 were referred with a primary diagnosis of asthma. Patients underwent physiologic testing and their symptoms and quality of life were assessed using validated questionnaires. For patients who completed PR (n = 37), data obtained at the initial and exit visit was compared. Characteristics of completers were compared to non-completers to determine predictors of successful completion. RESULTS: Individuals with asthma completing PR had improvement from baseline to exit visit in Six Minute Walk Distance (326 vs. 390 feet; p < 0.0001), decreased body mass index (33 vs. 32 kg/m2; p < 0.046), decreased Beck Depression Inventory scores (15 vs. 9; p < 0.0009), and increased Short Form-36 scores (345 vs. 445; p = 0.0005). In a multivariate logistic regression analysis, lower depression scores predicted completion (OR 1.08, 95% CI 1.02-1.15, p = 0.02). CONCLUSION: Patients with asthma who completed PR had improvement in physical function and emotional well-being. Depression is a risk factor for non-completion of PR. Further research is needed to determine which patients will benefit most from therapy.

The endocrine-disrupting compound, nonylphenol, inhibits neurotrophin-dependent neurite outgrowth.

Endocrine-disrupting compounds (EDCs) may interfere with neuronal development due to high levels of accumulation in biological tissue and potentially aberrant steroid signaling. Treatment of dissociated embryonic Xenopus spinal cord neurons with the EDC, nonylphenol (NP), did not alter cell survival or neurite outgrowth but inhibited neurotrophin-induced neurite outgrowth, effects that were recapitulated by treatment with comparable concentrations of 17 beta-estradiol (E2) and beta-estradiol 6-(O-carboxy-methyl)oxime: BSA (E2-BSA), but not a synthetic androgen. Effects of NP were not inhibited by the nuclear estrogen receptor antagonist, ICI 182,780, but were inhibited by the G protein antagonist, pertussis toxin. Nerve growth factor (NGF)-induced neurite outgrowth in Xenopus neurons was shown to require MAPK signaling. NP did not affect TrkA expression, MAPK signaling, or phosphatidylinositol 3' kinase-Akt-glycogen synthase kinase 3 beta (PI3K-Akt-GSK3 beta) signaling in Xenopus. The ability of NP to inhibit NGF-induced neurite outgrowth without altering survival was recapitulated in the rat pheochromocytoma (PC12) cell line. As with Xenopus neurons, the inhibitory actions of NP in PC12 cells were not antagonized by ICI 182,780 and did not involve alterations in signaling along either the MAPK or PI3K-Akt-GSK3 beta pathways. NP did significantly inhibit the ability of NGF to increase protein kinase A activity in this cell line. These data have important implications with respect to potentially deleterious effects of NP exposure during early neural development and highlight the fact that bioaccumulation of EDCs, such as NP, may elicit very disparate effects along divergent signaling pathways than those that arise from the actions of physiological levels of endogenous estrogens.