Interhospital Variability in Cardiac Rehabilitation Use After Cardiac Surgery Among Medicare Beneficiaries.

OBJECTIVE: Despite guideline recommendation, cardiac rehabilitation (CR) following cardiac surgery remains underutilized, and the extent of interhospital variability is not well understood. This study evaluated determinants of interhospital variability in CR use and outcomes. METHODS: This retrospective cohort study included 166,809 Medicare beneficiaries undergoing cardiac surgery who were discharged alive between 07/01/2016 and 12/31/2018. CR participation was identified in outpatient facility claims within a year of discharge. Hospital-level CR rates were tabulated, and multilevel models evaluated the extent to which patient, organizational, and regional factors accounted for interhospital variability. Adjusted 1-year mortality and readmission rates were also calculated for each hospital quartile of CR use. RESULTS: Overall, 90,171 (54.1%) participated in at least one CR session within a year of discharge. Interhospital CR rates ranged from 0.0% to 96.8%. Hospital factors that predicted CR use included non-teaching status and lower hospital volume. Before adjusting for patient, organizational, and regional factors, 19.3% of interhospital variability was attributable to the admitting hospital. After accounting for covariates, 12.3% of variation was attributable to the admitting hospital. Patient (0.5%), structural (2.8%), and regional (3.7%) factors accounted for the remaining explained variation. Hospitals in the lowest quartile of CR use had higher adjusted 1-year mortality rates (Q1 = 6.7%, Q4 = 5.2%, p < 0.001) and readmission rates (Q1 = 37.6%, Q4 = 33.9%, p<0.001). CONCLUSION: Identifying best practices among high CR use facilities and barriers to access in low CR use hospitals may reduce interhospital variability in CR use and advance national improvement efforts.

The relationship between discharge location and cardiac rehabilitation use after cardiac surgery.

BACKGROUND: Cardiac rehabilitation (CR) is a guideline-recommended risk-reduction program offered to cardiac surgical patients. Despite CR's association with better outcomes, attendance remains poor. The relationship between discharge location and CR use is poorly understood. METHODS: This study was a nationwide, retrospective cohort analysis of Medicare fee-for-service claims for beneficiaries undergoing coronary artery bypass grafting and/or surgical aortic valve repair between July 1, 2016, and December 31, 2018. The primary outcome was attendance of any CR session. Discharge location was categorized as home discharge or discharge to extended care facility (ECF) (including skilled nursing facility, inpatient rehabilitation, and long-term acute care). Multivariable logistic regression models evaluated the association between discharge location, CR attendance, and 1-year mortality. RESULTS: Of the 167,966 patients who met inclusion criteria, 34.1% discharged to an ECF. Overall CR usage rate was 53.9%. Unadjusted and adjusted CR use was lower among patients discharged ECFs versus those discharged home (42.1% vs 60.0%; adjusted odds ratio, 0.66; P < .001). Patients discharged to long-term acute care were less likely to use CR than those discharged to skilled nursing facility or inpatient rehabilitation (reference category: home; adjusted odds ratio for long-term acute care, 0.36, adjusted odds ratio for skilled nursing facility, 0.69, and adjusted odds ratio for inpatient rehabilitation, 0.71; P < .001). CR attendance was associated with a greater reduction in adjusted 1-year mortality in patients discharged to ECFs (9.7% reduction) versus those discharged home (4.3% reduction). CONCLUSIONS: In this national analysis of Medicare beneficiaries, discharge to ECF was associated with lower CR use, despite a greater association with improved 1-year mortality. Interventions aimed at increasing CR enrollment at ECFs may improve CR use and advance surgical quality.

Biofilm-derived oxylipin 10-HOME mediated immune response in women with breast implants.

Breast implant illness (BII) is a poorly understood disease in which patients develop symptoms typical of autoimmune conditions following breast implantation. There is no known underlying cause, and patients often resort to breast implant removal and capsulectomy to alleviate symptoms. In this issue of the JCI, Khan and colleagues examined 86 breast explants from patients that reported BII symptoms and 55 control explants. The BII group showed a disproportionally high degree of biofilm, which was associated with oxylipin (10-HOME) on the implant surfaces. Injections of 10-HOME in the mammary fat pad of a murine model recapitulated BII symptoms and increased Th1 cell populations. Notably, macrophages in the periprosthetic tissue from BII patients were more likely to exhibit a proinflammatory phenotype, and naive T cells exposed to 10-HOME caused naive macrophages to differentiate to a proinflammatory phenotype. This work provides a pathophysiologic mechanism for a currently understudied and poorly characterized disease.

Cardiac Rehabilitation Reduces 2-Year Mortality After Coronary Artery Bypass Grafting.

BACKGROUND: Cardiac rehabilitation (CR) is a supervised outpatient exercise and risk reduction program offered to patients who have undergone coronary revascularization procedures. Multiple professional societal guidelines support the use of CR after coronary artery bypass grafting (CABG) based on studies in combined percutaneous coronary intervention and CABG populations with surrogate outcomes. This statewide analysis of patients undergoing CABG evaluated the relationship between CR use and long-term mortality. METHODS: Medicare fee-for-service claims were linked to surgical data for patients discharged alive after isolated CABG from January 1, 2015, through September 30, 2019. Outpatient facility claims were used to identify any CR use within 1 year of discharge. Death within 2 years of discharge was the primary outcome. Mixed-effects logistic regression was used to predict CR use, adjusting for a variety of comorbidities. Unadjusted and inverse probability treatment weighting (IPTW) were used to compare 2-year mortality among CR users vs nonusers. RESULTS: A total of 3848 of 6412 patients (60.0%) were enrolled in CR for an average of 23.2 (SD, 12.0) sessions, with 770 of 6412 (12.0%) completing all recommended 36 sessions. Logistic regression identified increasing age, discharge to home (vs extended care facility), and shorter length of stay as predictors of postdischarge CR use (P < .05). Unadjusted and IPTW analyses showed significant reduction in 2-year mortality in CR users compared with CR nonusers (unadjusted: 9.4% reduction; 95% CI, 10.8%-7.9%; P < .001; IPTW: -4.8% reduction; 95% CI, 6.0%-3.5%; P < .001). CONCLUSIONS: These data suggest that CR use is associated with lower 2-year mortality. Future quality initiatives should consider identifying and addressing root causes of poor CR enrollment and completion.

Role of IL4 and GMCSF in Predicting Survival in Esophageal Cancer.

BACKGROUND: Esophageal cancer (EC) originates in the setting of chronic inflammation. Although previous studies have sought to understand the role of inflammatory signaling in EC, the effect of these immunologic changes on patient outcomes remains understudied. This study's objective was to identify relationships between cytokine levels and prognosis in a mixed cohort of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) patients. STUDY DESIGN: A total of 37 serum cytokines were profiled at the time of resection using multiplex ELISA in 47 patients (42 esophageal adenocarcinoma, 5 esophageal squamous cell carcinoma). Cytokine levels were median-binarized and assessed using Cox regression models. Findings were validated at the RNA level using The Cancer Genome Atlas EC cohort (81 esophageal adenocarcinoma, 81 esophageal squamous cell carcinoma). RESULTS: Univariable analysis revealed high serum interleukin 4 (IL4) and granulocyte-macrophage colony-stimulating factor (GMCSF) were negatively associated with overall survival (p = 0.046, p = 0.040). Multivariable analysis determined both high serum IL4 or high serum GMCSF were negatively associated with survival independent of important clinical factors (hazard ratio [HR] 7.55, p < 0.001; HR 5.24, p = 0.001). These findings were validated at the RNA level in The Cancer Genome Atlas EC cohort, where multivariable analysis identified high IL4 expression, high CSF2 expression (encodes GMCSF), and advanced pathologic stage as independent negative predictors of survival when controlled for clinical factors (HR 2.35, p = 0.012; HR 1.97, p = 0.040). CONCLUSIONS: These results show that high IL4/GMCSF levels are negatively associated with survival in EC. These relationships are independent of pathologic stage and are identified across modalities, histologic subtypes, and the presence/absence of neoadjuvant therapy.

Interhospital variability in failure to rescue rates following aortic valve surgery.

Objective: This study evaluated interhospital variability and determinants of failure-to-rescue for patients undergoing surgical aortic valve replacement. Methods: An observational study was conducted among 28,842 patients undergoing aortic valve replacement with or without coronary artery bypass grafting between July 2011 and June 2017 across 90 hospitals participating in the Society of Thoracic Surgeons Adult Cardiac Surgery Database. Postoperative complications were defined as major (stroke, renal failure, reoperation, prolonged ventilation, sternal infection) and overall (major plus 14 other morbidities). Hospital terciles of observed to expected (O/E) mortality were compared on crude rates of major and overall complications, operative mortality, and failure to rescue (among major and overall complications). The correlation between hospital observed and expected failure-to-rescue rates was assessed. Results: Median Society of Thoracic Surgeons Adult Cardiac Surgery Database predicted mortality risk was similar across hospital O:E mortality terciles (P = .10). As expected, mortality rates significantly increased across terciles (low O/E tercile: 1.6%, high O/E tercile: 4.7%; P < .001). Failure-to-rescue rates increased substantially across hospital mortality terciles among patients with major (low tercile, 8.8% and high tercile, 20.8%) and overall (low tercile, 3.0% and high tercile, 8.9%) complications. Hospital-level expected failure to rescue had a higher correlation with observed complications for overall complications (R2 = 0.71) compared with Society of Thoracic Surgeons major complications (R2 = 0.24). Conclusions: Considerable interhospital variation exists in failure-to-rescue rates following aortic valve replacement. Hospitals in the low O/E mortality tercile experience failure to rescue nearly one-third less than those in the high O/E mortality tercile. Efforts to advance quality will benefit from identifying and disseminating optimal rescue strategies in this patient population.

Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair.

Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell RNA sequencing of human diabetic wounds, we identified increased JMJD3 in diabetic wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that IL-6, a cytokine increased in diabetic wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism. Interestingly, RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3f/fLyz2Cre+) identified that the STING gene (Tmem173) is regulated by JMJD3 in wound macrophages. STING limits inflammatory cytokine production by wound macrophages during healing. However, in diabetic mice, its role changes to limit wound repair and enhance inflammation. This finding is important since STING is associated with chronic inflammation, and we found STING to be elevated in human and murine diabetic wound macrophages at late time points. Finally, we demonstrate that macrophage-specific, nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING. Taken together, this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds.

Assessing donor-recipient size metrics for heart transplant outcomes: UNOS database analysis.

STUDY: There is no widely accepted donor to recipient size-match metric to predict outcomes in cardiac transplant. The predictive ability of size-match metrics has not been studied when recipients are stratified by heart failure etiology. We sought to assess the performance of commonly used size metrics to predict survival after heart transplant, accounting for restrictive versus non-restrictive pathology. METHODS: The UNOS registry was queried from 2000 to 2017 for all primary isolated heart transplants. Donor-recipient ratios were calculated for commonly used size metrics and their association with survival was assessed using continuous, nonlinear analysis. RESULTS: 29 817 patients were identified. Height (P < .001), predicted heart mass (PHM) (P = .003), ideal body weight (IBW) (P < .001) and body mass index (BMI) (P = .003) ratios were significantly associated with survival, while weight and body surface area (BSA) ratios were not. When stratified, only BMI ratio retained significance for both restrictive (P = .051) and non-restrictive (P = .003) subsets. Recipients with restrictive etiology had increased risk of mortality with both a lower and higher BMI ratio. CONCLUSIONS: While many metrics show association with survival in the non-restrictive subset, BMI is the only metric that retains significance in the restrictive subset. Recipients with restrictive and non-restrictive etiologies of heart failure tolerate size mismatch differently.

Development of malignancies and their outcomes in patients supported on continuous-flow left ventricular assist devices-a systematic review.

BACKGROUND: With increased use of continuous-flow left ventricular assist devices (CF-LVAD), development of malignant tumors in this population is not uncommon. We sought to evaluate malignancies in CF-LVAD patients and evaluate the outcomes of treatment strategies. METHODS: Overall, 18 articles consisting of 28 patients were identified who developed malignancies after CF-LVAD placement. Patient-level data were extracted for systematic review. RESULTS: Median patient age was 60 years [59-67] and 85.7% (24/28) were male. CF-LVAD was placed as bridge-to-transplant (BTT) in 60.9% (14/23) of patients. The three most common malignancy types were GI in 35.7% (10/28) of patients, lung in 21.4% (6/28) and skin in 10.7% (3/28). Median time from CF-LVAD implant to malignancy diagnosis was 6.9 [2.5-12.8] months. Metastatic disease occurred in 17.9% (5/28) over a median time of 5.0 [1.0-82.0] months from the diagnosis. Surgical resection of the malignancy was performed in 57.1% (16/28) of patients. Our results showed that while there was a significantly higher probability of survival among patients who underwent surgery versus those who did not, when only stage I and II patients were included in the analysis, this difference was no longer statistically significant. Three patients were relisted for heart transplant after surgical treatment, and two received the transplant. CONCLUSIONS: Surgical management of malignancies in patients on CF-LVADs may improve survival and transplant eligibility status, therefore, a CF-LVAD should not always preclude surgical treatment.

Bernard J. Miller: MD, ScD. (Hon), FACS: Lifelong Surgeon-Scientist and Critical Contributor to the Gibbon Heart-Lung Machine.

Bernard J. Miller, MD, ScD. (Hon), FACS, is known as a critical contributor for his work in the John H. Gibbon, MD, laboratory for his work on the heart-lung machine (HLM). In this setting, Dr. Miller developed the fluid control servo system, which was necessary to prevent malfunctioning of the HLM and prevent air emboli. Additionally, Dr. Miller assisted in conceiving and testing the left ventricular vent, the positive-negative pressure ventilator, and the HLM oxygenator; these inventions were all the product of extensive collaboration between the International Business Machines Corporation and the members of Dr. Gibbon's laboratory. Furthermore, Dr. Miller was a surgical assistant and perfusionist in the first successful open-heart surgery. Herein, we seek to describe Dr. Miller's story and his contributions to the HLM, as well as the contributions that were developed by the laboratory at that time. Additionally, we describe critical events leading up to the first successful use of the HLM on May 6, 1953, including a previously unreported use of the HLM for partial bypass of the right heart at Pennsylvania Hospital in 1952. Finally, we present the rest of Dr. Miller's professional and personal successes after his work on the HLM ended.

The Pathway to Low Outlier Status in Venous Thromboembolism Events: An Analysis of Pancreatic Surgery in the National Surgical Quality Improvement Program.

Purpose: Our institution's hepatopancreaticobiliary surgery service (HPBS) has demonstrated low rates of venous thromboembolism (VTE). We sought to determine whether the HPBS's regimented multimodal VTE prophylaxis pathway, which includes the use of mechanical prophylaxis, pharmacological prophylaxis, and ambulation, plays a role in achieving low VTE rates. Methods: We compared pancreatic surgeries in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) participant user file with our institution's data from 2011 to 2016 using univariate, multivariate, and matching statistics. Results: Among 36,435 NSQIP operations, 850 (2.3%) underwent surgery by the HPBS. The HPBS achieved lower VTE rates than the national cohort (2.0% vs. 3.5%, p = 0.018). Upon multivariate analysis, having an operation performed by the HPBS independently conferred lower odds of VTE incidence in the matched cohort (odds ratio = 0.530, p = 0.041). Conclusions: We identified an independent correlation between the HPBS and decreased VTE incidence, which we believe to be due to strict adherence to and team participation in a high risk VTE prophylaxis pathway, including inpatient pharmacological prophylaxis, thromboembolic deterrent stockings, sequential compression devices, and mandatory ambulation.

Global knockout of ROMK potassium channel worsens cardiac ischemia-reperfusion injury but cardiomyocyte-specific knockout does not: Implications for the identity of mitoKATP.

The renal-outer-medullary­potassium (ROMK) channel, mutated in Bartter's syndrome, regulates ion exchange in kidney, but its extra-renal functions remain unknown. Additionally, ROMK was postulated to be the pore-forming subunit of the mitochondrial ATP-sensitive K+ channel (mitoKATP), a mediator of cardioprotection. Using global and cardiomyocyte-specific knockout mice (ROMK-GKO and ROMK-CKO respectively), we characterize the effects of ROMK knockout on mitochondrial ion handling, the response to pharmacological KATP channel modulators, and ischemia/reperfusion (I/R) injury. Mitochondria from ROMK-GKO hearts exhibited a lower threshold for Ca2+-triggered permeability transition pore (mPTP) opening but normal matrix volume changes during oxidative phosphorylation. Isolated perfused ROMK-GKO hearts exhibited impaired functional recovery and increased infarct size when I/R was preceded by an ischemic preconditioning (IPC) protocol. Because ROMK-GKO mice exhibited severe renal defects and cardiac remodeling, we further characterized ROMK-CKO hearts to avoid confounding systemic effects. Mitochondria from ROMK-CKO hearts had unchanged matrix volume responses during oxidative phosphorylation and still swelled upon addition of a mitoKATP opener, but exhibited a lower threshold for mPTP opening, similar to GKO mitochondria. Nevertheless, I/R induced damage was not exacerbated in ROMK-CKO hearts, either ex vivo or in vivo. Lastly, we examined the response of ROMK-CKO hearts to ex vivo I/R injury with or without IPC and found that IPC still protected these hearts, suggesting that cardiomyocyte ROMK does not participate significantly in the cardioprotective pathway elicited by IPC. Collectively, our findings from these novel strains of mice suggest that cardiomyocyte ROMK is not a central mediator of mitoKATP function, although it can affect mPTP activation threshold.

Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death.

Adult cardiomyocytes are postmitotic cells that undergo very limited cell division. Thus, cardiomyocyte death as occurs during myocardial infarction has very detrimental consequences for the heart. Mitochondria have emerged as an important regulator of cardiovascular health and disease. Mitochondria are well established as bioenergetic hubs for generating ATP but have also been shown to regulate cell death pathways. Indeed many of the same signals used to regulate metabolism and ATP production, such as calcium and reactive oxygen species, are also key regulators of mitochondrial cell death pathways. It is widely hypothesized that an increase in calcium and reactive oxygen species activate a large conductance channel in the inner mitochondrial membrane known as the PTP (permeability transition pore) and that opening of this pore leads to necroptosis, a regulated form of necrotic cell death. Strategies to reduce PTP opening either by inhibition of PTP or inhibiting the rise in mitochondrial calcium or reactive oxygen species that activate PTP have been proposed. A major limitation of inhibiting the PTP is the lack of knowledge about the identity of the protein(s) that form the PTP and how they are activated by calcium and reactive oxygen species. This review will critically evaluate the candidates for the pore-forming unit of the PTP and discuss recent data suggesting that assumption that the PTP is formed by a single molecular identity may need to be reconsidered.

Perfused murine heart optical transmission spectroscopy using optical catheter and integrating sphere: Effects of ischemia/reperfusion.

Tissue transmission optical absorption spectroscopy provides dynamic information on metabolism and function. Murine genetic malleability makes it a major model for heart research. The diminutive size of the mouse heart makes optical transmission studies challenging. Using a perfused murine heart center mounted in an integrating sphere for light collection with a ventricular cavity optical catheter as an internal light source provided an effective method of optical data collection in this model. This approach provided high signal to noise optical spectra which when fit with model spectra provided information on tissue oxygenation and redox state. This technique was applied to the study of cardiac ischemia and ischemia reperfusion which generates extreme heart motion, especially during the ischemic contracture. The integrating sphere reduced motion artifacts associated with a fixed optical pickup and methods were developed to compensate for changes in tissue thickness. During ischemia, rapid decreases in myoglobin oxygenation occurred along with increases in cytochrome reduction levels. Surprisingly, when ischemic contracture occurred, myoglobin remained fully deoxygenated, while the cytochromes became more reduced consistent with a further, and critical, reduction of mitochondrial oxygen tension during ischemic contraction. This optical arrangement is an effective method of monitoring murine heart metabolism.

3D organ modeling with open-source software.

To date, 3D organ modeling has not reached widespread clinical use, despite showing promise in medical literature. The majority of anatomic modeling that is presented in the literature is performed with proprietary software, presenting certain barriers to use, such as price for usage rights. Open-source software not only circumvents this barrier, but also often provides greater customization offered by global communities. In this proof-of-concept experiment, a HeartMate II LVAD inflow cannula was "virtually fit" in a patient's left ventricle using only open-source software. Open-source programs provide a legitimate alternative to the proprietary software options.

Adherence to Inpatient Venous Thromboembolism Prophylaxis: A Single Institution's Concurrent Review.

Hospital-acquired venous thromboembolism (VTE) affects morbidity and mortality and increases health care costs. Poor adherence to recommended prophylaxis may be a potential cause of ongoing events. This study aims to identify institutional adherence rates and barriers to optimal VTE prophylaxis. The authors performed patient and nurse interviews and a concurrent review of clinical documentation, utilizing a cloud-based, HIPAA-compliant tool, on a convenience sample of hospitalized patients. Adherence and agreement between different assessment modalities were calculated. Seventy-six patients consented for participation. Nurse documented adherence was 66% (29/44), 44% (27/61), and 89% (50/56) for mechanical, ambulatory, and chemoprophylactic prophylaxis, respectively. Patient report and nurse documentation showed moderate agreement for mechanical and no agreement for ambulatory adherence (κ = 0.51 and 0.07, respectively). Concurrent review using a cloud-based tool can provide robust, timely, and relevant information on adherence to recommended VTE prophylaxis. Iterative concurrent reviews can guide efforts to improve adherence and reduce rates of hospital-acquired VTE.

Device exchange versus nonexchange modalities in left ventricular assist device-specific infections: A systematic review and meta-analysis.

No standardized treatment algorithm exists for the management of continuous-flow left ventricular assist device (CF-LVAD)-specific infections. The aim of this systematic review and meta-analysis was to compare the outcomes of CF-LVAD-specific infections as managed by device exchange to other treatment modalities not involving device exchange. Electronic search was performed to identify all studies in the English literature relating to the management of CF-LVAD-specific infections. All identified articles were systematically assessed for selection criteria. Thirteen studies with 158 cases of CF-LVAD-specific infection were pooled for analysis. Overall, 18/158 (11.4%) patients underwent CF-LVAD exchange, and 140/158 (88.6%) patients were treated with non-exchange modalities. The proportion of patients with isolated driveline infections or pump or pocket infections did not differ significantly between the groups. During a mean follow-up of 290 days, there were no significant differences in the overall mortality [exchange 17.6% (4.3-50.6) vs. non-exchange 23.3% (15.8-32.9), P = 0.67] and infection recurrence rates [exchange 26.7% (8.7-58.0) vs. non-exchange 38.6% (15.4-68.5), P = 0.56]. In the setting of CF-LVAD-specific infections, device exchange does not appear to confer an advantage in the overall mortality and infection recurrence as compared to non-exchange modalities.