A Novel Model Incorporating Pectoralis Muscle Measures to Predict Mortality After Ventricular Assist Device Implantation.

BACKGROUND: We have previously demonstrated that pectoralis muscle mass and tissue attenuation obtained on preoperative CT scans were powerful predictors of mortality after left ventricular assist device implantation. In this analysis, we confirm our findings in a separate left ventricular assist device implantation cohort, and we present a novel, user-friendly mortality-prediction model incorporating these measures. METHODS AND RESULTS: Patients with chest CTs performed ≤ 3 months prior to left ventricular assist device implantation at University of Minnesota (n = 143) and Houston Methodist Hospital (n = 133) were identified. Unilateral pectoralis muscle mass indexed to body surface area (PMI) and attenuation (approximated by mean Hounsfield units) (PHUm) were measured on preoperative chest CT scans. To develop a prediction model incorporating pectoralis muscle measures, we implemented a cross-validated model-selection approach using Cox proportional hazards regression models. The final model included PHUm, PMI, African American race, creatinine, total bilirubin, body mass index, bridge to transplant, and presence or absence of contrast. Receiver-operating characteristic curves for 30-, 90- and 365-day survival were generated. The area under the curve for the model at 30, 90 and 365 days was 0.78, 0.76 and 0.76, respectively. CONCLUSIONS: The Minnesota Pectoralis Risk Score had favorable discrimination in this multicenter dataset. These skeletal-muscle measures appear to add important information to preoperative risk assessment.

Delayed autologous stem cell transplantation following cardiac transplantation experience in patients with cardiac amyloidosis.

This study sought to retrospectively investigate the outcomes of patients with light-chain amyloidosis (AL) with advanced cardiac involvement who were treated with a strategy of heart transplantation (HT) followed by delayed autologous stem cell transplantation (ASCT) at 1-year posttransplant. Patients with AL amyloidosis with substantial cardiac involvement have traditionally had very poor survival (eg, several months). A few select centers have reported their outcomes for HT followed by a strategy of early ASCT (ie, 6 months) for CA. The outcomes of patients undergoing a delayed strategy have not been reported. All patients with AL amyloidosis at a single institution undergoing evaluation for HT from 2004-2018 were included. Retrospective analyses were performed. Sixteen patients underwent HT (including two combined heart-kidney transplant) for AL amyloidosis. ASCT was performed in a total of nine patients to date at a median 13.5 months (12.8-32.9 months) post-HT. Survival was 87.5% at 1 year and 76.6% at 5 years, comparable to institutional outcomes for nonamyloid HT recipients. In addition to these 16 patients, two patients underwent combined heart-lung transplantation. A strategy of delayed ASCT 1-year post-HT for patients with AL amyloidosis is feasible, safe, and associated with comparable outcomes to those undergoing an earlier ASCT strategy.

AIBP Limits Angiogenesis Through γ-Secretase-Mediated Upregulation of Notch Signaling.

RATIONALE: Angiogenesis improves perfusion to the ischemic tissue after acute vascular obstruction. Angiogenesis in pathophysiological settings reactivates signaling pathways involved in developmental angiogenesis. We showed previously that AIBP (apolipoprotein A-I [apoA-I]-binding protein)-regulated cholesterol efflux in endothelial cells controls zebra fish embryonic angiogenesis. OBJECTIVE: This study is to determine whether loss of AIBP affects angiogenesis in mice during development and under pathological conditions and to explore the underlying molecular mechanism. METHODS AND RESULTS: In this article, we report the generation of AIBP knockout (Apoa1bp-/-) mice, which are characterized of accelerated postnatal retinal angiogenesis. Mechanistically, AIBP triggered relocalization of γ-secretase from lipid rafts to nonlipid rafts where it cleaved Notch. Consistently, AIBP treatment enhanced DLL4 (delta-like ligand 4)-stimulated Notch activation in human retinal endothelial cells. Increasing high-density lipoprotein levels in Apoa1bp-/- mice by crossing them with apoA-I transgenic mice rescued Notch activation and corrected dysregulated retinal angiogenesis. Notably, the retinal vessels in Apoa1bp-/- mice manifested normal pericyte coverage and vascular integrity. Similarly, in the subcutaneous Matrigel plug assay, which mimics ischemic/inflammatory neovascularization, angiogenesis was dramatically upregulated in Apoa1bp-/- mice and associated with a profound inhibition of Notch activation and reduced expression of downstream targets. Furthermore, loss of AIBP increased vascular density and facilitated the recovery of blood vessel perfusion function in a murine hindlimb ischemia model. In addition, AIBP expression was significantly increased in human patients with ischemic cardiomyopathy. CONCLUSIONS: Our data reveal a novel mechanistic connection between AIBP-mediated cholesterol metabolism and Notch signaling, implicating AIBP as a possible druggable target to modulate angiogenesis under pathological conditions.

Outflow cannula alignment in continuous flow left ventricular devices is associated with stroke.

We sought to evaluate whether differences in left ventricular assist device (LVAD) canula alignment are associated with stroke. There is a paucity of clinical data on contribution of LVAD canulae alignment to strokes. We conducted a retrospective analysis of patients who underwent LVAD implantation at Houston Methodist hospital from 2011 to 2016 and included those who had undergone cardiac computed tomography (CT) with contrast. LVAD graft alignment using X-ray, echocardiography, and cardiac CT was evaluated. The primary outcome was stroke within 1 year of LVAD implantation. Of the 101 patients that underwent LVAD Implantation and cardiac CT scan during the study period, 78 met inclusion criteria. The primary outcome occurred in 12 (15.4%) patients with a median time to stroke of 77 days (interquartile range: 42-132 days). Of these, 10 patients had an ischemic and two had hemorrhagic strokes. The predominant device type was Heart Mate II (94.8%). Patients with LVAD outflow cannula to aortic angle lesser than 37.5° and those with outflow graft diameter of anastomosis less than 1.5 cm (assessed by cardiac CT) had significantly higher stroke risk (p < 0.001 and p = 0.01 respectively). In HMII patients, a lower LVAD speed at the time of CT scan was associated with stroke. Further studies are needed to identify optimal outflow graft configuration to mitigate stroke risk.

Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice.

Anthracyclines such as doxorubicin (Dox) are effective chemotherapies, but their use is limited by cardiac toxicity. We hypothesized that plasma proteomics in women with breast cancer could identify new mechanisms of anthracycline cardiac toxicity. We measured changes in 1317 proteins in anthracycline-treated patients (n = 30) and replicated key findings in a second cohort (n = 31). An increase in the heme-binding protein hemopexin (Hpx) 3 months after anthracycline initiation was associated with cardiac toxicity by echocardiography. To assess the functional role of Hpx, we administered Hpx to wild-type (WT) mice treated with Dox and observed improved cardiac function. Conversely, Hpx-/- mice demonstrated increased Dox cardiac toxicity compared to WT mice. Initial mechanistic studies indicate that Hpx is likely transported to the heart by circulating monocytes/macrophages and that Hpx may mitigate Dox-induced ferroptosis to confer cardioprotection. Together, these observations suggest that Hpx induction represents a compensatory response during Dox treatment.

Tissue plasminogen activator in left ventricular assist device-related intravascular hemolysis after failed augmented anticoagulation.

OBJECTIVES: We sought to examine the efficacy and safety of adding fibrinogen-guided low-dose multi-day Alteplase™ tissue plasminogen activator (tPA) in the management of intravascular hemolysis (IVH) in patients with the HeartMate II (HM-II) continuous flow (CF) left ventricular assist device (LVAD) who failed to achieve IVH resolution with conventional augmented anticoagulation (AAC). BACKGROUND: IVH in patients with LVAD is often treated with AAC, failing which pump exchange is considered. We hypothesized that a trial of low-dose tPA after failed AAC therapy could resolve IVH and prevent pump exchange in some patients. METHODS: We performed a retrospective study of 31 HM-II CF LVAD patients admitted to our center from January 2015 to January 2020 for IVH management who received tPA following failed AAC. Primary 6-month outcomes included successful IVH resolution, unsuccessful IVH resolution requiring pump exchange, gastrointestinal bleeding, ischemic and hemorrhagic cerebrovascular accident (CVA), and death. RESULTS: Thirty-one patients with IVH were treated with tPA following failed AAC. Successful resolution of IVH occurred in 22/31 (71%) patients. Pump exchange occurred in 9/31 (29%) patients. Gastrointestinal bleeding occurred in 7/31 (22.6%) patients. Ischemic CVA occurred in 6/31 (19.4%) patients. CONCLUSIONS: Management of IVH with administration of low-dose tPA after failed AAC is feasible and may prevent pump exchange in some patients.

Baseline global longitudinal strain predictive of anthracycline-induced cardiotoxicity.

BACKGROUND: Cancer therapy-related cardiac dysfunction (CTRD) is a major source of morbidity and mortality in long-term cancer survivors. Decreased GLS predicts decreased left ventricular ejection fraction (LVEF) in patients receiving anthracyclines, but knowledge regarding the clinical utility of baseline GLS in patients at low-risk of (CTRD) is limited. OBJECTIVES: The purpose of this study was to investigate whether baseline echocardiographic assessment of global longitudinal strain (GLS) before treatment with anthracyclines is predictive of (CTRD) in a broad cohort of patients with normal baseline LVEF. METHODS: Study participants comprised 188 patients at a single institution who underwent baseline 2-dimensional (2D) speckle-tracking echocardiography before treatment with anthracyclines and at least one follow-up echocardiogram 3 months after chemotherapy initiation. Patients with a baseline LVEF <55% were excluded from the analysis. The primary endpoint, (CTRD), was defined as an absolute decline in LVEF > 10% from baseline and an overall reduced LVEF <50%. Potential and known risk factors were evaluated using univariable and multivariable Cox proportional hazards regression analysis. RESULTS: Twenty-three patients (12.23%) developed (CTRD). Among patients with (CTRD), the mean GLS was -17.51% ± 2.77%. The optimal cutoff point for (CTRD) was -18.05%. The sensitivity was 0.70 and specificity was 0.70. The area under ROC curve was 0.70. After adjustment for cardiovascular and cancer therapy related risk factors, GLS or decreased baseline GLS ≥-18% was predictive of (CTRD) (adjusted hazards ratio 1.17, 95% confidence interval 1.00, 1.36; p = 0.044 for GLS, or hazards ratio 3.54; 95% confidence interval 1.34, 9.35; p = 0.011 for decreased GLS), along with history of tobacco use, pre-chemotherapy systolic blood pressure, and cumulative anthracycline dose. CONCLUSIONS: Baseline GLS or decreased baseline GLS was predictive of (CTRD) before anthracycline treatment in a cohort of cancer patients with a normal baseline LVEF. This data supports the implementation of strain-protocol echocardiography in cardio-oncology practice for identifying and monitoring patients who are at elevated risk of (CTRD).

Heart Failure Severity Stratification Beyond INTERMACS Profiles: A Step Toward Optimal Left Ventricular Assist Device Timing.

The purpose of this analysis is to determine whether pectoralis muscle measures quantified on pre left ventricular assist device (LVAD) computerized tomography (CT) scans can identify subgroups of patients with differential disease severity within each Interagency Registry for Mechanical Circulatory Support (INTERMACS) profile. Patients with chest CTs performed ≤3 months before LVAD implantation at University of Minnesota (n = 143) and Houston Methodist Hospital (n = 133) were identified from the larger LVAD cohorts (University of Minnesota n = 353, Houston Methodist =278). Unilateral Pectoralis muscle mass indexed to body surface area and pectoralis muscle attenuation were measured on preoperative chest CT scans. Patients within each INTERMACS profile were separated into HIGH and LOW PEC muscle groups. Kaplan-Meier and multivariable cox regression analyses were performed to compare mortality among INTERMACS profiles by HIGH and LOW PEC muscle groups. INTERMACS 3 and 4 patients in the HIGH PEC groups had the highest survival on LVAD support (1 year survival 85% vs. 68%, log rank P = 0.0001). Being in this group was associated with a 60% reduction in the hazards rate (HR) of death after LVAD (adjusted HR 0.40, 95% confidence interval 0.25-0.62). Additionally, renal function deterioration in the year before LVAD was associated with lower INTERMACS profiles and lower measured pectoralis muscle tissue attenuation at the time of LVAD implantation. INTERMACS 3 and 4 patients with the highest pectoralis muscle measures had the best survival after LVAD. The association between renal function deterioration and sarcopenia suggests these muscle changes are progressive. Computerized tomography quantification of sarcopenia may help identify optimal LVAD implantation timing.

Platelet rich plasma concentration improves biologic mesh incorporation and decreases multinucleated giant cells in a dose dependent fashion.

Platelet rich plasma (PRP) has been shown to improve incorporation and reduce inflammation in ventral hernia repair (VHR) with acellular dermal matrix (ADM). The concentration of platelets in PRP varies in clinical studies and an ideal concentration has yet to be defined. The effects of varied concentrations of PRP on ADM incorporation and inflammatory cell infiltration in a rat model of VHR. We hypothesized that increasing concentration of PRP would lead to improved incorporation, decreased CD8+ and multinucleated giant cell (MNGC) infiltrate. Lewis rats underwent ventral hernia creation and repair 30 days later with porcine non-crosslinked ADM. PRP was applied to the mesh prior to skin closure at concentrations of 1 × 104 plt/µL (PRP-LOW), 1 × 106 plt/µL (PRP-MID), or 1 × 107 plt/µL (PRP-HIGH) and tissue harvested at 2 and 4 weeks. Cellularization, tissue deposition, and mesh thickness using hematoxylin and eosin and Masson's trichrome, and neovascularization was assessed with VVG staining, to establish the relationship of PRP concentration to metrics of incorporation. MNGC and CD8+ T-cell infiltration were quantified to establish the relationship of inflammatory cell infiltration in response to PRP concentration. Lymphocyte infiltration was assessed using immunohistochemical staining for CD8. PRP-HIGH treated had significantly greater tissue deposition at 4 weeks. PRP-MID showed increasing mesh thickness at 2 weeks. Cell infiltration was significantly higher with PRP-HIGH at both 2 and 4 weeks while PRP-LOW showed increased cell infiltration only at 4 weeks. At both time points there was a trend towards a dose dependent response in cell infiltration to PRP concentration. Neovascularization was highest with MID-plt at 2 weeks, yet no significant differences were noted compared to controls. CD8+ cell infiltrate was significantly decreased at 2 and 4 weeks in PRP-LOW and PRP-MID treated groups. PRP at all concentrations significantly decreased MNGC infiltration at 2 weeks while only PRP-HIGH and PRP-MID had significant reductions in MNGC at 4 weeks. Both MNGC and CD8+ cell infiltration demonstrated dose dependent reduction in relation to PRP concentration. Increasing platelet concentrations of PRP correlated with improved incorporation, tissue deposition, and decreased scaffold degradation. These findings were associated with a blunted foreign body response. These findings suggest PRP reduces inflammation which may be beneficial for ADM incorporation in VHR.

Association between digoxin use and gastrointestinal bleeding in contemporary continuous flow left ventricular assist device support.

BACKGROUND: Assess the association between digoxin use and gastrointestinal bleeding (GIB) in a multicenter continuous flow left ventricular assist device (LVAD) cohort. METHODS: Patients implanted with continuous flow LVADs with data on GIB and digoxin use from two centers were included in the analysis (n = 649). GIB events were captured up to 2 years of follow-up. Digoxin use was defined as digoxin prescribed at discharge or within the first 3 months after LVAD implantation. A negative binomial regression model was performed to determine the association between digoxin use and number of GIB events over the follow-up period. RESULTS: Mean age of the cohort was 57 years (±14) and 45% (293/649) were bridge to transplant (BTT). Digoxin was prescribed in 33% of patients. Digoxin use was associated with an unadjusted 32% reduction in the incidence of rate of all cause GIB (IRR 0.68, 95% CI 0.46-0.99, p = 0.049). After adjusting for age, sex, Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, renal function, and implanting center there was still a 34% reduction in the incidence rate (IRR 0.67, 95% CI 0.45-0.99, p = 0.048). When limiting the analysis to those with likely arteriovenous malformation associated GIB, the association strengthened (unadjusted: IRR 0.48, 95 % CI 0.26-0.89, p = 0.02, adjusted: IRR 0.47, 95 % CI 0.25-0.9, p = 0.022). CONCLUSIONS: In this multicenter study, inclusive of contemporary devices, digoxin use was associated with reduced GIB events. Prospective data will be required to confirm this association.

Endothelial Dysfunction-related Neurological Bleeds with Continuous Flow-Left Ventricular Assist Devices Measured by Digital Thermal Monitor.

Endothelial dysfunction has been demonstrated in patients with Continuous Flow-Left Ventricular Assist Devices (CF-LVADs) but association with adverse events has not been shown. We used a noninvasive, operator-independent device called VENDYS® to assess vasodilatory function based on digital thermal measurements postrelease of a brachial artery occlusion in ambulatory patients with CF-LVAD (n = 56). Aortic valve opening and pulse perception were also documented before the test. Median duration of CF-LVAD support was 438 days. The VENDYS® test generates a vascular reactivity index (VRI). Outcomes for the CF-LVAD patients were compared between VRI < 1 and VRI ≥ 1. The bleeding events were driven primarily by a difference in neurologic bleeds. Multivariate analysis showed that VRI < 1 correlated with future bleeding events (HR: 5.56; P = 0.01). The C-statistic with the VRI dichotomized as above was 0.82. There was a trend toward a worse survival in patients with poor endothelial function. Endothelial vasodilatory dysfunction measured by a simple test utilizing digital thermal monitoring can predict adverse bleeding events in patients with CF-LVADs.

Innovative Modeling Techniques and 3D Printing in Patients with Left Ventricular Assist Devices: A Bridge from Bench to Clinical Practice.

Left ventricular assist devices (LVAD) cause altered flow dynamics that may result in complications such as stroke, pump thrombosis, bleeding, or aortic regurgitation. Understanding altered flow dynamics is important in order to develop more efficient and durable pump configurations. In patients with LVAD, hemodynamic assessment is limited to imaging techniques such as echocardiography which precludes detailed assessment of fluid dynamics. In this review article, we present some innovative modeling techniques that are often used in device development or for research purposes, but have not been utilized clinically. Computational fluid dynamic (CFD) modeling is based on computer simulations and particle image velocimetry (PIV) employs ex vivo models that helps study fluid characteristics such as pressure, shear stress, and velocity. Both techniques may help elaborate our understanding of complications that occur with LVAD and could be potentially used in the future to troubleshoot LVAD-related alarms. These techniques coupled with 3D printing may also allow for patient-specific device implants, lowering the risk of complications increasing device durability.

Immune Checkpoint Inhibitor-Related Adverse Cardiovascular Events in Patients With Lung Cancer.

OBJECTIVES: The purpose of this study was to evaluate whether immune checkpoint inhibitors (ICIs) are associated with an increased risk of major adverse cardiovascular events (MACE) compared with non-ICI therapies in patients with lung cancer. BACKGROUND: ICIs activate the host immune system to target cancer cells. Though uncommon, cardiovascular immune-related adverse events can be life-threatening. METHODS: A retrospective single-institution cohort study of 252 patients with pathologically confirmed lung cancer who received ICI or non-ICI therapy was analyzed. The primary endpoint was MACE, defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure. RESULTS: During a median follow-up of 6 months, MACE occurred in 13.3% of ICI-treated patients, with a median time to event of 51 days, compared with 10.3% and 64 days in non-ICI patients. ICIs were not associated with MACE (hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.57 to 2.43; p = 0.66) in a univariable Fine-Gray regression analysis incorporating noncardiovascular death as a competing risk. Multivariable regression analyses determined that patients treated with ICIs with elevated serum troponin I >0.01 ng/ml (HR: 7.27; 95% CI: 2.72 to 19.43; p < 0.001) and B-type natriuretic peptide (BNP) >100 pg/ml (HR: 2.65; 95% CI: 1.01 to 6.92; p = 0.047) had an increased risk of MACE. Patients pre-treated or receiving combined immunotherapy with ICIs and vascular endothelial growth factor inhibitors (VEGFIs) or tyrosine kinase inhibitors (TKIs) had an increased risk of MACE (HR: 2.15; 95% CI: 1.05 to 4.37; p = 0.04). CONCLUSIONS: ICIs were not independently associated with an increased risk of MACE in patients with lung cancer, although power is an important limitation in these analyses. ICI-associated cardiotoxicity was associated with elevations in serum troponin and BNP, and combined immunotherapy with VEGFIs or TKIs. Future studies are needed to further define the role of cardiac biomarkers as a monitoring strategy with ICI therapy.

Incidence and outcomes of cancer treatment-related cardiomyopathy among referrals for advanced heart failure.

BACKGROUND: Approximately 2-3% of patients undergoing advanced heart failure therapies such as left ventricular assist devices (LVAD) and orthotropic heart transplantation (OHT) have chemotherapy-related cardiomyopathy, according to analyses of large databases such as United Network for Organ Sharing (UNOS) or Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registries. While these studies have shown similar survival outcomes post-interventions, these databases by definition exclude patients referred for advanced therapies but do not receive them, and thus there is little data on overall outcomes of such patients. Given the lack of nuance in the diagnoses in large registries and the possibility that many cancer treatment-related cardiomyopathy (CCMP) patients might be misclassified by the generic "non-ischemic" or "dilated" cardiomyopathies, we investigated the incidence and clinical outcomes of CCMP patients among advanced heart failure (HF) referrals at a single high volume institution. METHODS: All referrals from 2013 to 2016 were evaluated for type of cardiomyopathy, with careful chart review. Outcomes such as LVAD, OHT and death were compared between CCMP and other cardiomyopathies. RESULTS: Of 553 referrals for advanced HF, 19 (3.4%) were for CCMP. There was a higher percentage of patients receiving advanced therapies in the CCMP vs. non-ischemic cardiomyopathy (NICMP) and ischemic cardiomyopathy (ICMP) (42.1% vs 30.2% vs 33.6%, not significant). Of the CCMP patients, 3 had OHT directly, 2 had LVAD followed by OHT, and 3 had LVADs as bridge to candidacy or destination therapy. Fifty-eight percent of the CCMP did not receive LVAD or OHT compared to 69.8% and 66.3 of the NICMP and ICMP, respectively (p = 0.0388). Independent of type of advanced therapy, survival was significantly higher in the CCMP group compared to NICMP and ICMP (93.3% vs 84.8% vs 73.8%, respectively P = 0.0021 for 1 year, 93.3% vs 76.2% vs 58.3%, respectively, P = < 0.0001 for 3 year). CONCLUSIONS: In a single institution, CCMP accounts for more than 3% of all referrals for advanced HF therapies and almost 8% of NICMP. Contrary to concerns for previous cancer and sequelae of cancer treatment excluding patients for advanced therapies, a higher percentage of CCMP underwent advanced HF therapies and with similar outcomes. This is the first study to show that among patients referred for advanced therapies, CCMP patients do not have inferior outcomes compared to other cardiomyopathies regardless of the selected management strategy.