Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart Failure: The ARIES-HM3 Randomized Clinical Trial.

IMPORTANCE: Left ventricular assist devices (LVADs) enhance quality and duration of life in advanced heart failure. The burden of nonsurgical bleeding events is a leading morbidity. Aspirin as an antiplatelet agent is mandated along with vitamin K antagonists (VKAs) with continuous-flow LVADs without conclusive evidence of efficacy and safety. OBJECTIVE: To determine whether excluding aspirin as part of the antithrombotic regimen with a fully magnetically levitated LVAD is safe and decreases bleeding. DESIGN, SETTING, and PARTICIPANTS: This international, randomized, double-blind, placebo-controlled study of aspirin (100 mg/d) vs placebo with VKA therapy in patients with advanced heart failure with an LVAD was conducted across 51 centers with expertise in treating patients with advanced heart failure across 9 countries. The randomized population included 628 patients with advanced heart failure implanted with a fully magnetically levitated LVAD (314 in the placebo group and 314 in the aspirin group), of whom 296 patients in the placebo group and 293 in the aspirin group were in the primary analysis population, which informed the primary end point analysis. The study enrolled patients from July 2020 to September 2022; median follow-up was 14 months. Intervention: Patients were randomized in a 1:1 ratio to receive aspirin (100 mg/d) or placebo in addition to an antithrombotic regimen. MAIN OUTCOMES AND MEASURES: The composite primary end point, assessed for noninferiority (-10% margin) of placebo, was survival free of a major nonsurgical (>14 days after implant) hemocompatibility-related adverse events (including stroke, pump thrombosis, major bleeding, or arterial peripheral thromboembolism) at 12 months. The principal secondary end point was nonsurgical bleeding events. RESULTS: Of the 589 analyzed patients, 77% were men; one-third were Black and 61% were White. More patients were alive and free of hemocompatibility events at 12 months in the placebo group (74%) vs those taking aspirin (68%). Noninferiority of placebo was demonstrated (absolute between-group difference, 6.0% improvement in event-free survival with placebo [lower 1-sided 97.5% CI, -1.6%]; P < .001). Aspirin avoidance was associated with reduced nonsurgical bleeding events (relative risk, 0.66 [95% confidence limit, 0.51-0.85]; P = .002) with no increase in stroke or other thromboembolic events, a finding consistent among diverse subgroups of patient characteristics. CONCLUSIONS AND RELEVANCE: In patients with advanced heart failure treated with a fully magnetically levitated LVAD, avoidance of aspirin as part of an antithrombotic regimen, which includes VKA, is not inferior to a regimen containing aspirin, does not increase thromboembolism risk, and is associated with a reduction in bleeding events. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04069156.

Heart transplantation in Val142Ile mutation in the modern era: A single center experience.

Little is known about the post heart transplantation management of extra cardiac manifestations in patients with hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) in the new era of disease modifying treatment for ATTR amyloidosis. This is a retrospective study of all patients with hATTR-CM associated with the Val142Ile variant who underwent heart transplantation (HT) from January 2014 to February 2022. All 10 patients with the Val142Ile mutation were successfully transplanted, with a 1 year survival post heart transplantation (HT) of 90%, comparable to an age, sex, and race matched cohort of patients transplanted for non-amyloid indications. However, 4 (40%) of these patients developed progressive extracardiac manifestations requiring initiation of TTR silencer therapy with the small interfering RNA (siRNA) drug patisiran, which was well tolerated with no significant side effects in this population. We recommend formal neurologic evaluation and assessment of extracardiac manifestations annually as part of routine post-transplant care, and disease modifying therapy, aimed at TTR stabilization or silencing, should be initiated in the context of previously untreated extracardiac manifestations or evidence of subclinical neuropathy to prevent progression.

Sex differences in eligibility for advanced heart failure therapies.

OBJECTIVES: We investigated sex-based differences in eligibility for and outcomes after receipt of advanced heart failure (HF) therapies. BACKGROUND: Although women are more likely to die from HF than men, registry data suggest that women are less likely to receive heart transplant (HT) or left ventricular assist device (LVAD) for largely unknown reasons. METHODS: We performed a single-center retrospective cohort study of patients evaluated for advanced HF therapies from 2012 to 2016. Logistic regression was used to determine the association of sex with eligibility for HT/LVAD. Competing risks and Kaplan-Meier analysis were used to examine survival. RESULTS: Of 569 patients (31% women) evaluated, 223 (39.2%) were listed for HT and 81 (14.2%) received destination (DT) LVAD. Women were less likely to be listed for HT (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.21-0.61; P < .0001), based on allosensitization (P < .0001) and obesity (P = .02). Women were more likely to receive DT LVAD (adjusted OR 2.29, 95% CI 1.23-4.29; P = .01). Survival was similar between men and women regardless of whether they received HT and DT LVAD or were ineligible for therapy. CONCLUSION: Women are less likely to be HT candidates, but more likely to receive DT LVAD.

Validating patient prioritization in the 2018 Revised United Network for Organ Sharing Heart Allocation System: A single-center experience.

The 2018 Revised United Network for Organ Sharing Heart Allocation System (HAS) was proposed to reclassify status 1A candidates into groups of decreasing acuity; however, it does not take into account factors such as body mass index (BMI) and blood group which influence waitlist (WL) outcomes. We sought to validate patient prioritization in the new HAS at our center. We retrospectively evaluated patients listed for heart transplantation (n = 214) at Emory University Hospital from 2011 to 2017. Patients were reclassified into the 6-tier HAS. Multistate modeling and competing risk analysis were used to compare outcomes of transplantation and WL death/deterioration between new tiers. Additionally, a stratified sensitivity analysis by BMI and blood group was performed. Compared with tier 4 patients, there was progressively increasing hazard of WL death/deterioration in tier 3 (HR: 2.52, 95% CI: 1.37-4.63, P = .003) and tier 2 (HR: 5.03, 95% CI: 1.99-12.70, P < .001), without a difference in transplantation outcome. When stratified by BMI and blood group, this hierarchical association was not valid in patients with BMI ≥30 kg/m2 and non-O blood groups in our cohort. Therefore, the 2018 HAS accurately prioritizes the sickest patients in our cohort. Factors such as BMI and blood group influence this relationship and iterate that the system can be further refined.

Impact of insurance type on eligibility for advanced heart failure therapies and survival.

BACKGROUND: Medicaid insurance in Georgia provides limited reimbursement for heart transplant (HT) and left ventricular assist devices (LVAD). We examined whether insurance type affects eligibility for and survival after receipt of HT or LVAD. METHODS AND RESULTS: We retrospectively identified patients evaluated for HT/LVAD from 2012 to 2016. We used multivariable logistic and Cox proportional hazards regression to examine the association of insurance type on treatment eligibility and 1-year survival. Of 569 patients evaluated, 282 (49.6%) had private, 222 (39.0%) had Medicare, and 65 (11.4%) had Medicaid insurance. Patients with Medicaid were younger, more likely to be Black, with fewer medical comorbidities. In adjusted models, Medicare and Medicaid insurance predicted lower odds of eligibility for HT, but did not affect survival after HT. Among those ineligible for HT, Medicaid patients were less likely to receive destination therapy (DT) LVAD (adj OR 0.08, 95% CI 0.01-0.66; P = .02) and had increased risk of death (adj HR = 2.03, 95% CI 1.13-3.63; P = .01). CONCLUSIONS: Despite younger age and fewer comorbidities, patients with Medicaid insurance are less likely to receive DT LVAD and have an increased risk of death once deemed ineligible for HT. Medicaid patients in Georgia need improved access to DT LVAD.

De novo DQ donor-specific antibodies are associated with worse outcomes compared to non-DQ de novo donor-specific antibodies following heart transplantation.

BACKGROUND: Antibody-mediated rejection (AMR) resulting from de novo donor-specific antibodies (dnDSA) leads to adverse outcomes following heart transplantation (HTx). It remains unclear what role dnDSA to specific HLA antigens play in adverse outcomes. This study compares outcomes in patients developing dnDSA to DQ antigens with those developing non-DQ dnDSA and those free from dnDSA. METHODS: The present study was a single-center, retrospective analysis of 122 consecutive HTx recipients. The primary outcome was a composite of death or graft dysfunction. RESULTS: After 3.3 years of follow-up, 31 (28%) patients developed dnDSA. Mean time to dnDSA was 539 days. Of 31 patients, 19 developed DQ antibodies and 12 developed non-DQ antibodies. Compared to non-DQ dnDSA, DQ antibodies presented with higher MFI values (P=.001) were more likely persistent (P=.001) and appeared later post-HTx (654 vs 359 days, P=.035). In a multivariable analysis, DQ dnDSA was associated with increased risk of the primary endpoint (HR 6.15, 95% CI 2.57-14.75, P=.001), whereas no increased risk was seen with non-DQ dnDSA (P=.749). CONCLUSIONS: dnDSA to DQ antigens following HTx are associated with increased risk of death and graft dysfunction.

Improved Outcomes for Women on the Heart Transplant Wait List in the Modern Era.

BACKGROUND: Whether the routine use of continuous-flow left ventricular assist devices (LVAD) has affected gender differences in outcomes for patients listed for heart transplantation (HT) is unclear. METHODS AND RESULTS: We identified 20,468 adults (25% women) listed as status 1A or 1B for HT from 2000 to 2014. Sex differences in removal from the wait list during the first 365 days due to death or deterioration was assessed with the use of Kaplan-Meier survival analysis. Patients were stratified according to listing before (era 1) or after (era 2) Food and Drug Administration approval of the Heartmate II LVAD on April 22, 2008. Freedom from death or deterioration on the wait list was higher for men than for women (70% vs 64%; P < .001). After adjusting for risk factors, women had a higher risk of removal from the wait list at 365 days during both era 1 (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.10-1.36; P < .001) and era 2 (HR 1.15, 95% CI 1.01-1.31; P = .029). Further adjustment for LVAD use eliminated the higher risk for women in era 2 (HR 1.14, 95% CI 0.99-1.29; P = .053) and not in era 1 (HR 1.22, 95% CI 1.10-1.36; P < .001). CONCLUSIONS: The higher risk for death or deterioration in women waiting for HT has improved in the modern era.

Moderate-to-large increases in perioperative serum sodium concentration associated with adverse neurologic events after continuous flow left ventricular assist device implantation.

OBJECTIVE: It was hypothesized that preoperative hyponatremia is associated with increased 30-day mortality after left ventricular assist device placement, and that large increases in sodium concentration are associated with adverse neurologic events and 30-day mortality. DESIGN: Data were collected retrospectively on all patients having continuous flow left ventricular assist device implantation between January 1, 2009 and March 31, 2013. Preoperative variables, operative variables, and perioperative sodium concentrations were recorded. Both 30-day mortality and 72-hour adverse neurologic events (stroke or seizure) were recorded as primary outcome variables. Preoperative sodium and Δ sodium (postoperative sodium-preoperative sodium) were analyzed as tests for 30-day mortality and adverse neurologic events using receiver operating characteristic curves. Both crude and adjusted logistic regression analyses were used to estimate odds ratios for the outcome variables. SETTING: Tertiary care academic medical center. PARTICIPANTS: Patients having durable continuous flow left ventricular assist device placement. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 88 patients, 30-day mortality was 14% (12 of 88) and the rate of perioperative stroke or seizure was 9% (8 of 88). There were 3 strokes and 5 tonic-clonic seizures. Preoperative sodium was a poor discriminative test for 30-day mortality and stroke or seizure (AUC=0.47 and 0.57, respectively). Δ sodium was a poor discriminative test for 30-day mortality, but a fair discriminative test for stroke or seizure (AUC=0.55 and 0.78, respectively). Δ sodium was a good discriminative test for seizure alone (AUC=0.82) and a fair discriminative test for stroke alone (AUC=0.70). It also increased the odds of stroke or seizure significantly, even when adjusting for possible confounders. CONCLUSIONS: Moderate-to-large increases in sodium concentration during left ventricular assist device placement appear to be associated with adverse postoperative neurologic events. Preoperative hyponatremia has no relationship with 30-day mortality or adverse perioperative neurologic events.

Anti-inflammatory and antiatherogenic role of BMP receptor II in endothelial cells.

OBJECTIVE: Atherosclerosis is an inflammatory disease with multiple underlying metabolic and physical risk factors. Bone morphogenic protein 4 (BMP4) expression is increased in endothelium in atherosclerosis-prone regions and is known to induce endothelial inflammation, endothelial dysfunction, and hypertension. BMP actions are mediated by 2 different types of BMP receptors (BMPRI and BMPRII). Here, we show a surprising finding that loss of BMPRII expression causes endothelial inflammation and atherosclerosis. APPROACH AND RESULTS: Using BMPRII siRNA and BMPRII(+/-) mice, we found that specific knockdown of BMPRII, but not other BMP receptors (Alk1, Alk2, Alk3, Alk6, ActRIIa, and ActRIIb), induced endothelial inflammation in a ligand-independent manner by mechanisms mediated by reactive oxygen species, nuclear factor-KappaB, and reduced nicotinamide adenine dinucleotide phosphate oxidases. Further, BMPRII(+/-)ApoE(-/-) mice developed accelerated atherosclerosis compared with BMPRII(+/+)ApoE(-/-) mice. Interestingly, we found that multiple proatherogenic stimuli, such as hypercholesterolemia, disturbed flow, prohypertensive angiotensin II, and the proinflammatory cytokine (tumor necrosis factor-α), downregulated BMPRII expression in endothelium, whereas antiatherogenic stimuli, such as stable flow and statin treatment, upregulated its expression in vivo and in vitro. Moreover, BMPRII expression was significantly diminished in human coronary advanced atherosclerotic lesions. Also, we were able to rescue the endothelial inflammation induced by BMPRII knockdown by overexpressing the BMPRII wild type, but not by the BMPRII short form lacking the carboxyl-terminal tail region. CONCLUSIONS: These results suggest that BMPRII is a critical, anti-inflammatory, and antiatherogenic protein that is commonly targeted by multiple pro- and antiatherogenic factors. BMPRII may be used as a novel diagnostic and therapeutic target in atherosclerosis.

The Society of Thoracic Surgeons Intermacs 2023 Annual Report: Focus on Magnetically Levitated Devices.

The 14th Annual Report from The Society of Thoracic Surgeons (STS) Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) describes outcomes of 27,493 patients with a continuous-flow left ventricular assist device (LVAD) from the past decade (2013-2022). In 2022, 2517 primary LVADs were implanted, of which 2512 (99.8%) were fully magnetically levitated (Mag-Lev) devices. This shift to nearly exclusive use of a Mag-Lev device led us to examine its outcomes compared with contemporary (2018-2022) and historical (2013-2017) non-Mag-Lev cohorts. Patients supported by a Mag-Lev device (n = 10,920) had a higher 1- and 5-year survival of 86% (vs 79% and 81%, P < .0001) and 64% (vs 44% and 44%, P < .0001), respectively, than those receiving non-Mag-Lev devices during the contemporary and historical eras. Over 5 years, freedom from gastrointestinal bleeding (72% vs 60%, P < .0001), stroke (87% vs 67%, P < .0001), and device malfunction/pump thrombus (83% vs 54%, P < .0001), but not device-related infection (61% vs 64%, P = .93), was higher with Mag-Lev devices compared with non-Mag-Lev support during the contemporary era. In this large primacy cohort of real-world patients with advanced heart failure, this report underscores marked improvements in short- and intermediate-term survival and reduction of adverse events with a contemporary Mag-Lev LVAD.

Detection of differentially methylated gene promoters in failing and nonfailing human left ventricle myocardium using computation analysis.

Human dilated cardiomyopathy (DCM) is characterized by congestive heart failure and altered myocardial gene expression. Epigenetic changes, including DNA methylation, are implicated in the development of DCM but have not been studied extensively. Clinical human DCM and nonfailing control left ventricle samples were individually analyzed for DNA methylation and expressional changes. Expression microarrays were used to identify 393 overexpressed and 349 underexpressed genes in DCM (GEO accession number: GSE43435). Gene promoter microarrays were utilized for DNA methylation analysis, and the resulting data were analyzed by two different computational methods. In the first method, we utilized subtractive analysis of DNA methylation peak data to identify 158 gene promoters exhibiting DNA methylation changes that correlated with expression changes. In the second method, a two-stage approach combined a particle swarm optimization feature selection algorithm and a discriminant analysis via mixed integer programming classifier to identify differentially methylated gene promoters. This analysis identified 51 hypermethylated promoters and six hypomethylated promoters in DCM with 100% cross-validation accuracy in the group assignment. Generation of a composite list of genes identified by subtractive analysis and two-stage computation analysis revealed four genes that exhibited differential DNA methylation by both methods in addition to altered gene expression. Computationally identified genes (AURKB, BTNL9, CLDN5, and TK1) define a central set of differentially methylated gene promoters that are important in classifying DCM. These genes have no previously reported role in DCM. This study documents that rigorous computational analysis applied to microarray analysis of healthy and diseased human heart samples helps to define clinically relevant DNA methylation and expressional changes in DCM.

Beyond Alternans: Detection of Higher-Order Periodicity in Ex-Vivo Human Ventricles Before Induction of Ventricular Fibrillation.

Background: Repolarization alternans, defined as period-2 oscillation in the repolarization phase of the action potentials, is one of the cornerstones of cardiac electrophysiology as it provides a mechanistic link between cellular dynamics and ventricular fibrillation (VF). Theoretically, higher-order periodicities (e.g., period-4, period-8,...) are expected but have very limited experimental evidence. Methods: We studied explanted human hearts, obtained from the recipients of heart transplantation at the time of surgery, using optical mapping technique with transmembrane voltage-sensitive fluorescent dyes. The hearts were stimulated at an increasing rate until VF was induced. The signals recorded from the right ventricle endocardial surface just before the induction of VF and in the presence of 1:1 conduction were processed using the Principal Component Analysis and a combinatorial algorithm to detect and quantify higher-order dynamics. Results: A prominent and statistically significant 1:4 peak (corresponding to period-4 dynamics) was seen in three of the six studied hearts. Local analysis revealed the spatiotemporal distribution of higher-order periods. Period-4 was localized to temporally stable islands. Higher-order oscillations (period-5, 6, and 8) were transient and primarily occurred in arcs parallel to the activation isochrones. Discussion: We present evidence of higher-order periodicities and the co-existence of such regions with stable non-chaotic areas in ex-vivo human hearts before VF induction. This result is consistent with the period-doubling route to chaos as a possible mechanism of VF initiation, which complements the concordant to discordant alternans mechanism. The presence of higher-order regions may act as niduses of instability that can degenerate into chaotic fibrillation.

Gender and Race Differences in HeartMate3 Left Ventricular Assist Device as a Bridge to Transplantation.

BACKGROUND: Gender and racial disparities exist after left ventricular assist device (LVAD) implantation. Compared with older devices, the HeartMate 3 (HM3) (Abbott Cardiovascular) has demonstrated improved survival. Whether HM3 differentially improves outcomes by gender or race and ethnic groups is unknown. OBJECTIVES: The purpose of this study is to examine differences by gender and race in the use of HM3 among patients listed for heart transplantation (HT) and associated waitlist and post-transplant outcomes. METHODS: The authors examined all patients (20% women, 33% Black) who received LVADs as bridge to transplantation (BTT) between January 2018 and June 2020, in the OPTN (Organ Procurement and Transplantation Network) database. Trends in use of HM3 were evaluated by gender and race. Competing events of death/delisting and transplantation were evaluated using subdistribution hazard models. Post-transplant outcomes were evaluated using multivariate logistic regression adjusted for demographic, clinical, and donor characteristics. RESULTS: Of 11,524 patients listed for HT during the study period, 955 (8.3%) had HM3 implanted as BTT. Use of HM3 increased for all patients, with no difference in use by gender (P = 0.4) or by race (P = 0.2). Competing risk analysis did not demonstrate differences in transplantation or death/delisting in men compared with women (HT: adjusted HR [aHR]: 0.92 [95% CI: 0.70-1.21]; death/delisting: aHR: 0.91 [95% CI: 0.59-1.42]), although Black patients were transplanted fewer times than White patients (HT: aHR: 0.72 [95% CI: 0.57-0.91], death/delisting: aHR: 1.36 [95% CI: 0.98-1.89]). One-year post-transplant survival was comparable by gender (aHR: 0.52 [95% CI: 0.21-1.70]) and race (aHR: 0.76 [95% CI: 0.34-1.70]), with no differences in rates of stroke, acute rejection, or graft failure. CONCLUSIONS: Use of HM3 among patients listed for HT has increased over time and by gender and race. Black patients with HM3 were less likely to be transplanted compared with White patients, but there were no differences in post-transplant outcomes between these groups or between men and women.

Higher-Order Dynamics Beyond Repolarization Alternans in Ex-Vivo Human Ventricles are Independent of the Restitution Properties.

Background: Repolarization alternans, defined as period-2 oscillation in the repolarization phase of the action potentials, provides a mechanistic link between cellular dynamics and ventricular fibrillation (VF). Theoretically, higher-order periodicities (e.g., periods 4, 6, 8,...) are expected but have minimal experimental evidence. Methods: We studied explanted human hearts obtained from recipients of heart transplantation at the time of surgery. Optical mapping of the transmembrane potential was performed after staining the hearts with voltage-sensitive fluorescent dyes. Hearts were stimulated at an increasing rate until VF was induced. Signals recorded from the right ventricle endocardial surface prior to induction of VF and in the presence of 1:1 conduction were processed using the Principal Component Analysis and a combinatorial algorithm to detect and quantify higher-order dynamics. Results were correlated to the underlying electrophysiological characteristics as quantified by restitution curves and conduction velocity. Results: A prominent and statistically significant global 1:4 peak (corresponding to period-4 dynamics) was seen in three of the six studied hearts. Local (pixel-wise) analysis revealed the spatially heterogeneous distribution of periods 4, 6, and 8, with the regional presence of periods greater than two in all the hearts. There was no significant correlation between the underlying restitution properties and the period of each pixel. Discussion: We present evidence of higher-order periodicities and the co-existence of such regions with stable non-chaotic areas in ex-vivo human hearts. We infer from the independence of the period to the underlying restitution properties that the oscillation of the excitation-contraction coupling and calcium cycling mechanisms is the primary mechanism of higher-order dynamics. These higher-order regions may act as niduses of instability that can degenerate into chaotic fibrillation and may provide targets for substrate-based ablation of VF.

Outflow graft obstruction after left ventricular assist device implantation: a retrospective, single-centre case series.

AIMS: Outflow graft obstruction is a poorly described complication following left ventricular assist device (LVAD) surgery. We sought to define the incidence of LVAD outflow graft obstruction and assess clinical outcomes with a percutaneous treatment strategy. METHODS AND RESULTS: From January 2012 to October 2020, 322 patients with LVAD were managed at our institution. Patients with LVAD outflow graft obstruction were identified by cardiac computed tomography with angiography and invasive haemodynamic assessment and were subsequently treated with percutaneous intervention. Poisson regression was used to analyse time-dependent differences in the incidence of LVAD outflow graft obstruction. Kaplan-Meier analysis was used to estimate survival. Twenty patients (6.2%) developed haemodynamically significant LVAD outflow graft obstruction at a rate of 0.03 events per patient-year. Outflow graft obstruction presented a median of 33 (26-49) months after surgery. Patients presented with low estimated LVAD pump flow (95%), heart failure (90%), or both (85%), and 59% developed cardiogenic shock prior to intervention. The most common aetiology identified by cardiac computed tomography with angiography was external compression of the outflow graft (78%). On presentation, the median peak gradient in the outflow graft was 78 (64-100) mmHg. Outflow graft stenting was 100% successful with no in-hospital mortality, and it reduced the peak outflow graft gradient to 10 (2-17) mmHg (P < 0.001). Outflow graft stenting was durable with two patients (10%) requiring a repeat procedure over a median follow-up of 13 (7-20) months and did not impact survival. CONCLUSIONS: Left ventricular assist device outflow graft obstruction is a relatively common and underappreciated cause of recurrent heart failure and LVAD dysfunction. Outflow graft stenting can be achieved with low morbidity and provides a long-term solution to this complication.

Racial disparity persists after on-pump and off-pump coronary artery bypass grafting.

BACKGROUND: Race has been shown to be an independent risk factor for operative mortality after coronary artery bypass grafting (CABG). This study sought to determine the extent to which race is a risk factor for adverse events, long-term mortality, and whether off-pump surgery (OPCAB) modifies that risk. METHODS AND RESULTS: The Society of Thoracic Surgeons Adult Cardiac Database at Emory Healthcare affiliated hospitals was queried for all primary isolated CABG records from 1997 to 2007. A propensity score was formulated to balance the patient groups with respect to treatment assignment (OPCAB or CABG on cardiopulmonary bypass). Multivariable logistic regression was used to assess the impact of black race and OPCAB on in-hospital outcomes (death, stroke, myocardial infarction, and their composite, major adverse cardiac events). Cox proportional hazards regression model and Kaplan-Meier curves determined whether black race affected long-term all-cause mortality. Interaction terms were constructed to test whether OPCAB surgery influences surgical results differently in black patients than in white patients. There were 12 874 consecutive CABG patients, including 2033 (15.8%) blacks and 10 841 (84.2%) whites. Survival at 3, 5, and 10 years for blacks (87.5%, 81.4%, 63.8%) was significantly lower than for whites (90.7%, 85.2%, 67.1%, P<0.001). Blacks (adjusted odds ratio, 0.77; 95% CI, 0.44 to 1.36) and whites (adjusted odds ratio, 0.72; 95% CI, 0.53 to 0.99) who had OPCAB had lower risk-adjusted odds of major adverse cardiac events than their racial counterparts who had CABG on cardiopulmonary bypass. CONCLUSIONS: Short- and long-term outcomes are significantly worse in black than in white patients undergoing primary isolated CABG. OPCAB does not narrow the disparity in outcomes between blacks and whites.

Mortality in status 2 patients listed for heart transplantation in the United States: Will understanding cause of death help justify implantation of left ventricular assist devices into less sick patients?

OBJECTIVE: It remains unclear whether left ventricular assist device (LVAD) implantation in non-inotrope dependent patients is of clinical benefit. This study sought to evaluate cause of death in patients listed for heart transplant (HT) to determine the relative risks and benefits of implanting LVAD into patients who are less sick than those included in the original clinical trials. METHODS: We examined death as the primary outcome in 23,098 patients listed for HT from 2006 to 2014 using proportional subdistribution hazards modeling. Cause of death was examined as a secondary outcome using χ2 tests. RESULTS: 1859 (8.1%) patients were removed from the wait list for death, including 229 (2.7%) status 1A, 349 (4.6%) status 1B, 246 (13.2%) status 2, and 1035 (26.0%) status 7 patients (P < 0.0001). Status 2 patients who received LVAD while listed had a higher risk of death compared to those who did not (adjusted HR 1.68; 95% CI 1.09-2.59; P = 0.02), while there was no increased risk of death in status 1A (HR 1.02; 95% CI 0.68-1.51; P = 0.9) and status 1B (HR 0.89; 95% CI 0.65-1.23; P = 0.5) who received LVAD. Status 2 patients who received LVAD were more likely to die cerebrovascular causes (0.6% vs. 0.1%, P = 0.009) and organ failure (70.6% vs. 29.4%, P = 0.003). CONCLUSIONS: LVAD implantation in status 2 patients listed for HT is associated with a higher risk of death. More research is needed to determine the impact LVAD implantation will have on mortality in patients with ambulatory, non-inotrope dependent HF.

Decisional regret in left ventricular assist device patient-caregiver dyads.

BACKGROUND: The objective of this study was to investigate decisional regret among left ventricular assist device (LVAD) patients and their caregivers. METHODS: This study was a single center, cross-sectional survey of patients after LVAD implantation and their caregivers. Subjects were recruited at their outpatient heart failure appointments. Patients and caregivers at least three months from LVAD implantation completed a 5-item, validated decisional regret scale. Summative scores on a 0-100 point scale were determined for patient and caregivers (0 = no regret). Subgroup analysis included gender, LVAD indication (bridge to transplant (BTT) or destination therapy (DT)), time from LVAD implantation, and caregiver relationship. Dyad discordance was defined as a patient-caregiver difference of ≥2 points on any regret scale question. RESULTS: Fifty patients were approached for participation. Thirty-three LVAD patient-caregiver dyads were enrolled in the study (19 male, 14 female patients; 8 male, 25 female caregivers). Patients had a mean age of approximately 50 years. Caregivers had a mean age of approximately 54 years. Patients had a median regret score of 10 (Interquartile range (IQR): 0-30), while caregivers had a median regret score of 20 (IQR: 0-25). Median regret scores of female patients were significantly higher than that of male patients (27.5 vs 0, p = 0.0038). BTT patients had numerically lower regret than DT patients, but this was not statistically significant. Patients who had been implanted for greater than three years had the highest regret scores. Discordance in at least one domain of the regret scale was present in 19 out of 33 (57.6%) dyads. CONCLUSIONS: While decisional regret was reasonably low in this population, comparatively, there was significantly increased decisional regret among female patients and patients further from LVAD implantation. Differences between patients and caregivers were also observed. These findings highlight the need for robust support and continual attention to expectations before and after LVAD implantation.

Bone morphogenic protein antagonists are coexpressed with bone morphogenic protein 4 in endothelial cells exposed to unstable flow in vitro in mouse aortas and in human coronary arteries: role of bone morphogenic protein antagonists in inflammation and atherosclerosis.

BACKGROUND: Exposure to disturbed flow, including oscillatory shear stress, stimulates endothelial cells (ECs) to produce bone morphogenic protein (BMP) 4, which in turn activates inflammation, a critical atherogenic step. BMP activity is regulated by the level of BMP antagonists. Until now it was not known whether shear also regulates the expression of BMP antagonists and whether they play a role in EC pathophysiology. METHODS AND RESULTS: BMP antagonists follistatin, noggin, and matrix Gla protein were expressed in cultured bovine and human arterial ECs. Surprisingly, oscillatory shear stress increased expression of the BMP antagonists in ECs, whereas unidirectional laminar shear decreased such expression. Immunohistochemical studies with mouse aortas showed data consistent with in vitro findings: Only ECs in the lesser curvature exposed to disturbed flow, but not those in the greater curvature and straight arterial regions exposed to undisturbed flow, showed coexpression of BMP4 and the BMP antagonists. Similarly, in human coronary arteries, expression of BMP4 and BMP antagonists in ECs positively correlated with the severity of atherosclerosis. Monocyte adhesion induced by oscillatory shear stress was inhibited by knockdown of BMP4 or treatment with recombinant follistatin or noggin, whereas it was increased by knockdown of follistatin and/or noggin. CONCLUSIONS: The present results suggest that ECs coexpress BMP antagonists along with BMP4 in an attempt to minimize the inflammatory response by oscillatory shear stress as part of a negative feedback mechanism. The balance between the agonist, BMP4, and its antagonists may play an important role in the overall control of inflammation and atherosclerosis.