The Future of Durable Mechanical Circulatory Support: Emerging Technological Innovations and Considerations to Enable Evolution of the Field.

The field of durable mechanical circulatory support (MCS) has undergone an incredible evolution over the past few decades, resulting in significant improvements in longevity and quality of life for patients with advanced heart failure. Despite these successes, substantial opportunities for further improvements remain, including in pump design and ancillary technology, perioperative and postoperative management, and the overall patient experience. Ideally, durable MCS devices would be fully implantable, automatically controlled, and minimize the need for anticoagulation. Reliable and long-term total artificial hearts for biventricular support would be available; and surgical, perioperative, and postoperative management would be informed by the individual patient phenotype along with computational simulations. In this review, we summarize emerging technological innovations in these areas, focusing primarily on innovations in late preclinical or early clinical phases of study. We highlight important considerations that the MCS community of clinicians, engineers, industry partners, and venture capital investors should consider to sustain the evolution of the field.

Association of race and gender with primary caregiver relationships and eligibility for advanced heart failure therapies.

BACKGROUND: Caregiver support is considered necessary after heart transplant (HT) and left ventricular assist device (LVAD) for patients with end-stage heart failure (HF). Few studies have demonstrated how caregivers differ by gender and race, and whether that impacts therapy eligibility. METHODS: We examined caregiver relationships among 674 patients (32% women, 55% Black) evaluated at Emory University from 2011 to 2017. Therapy readiness was assessed using the Stanford Integrated Assessment for Transplant (SIPAT). Evaluation outcome according to caregiver relationship was compared using χ2 analysis. Multivariable logistic regression determined the association between caregiver and eligibility according to gender and race. RESULTS: Women and Black patients were less likely to have spouses as their support person (P < .001). Women were less likely to be considered eligible for advanced therapies (adjusted odds ratio [aOR] .64, 95% confidence interval [CI] .46-.89; P = .008), with Black women having lower eligibility than White women (aOR .28, 95% CI .11-.72; P = .008). Social support and SIPAT scores did not significantly influence eligibility by gender or race. CONCLUSION: Lack of caregiver support is considered a relative contraindication to advanced therapies. Type of caregiver in our cohort varied according to race and gender but did not explain differences in eligibility for advanced therapies.

Vascular Regenerative Capacity and the Obesity Paradox in Coronary Artery Disease.

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Representation matters: a call for inclusivity and equity in heart failure clinical trials.

The burden of heart failure remains substantial worldwide, and heart failure with reduced ejection fraction (HFrEF) affects approximately half of this population. Despite this global prevalence of HFrEF, the majority of contemporary clinical trials in HFrEF have underenrolled individuals from minoritized sex, gender, race, ethnicity, and socioeconomic groups. Moreover, significant disparities in access to HFrEF treatment and outcomes exist across these same strata. We provide a call to action for the inclusion of diverse populations in HFrEF clinical trials; catalogue several barriers to adequate representation in HFrEF clinical trials; and propose strategies to broaden inclusivity in future HFrEF trials.

Racial differences in outcomes after receiving advanced heart failure therapies.

PURPOSE OF REVIEW: Despite advances in medical and device-based therapies for advanced heart failure as well as public policy, disparities by race/ethnicity persist in heart failure clinical outcomes. The purpose of this review is to describe disparities in outcomes by race--ethnicity in patients after receipt of heart transplantation and left ventricular assist device (LVAD), and the current understanding of factors contributing to these disparities. RECENT FINDINGS: The proportion of black and Latinx patients receiving advanced heart failure therapies continues to rise, and they have worse hemodynamic profiles at the time of referral for heart transplantation and LVAD. Black patients have lower rates of survival after heart transplantation, in part because of higher rates of cellular and humoral rejection that may be mediated through unique gene pathways, and increased risk for allosensitization and de-novo donor-specific antibodies. Factors that have previously been cited as reasons for worse outcomes in race--ethnic minorities, including psychosocial risk and lower SES, may not be as strongly correlated with outcomes after LVAD. SUMMARY: Black and Latinx patients are sicker at the time of referral for advanced heart failure therapies. Despite higher psychosocial risk factors among race--ethnic minorities, outcomes after LVAD appear to be similar to white patients. Black patients continue to have lower posttransplant survival, because of a complex interplay of immunologic susceptibility, clinical and socioeconomic factors. No single factor accounts for the disparities in clinical outcomes for race--ethnic minorities, and thus consideration of these components together is critical in management of these patients.

HIF1α-dependent upregulation of ATAD2 promotes proliferation and migration of stomach cancer cells in response to hypoxia.

Stomach cancer is a difficult-to-treat disease. Lack of detection markers and limited understanding of the disease mechanisms contribute to the aggressive nature of stomach cancer cells (SCCs). Recently, an ATPase, ATAD2 has been found to be highly expressed in stomach cancer contributing to increased malignancy. However, nothing is known about the mechanism of ATAD2 upregulation and its involvement in stomach carcinogenesis. Since hypoxic microenvironment plays a crucial role in the progression of solid tumors like stomach cancer; we have examined the regulation and function of ATAD2 expression in hypoxic SCCs. ATAD2 is induced in hypoxia-treated SCCs. Stomach adenocarcinoma and metastatic tissues with high HIF1α level also show enhanced ATAD2 expression. In the absence of hypoxia-inducible factor HIF1α, ATAD2 protein level is found to be less indicating towards a potential correlation between them. We identify the presence of HIF1α-binding site (HBS) and HIF1α ancillary site (HAS) in the ATAD2 promoter. Using both in vitro and in vivo binding studies, we confirm that HIF1α binds with the ATAD2 promoter in hypoxic condition. ATAD2 upregulation promotes proliferation and migration of SCCs exposed to hypoxia. Thus, we identify ATAD2 as a hypoxia-responsive and HIF1α-regulated gene and elucidate that upregulated expression of ATAD2 enhances tumor-promoting functions in hypoxic SCCs. Therefore, we propose ATAD2 as a promising therapeutic target for stomach cancer.

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.

Bacopa monnieri-Induced Protective Autophagy Inhibits Benzo[a]pyrene-Mediated Apoptosis.

Benzo[a]pyrene (B[a]P) is capable of inducing oxidative stress and cellular injuries leading to cell death and associates with a significant risk of cancer development. Prevention of B[a]P-induced cellular toxicity with herbal compound through regulation of mitochondrial oxidative stress might protect cell death and have therapeutic benefit to human health. In this study, we demonstrated the cytoprotective role of Bacopa monnieri (BM) against B[a]P-induced apoptosis through autophagy induction. Pretreatment with BM rescued the reduction in cell viability in B[a]P-treated human keratinocytes (HaCaT) cells indicating the cytoprotective potential of BM against B[a]P. Moreover, BM was found to inhibit B[a]P-mediated reactive oxygen species (ROS)-induced apoptosis activation in HaCaT cells. Furthermore, BM was found to preserve mitochondrial membrane potential and inhibited release of cytochrome c in B[a]P-treated HaCaT cells. Bacopa monnieri induced protective autophagy; we knocked down Beclin-1, and data showed that BM was unable to protect from B[a]P-induced mitochondrial ROS-mediated apoptosis in Beclin-1-deficient HaCaT cells. Moreover, we established that B[a]P-induced damaged mitochondria were found to colocalize and degraded within autolysosomes in order to protect HaCaT cells from mitochondrial injury. In conclusion, B[a]P-induced apoptosis was rescued by BM treatment and provided cytoprotection through Beclin-1-dependent autophagy activation. Copyright © 2016 John Wiley & Sons, Ltd.

Janus kinase signaling activation mediates peritoneal inflammation and injury in vitro and in vivo in response to dialysate.

Peritoneal membrane pathology limits long-term peritoneal dialysis (PD). Here, we tested whether JAK/STAT signaling is implicated and if its attenuation might be salutary. In cultured mesothelial cells, PD fluid activated, and the pan-JAK inhibitor P6 reduced, phospho-STAT1 and phospho-STAT3, periostin secretion, and cleaved caspase-3. Ex vivo, JAK was phosphorylated in PD effluent cells from long-term but not new PD patients. MCP-1 and periostin were increased in PD effluent in long term compared with new patients. In rats, twice daily, PD fluid infusion induced phospho-JAK, mesothelial cell hyperplasia, inflammation, fibrosis, and hypervascularity after 10 days of exposure to PD fluid. Concomitant instillation of a JAK1/2 inhibitor virtually completely attenuated these changes. Thus, our studies directly implicate JAK/STAT signaling in the mediation of peritoneal membrane pathology as a consequence of PD.

Associations Between Preimplant Cancer Type and Left Ventricular Assist Device Outcomes: An INTERMACS Registry Analysis.

We used the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database to examine whether history of a solid versus hematologic malignancy impacts outcomes after left ventricular assist device (LVAD) implantation. We included LVAD recipients (2007-2017) with cancer history reported (N = 14,799, 21% female, 24% Black). Multivariate models examined the association between cancer type and post-LVAD mortality and adverse events. Competing risk analyses compared death and heart transplantation between cancer types and those without cancer in bridge-to-transplant (BTT) patients. A total of 909 (6.1%) patients had a history of cancer (4.9% solid tumor, 1.3% hematologic malignancy). Solid tumors were associated with higher mortality (adjusted hazard ratio [aHR] = 1.31, 95% confidence interval [CI] = 1.09-1.57), major bleeding (aHR = 1.15, 95% CI = 1.00-1.32), and pump thrombosis (aHR = 1.52, 95% CI = 1.09-2.13), whereas hematologic malignancies were associated with increased major infection (aHR = 1.43, 95% CI = 1.14-1.80). Compared to BTT patients without a history of cancer, solid tumor patients were less likely to undergo transplantation (adjusted subdistribution HR [aSHR] = 0.63, 95% CI = 0.45-0.89) and hematologic malignancy patients were as likely to experience death (aSHR = 1.16, 95% CI = 0.63-2.14) and transplantation (aSHR = 0.69, 95% CI = 0.44-1.08). Cancer history and type impact post-LVAD outcomes. As LVAD utilization in cancer survivors increases, we need strategies to improve post-LVAD outcomes in these patients.

Metabolomic signatures of ideal cardiovascular health in black adults.

Plasma metabolomics profiling is an emerging methodology to identify metabolic pathways underlying cardiovascular health (CVH). The objective of this study was to define metabolomic profiles underlying CVH in a cohort of Black adults, a population that is understudied but suffers from disparate levels of CVD risk factors. The Morehouse-Emory Cardiovascular (MECA) Center for Health Equity study cohort consisted of 375 Black adults (age 53 ± 10, 39% male) without known CVD. CVH was determined by the AHA Life's Simple 7 (LS7) score, calculated from measured blood pressure, body mass index (BMI), fasting blood glucose and total cholesterol, and self-reported physical activity, diet, and smoking. Plasma metabolites were assessed using untargeted high-resolution metabolomics profiling. A metabolome wide association study (MWAS) identified metabolites associated with LS7 score after adjusting for age and sex. Using Mummichog software, metabolic pathways that were significantly enriched in metabolites associated with LS7 score were identified. Metabolites representative of these pathways were compared across clinical domains of LS7 score and then developed into a metabolomics risk score for prediction of CVH. We identified novel metabolomic signatures and pathways associated with CVH in a cohort of Black adults without known CVD. Representative and highly prevalent metabolites from these pathways included glutamine, glutamate, urate, tyrosine and alanine, the concentrations of which varied with BMI, fasting glucose, and blood pressure levels. When assessed in conjunction, these metabolites were independent predictors of CVH. One SD increase in the novel metabolomics risk score was associated with a 0.88 higher LS7 score, which translates to a 10.4% lower incident CVD risk. We identified novel metabolomic signatures of ideal CVH in a cohort of Black Americans, showing that a core group of metabolites central to nitrogen balance, bioenergetics, gluconeogenesis, and nucleotide synthesis were associated with CVH in this population.

Fallacies of Using the Win Ratio in Cardiovascular Trials: Challenges and Solutions.

The win ratio was introduced into cardiovascular trials as a potentially better way of analyzing composite endpoints to account for the hierarchy of clinical significance of their components and to facilitate the inclusion of recurrent events. The basic concept of the win ratio is to define a hierarchy of clinical importance within the components of the composite outcome, form all possible pairs by comparing every subject in the treatment group with every subject in the control group, and then evaluate each pair for the occurrence of the components of the composite outcome in descending order of importance, starting at the most important and progressing down the hierarchy if the outcome does not result in a win in either pair until pairs are tied for the outcome after exhaustion of all components. Although the win ratio offers a novel method of depiction of outcomes in clinical trials, its advantages may be counterbalanced by several fallacies (such as ignoring ties and weighting each hierarchal component equally) and challenges in appropriate clinical interpretation (establishing clinical meaningfulness of the observed effect size). From this perspective, we discuss these and other fallacies and provide a suggested framework to overcome such limitations to enhance utility of this statistical method across the clinical trial enterprise.

Nanosensor technologies and the digital transformation of healthcare.

Nanosensors are nanoscale devices that measure physical attributes and convert these signals into analyzable information. In preparation, for the impending reality of nanosensors in clinical practice, we confront important questions regarding the evidence supporting widespread device use. Our objectives are to demonstrate the value and implications for new nanosensors as they relate to the next phase of remote patient monitoring and to apply lessons learned from digital health devices through real-world examples.

Predictors of 5-Year Mortality in Patients Managed With a Magnetically Levitated Left Ventricular Assist Device.

BACKGROUND: In advanced heart failure patients implanted with a fully magnetically levitated HeartMate 3 (HM3, Abbott) left ventricular assist device (LVAD), it is unknown how preimplant factors and postimplant index hospitalization events influence 5-year mortality in those able to be discharged. OBJECTIVES: The goal was to identify risk predictors of mortality through 5 years among HM3 LVAD recipients conditional on discharge from index hospitalization in the MOMENTUM 3 pivotal trial. METHODS: This analysis evaluated 485 of 515 (94%) patients discharged after implantation of the HM3 LVAD. Preimplant (baseline), implant surgery, and index hospitalization characteristics were analyzed individually, and as multivariable predictors for mortality risk through 5 years. RESULTS: Cumulative 5-year mortality in the cohort (median age: 62 years, 80% male, 65% White, 61% destination therapy due to transplant ineligibility) was 38%. Two preimplant characteristics (elevated blood urea nitrogen and prior coronary artery bypass graft or valve procedure) and 3 postimplant characteristics (hemocompatibility-related adverse events, ventricular arrhythmias, and estimated glomerular filtration rate <60 mL/min/1.73 m2 at discharge) were predictors of 5-year mortality. In 171 of 485 patients (35.3%) without any risk predictors, 5-year mortality was reduced to 22.6% (95% CI: 15.4%-32.7%). Even among those with 1 or more predictors, mortality was <50% at 5 years (45.7% [95% CI: 39.0%-52.8%]). CONCLUSIONS: Long-term survival in successfully discharged HM3 LVAD recipients is largely influenced by clinical events experienced during the index surgical hospitalization in tandem with baseline factors, with mortality of <50% at 5 years. In patients without identified predictors of risk, long-term 5-year mortality is low and rivals that achieved with heart transplantation, even though most were implanted with destination therapy intent. (MOMENTUM 3 IDE Clinical Study Protocol, NCT02224755; MOMENTUM 3 Pivotal Cohort Extended Follow-up PAS, NCT03982979).

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.

Circulating progenitor cells and outcomes in patients with coronary artery disease.

BACKGROUND: Low quantities of circulating progenitor cells (CPCs), specifically CD34+ populations, reflect impairment of intrinsic regenerative capacity. This study investigates the relationship between subsets of CPCs and adverse outcomes. METHODS: 1366 individuals undergoing angiography for evaluation of coronary artery disease (CAD) were enrolled into the Emory Cardiovascular Biobank. Flow cytometry identified CPCs as CD45med blood mononuclear cells expressing the CD34 epitope, with further enumeration of hematopoietic CPCs as CD133+/CXCR4+ cells and endothelial CPCs as vascular endothelial growth factor receptor-2 (VEGFR2+) cells. Adjusted Cox or Fine and Gray's sub-distribution hazard regression models analyzed the relationship between CPCs and 1) all-cause death and 2) a composite of cardiovascular death and non-fatal myocardial infarction (MI). RESULTS: Over a median 3.1-year follow-up period (IQR 1.3-4.9), there were 221 (16.6%) all-cause deaths and 172 (12.9%) cardiovascular deaths/MIs. Hematopoietic CPCs were highly correlated, and the CD34+/CXCR4+ subset was the best independent predictor. Lower counts (≤median) of CD34+/CXCR4+ and CD34+/VEGFR2+ cells independently predicted all-cause mortality (HR 1.46 [95% CI 1.06-2.01], p = 0.02 and 1.59 [95% CI 1.15-2.18], p = 0.004) and cardiovascular death/MI (HR 1.50 [95% CI 1.04-2.17], p = 0.03 and 1.47 [95% CI 1.01-2.03], p = 0.04). A combination of low CD34+/CXCR4+ and CD34+/VEGFR2+ CPCs predicted all-cause death (HR 2.1, 95% CI 1.4-3.0; p = 0.0002) and cardiovascular death/MI (HR 2.0, 95% CI 1.3-3.2; p = 0.002) compared to those with both lineages above the cut-offs. CONCLUSIONS: Lower levels of hematopoietic and endothelial CPCs indicate diminished endogenous regenerative capacity and independently correlate with greater mortality and cardiovascular risk in patients with CAD.