Distinct Transcriptomic and Proteomic Profile Specifies Patients Who Have Heart Failure With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support.

BACKGROUND: Extensive evidence from single-center studies indicates that a subset of patients with chronic advanced heart failure (HF) undergoing left ventricular assist device (LVAD) support show significantly improved heart function and reverse structural remodeling (ie, termed "responders"). Furthermore, we recently published a multicenter prospective study, RESTAGE-HF (Remission from Stage D Heart Failure), demonstrating that LVAD support combined with standard HF medications induced remarkable cardiac structural and functional improvement, leading to high rates of LVAD weaning and excellent long-term outcomes. This intriguing phenomenon provides great translational and clinical promise, although the underlying molecular mechanisms driving this recovery are largely unknown. METHODS: To identify changes in signaling pathways operative in the normal and failing human heart and to molecularly characterize patients who respond favorably to LVAD unloading, we performed global RNA sequencing and phosphopeptide profiling of left ventricular tissue from 93 patients with HF undergoing LVAD implantation (25 responders and 68 nonresponders) and 12 nonfailing donor hearts. Patients were prospectively monitored through echocardiography to characterize their myocardial structure and function and identify responders and nonresponders. RESULTS: These analyses identified 1341 transcripts and 288 phosphopeptides that are differentially regulated in cardiac tissue from nonfailing control samples and patients with HF. In addition, these unbiased molecular profiles identified a unique signature of 29 transcripts and 93 phosphopeptides in patients with HF that distinguished responders after LVAD unloading. Further analyses of these macromolecules highlighted differential regulation in 2 key pathways: cell cycle regulation and extracellular matrix/focal adhesions. CONCLUSIONS: This is the first study to characterize changes in the nonfailing and failing human heart by integrating multiple -omics platforms to identify molecular indices defining patients capable of myocardial recovery. These findings may guide patient selection for advanced HF therapies and identify new HF therapeutic targets.

Arterial Stiffness and Diabetes Risk in Framingham Heart Study and UK Biobank.

BACKGROUND: Microvascular damage from large artery stiffness (LAS) in pancreatic, hepatic, and skeletal muscles may affect glucose homeostasis. Our goal was to evaluate the association between LAS and the risk of type 2 diabetes using prospectively collected, carefully phenotyped measurements of LAS as well as Mendelian randomization analyses. METHODS: Carotid-femoral pulse wave velocity (CF-PWV) and brachial and central pulse pressure were measured in 5676 participants of the FHS (Framingham Heart Study) without diabetes. We used Cox proportional hazards regression to evaluate the association of CF-PWV and pulse pressure with incident diabetes. We subsequently performed 2-sample Mendelian randomization analyses evaluating the associations of genetically predicted brachial pulse pressure with type 2 diabetes in the UKBB (United Kingdom Biobank). RESULTS: In FHS, individuals with higher CF-PWV were older, more often male, and had higher body mass index and mean arterial pressure compared to those with lower CF-PWV. After a median follow-up of 7 years, CF-PWV and central pulse pressure were associated with an increased risk of new-onset diabetes (per SD increase, multivariable-adjusted CF-PWV hazard ratio, 1.36 [95% CI, 1.03-1.76]; P=0.030; central pulse pressure multivariable-adjusted CF-PWV hazard ratio, 1.26 [95% CI, 1.08-1.48]; P=0.004). In United Kingdom Biobank, genetically predicted brachial pulse pressure was associated with type 2 diabetes, independent of mean arterial pressure (adjusted odds ratio, 1.16 [95% CI, 1.00-1.35]; P=0.049). CONCLUSIONS: Using prospective cohort data coupled with Mendelian randomization analyses, we found evidence supporting that greater LAS is associated with increased risk of developing diabetes. LAS may play an important role in glucose homeostasis and may serve as a useful marker of future diabetes risk.

Bridge-to-transplant temporary mechanical circulatory support and risk of allosensitization.

INTRODUCTION: Since the 2018 change in the US adult heart allocation policy, more patients are bridged-to-transplant on temporary mechanical circulatory support (tMCS). Previous studies indicate that durable left ventricular assist devices (LVAD) may lead to allosensitization. The goal of this study was to assess whether tMCS implantation is associated with changes in sensitization. METHODS: We included patients evaluated for heart transplants between 2015 and 2022 who had alloantibody measured before and after MCS implantation. Allosensitization was defined as development of new alloantibodies after tMCS implant. RESULTS: A total of 41 patients received tMCS before transplant. Nine (22.0%) patients developed alloantibodies following tMCS implantation: 3 (12.0%) in the intra-aortic balloon pump group (n = 25), 2 (28.6%) in the microaxial percutaneous LVAD group (n = 7), and 4 (44.4%) in the veno-arterial extra-corporeal membrane oxygenation group (n = 9)-p = .039. Sensitized patients were younger (44.7 ± 11.6 years vs. 54.3 ± 12.5 years, p = .044), were more likely to be sensitized at baseline - 3 of 9 (33.3%) compared to 2 out of 32 (6.3%) (p = .028) and received more transfusions with red blood cells (6 (66.6%) vs. 8 (25%), p = .02) and platelets (6 (66.6%) vs. 5 (15.6%), p = .002). There was no significant difference in tMCS median duration of support (4 [3,15] days vs. 8.5 [5,14.5] days, p = .57). Importantly, out of the 11 patients who received a durable LVAD after tMCS, 5 (45.5%) became sensitized, compared to 4 out of 30 patients (13.3%) who only had tMCS-p = .028. CONCLUSIONS: Our findings suggest that patients bridged-to-transplant with tMCS, without significant blood product transfusions and a subsequent durable LVAD implant, have a low risk of allosensitization. Further studies are needed to confirm our findings and determine whether risk of sensitization varies by type of tMCS and duration of support.

Interrupted Time Series Analysis of Donor Heart Use Before and After the 2018 UNOS Heart Allocation Policy Change.

BACKGROUND: Donor heart scarcity remains the fundamental barrier to increased transplant access. We examined whether 2018 United Network for Organ Sharing (UNOS) policy changes have had an impact on donor heart acceptance rates. METHODS AND RESULTS: We performed an interrupted time series analysis in UNOS to evaluate for abrupt changes in donor heart-acceptance rates associated with the new policy. All adult donor offers were evaluated between 2015 and 2021 (n = 66,654 donors). Donor volumes and transplants increased during this period, but the donor acceptance rate declined significantly from 31% in quarter 3 of 2018 to 26% acceptance in quarter 3 of 2021 (slope change -0.4% per quarter; P < 0.001). We identified 2 trends associated with this decline: (1) a growing number of donors with high-risk features, and (2) decreased acceptance of donors with certain high-risk features in the new allocation system. CONCLUSIONS: Heart transplant volumes have increased in recent years as a result of increased donor volumes, but donor heart acceptance rates began decreasing under the current allocation system. Changes in the donor pool and acceptance patterns for certain donor-risk features may explain this shift and warrant further evaluation to maximize donor heart use.

Medical decisions in organ donors and heart transplant candidates with history of COVID-19 infection: An international practice survey.

BACKGROUND: A growing proportion of transplant donors and recipients have a history of COVID-19 infection. This study sought to characterize clinical practice after recipient or donor COVID-19 infection. METHODS: An online survey was distributed to heart transplant clinicians through a professional society message board and social media. Responses were collected between September 29 and November 5, 2021. RESULTS: There were 222 health care professionals (68% transplant cardiologists, 22% transplant surgeons, 10% other) across diverse geographic regions who completed the survey. While there was significant variation in donor acceptance, as it relates to past and current COVID-19 infection, the respondents were fairly cautious: 28% would not typically accept a donor with a history of COVID-19 regardless of the infection course and > 80% would not accept donors who had evidence of myocardial dysfunction during past COVID-19 infection, or who died of COVID-19 or its complications. The timing of candidate reactivation on the waiting list after COVID-19 infection also varied and often diverged from scenarios addressed by social guidelines. Eighty-one percent of the respondents felt COVID-19 vaccine should be mandatory before transplant, but this rate varied by geographic region. CONCLUSION: Our results reflect evolving experience of the heart transplant field at a time of lack of high-quality evidence. In the absence of longer-term outcome data for donors and transplant candidates with history of COVID-19 infection, clinicians remain cautious; however, this approach will likely need to be refined as an increasing proportion of the population will continue to be infected with COVID-19.

Mental health disorders and emergency resource use and outcomes in ventricular assist device supported patients.

There are limited data describing the prevalence of mental health disorders (MHDOs) in patients with ventricular assist devices (VADs), or associations between MHDOs and resource use or outcomes. We used the Nationwide Emergency Department Sample administrative database to analyze 44,041 ED encounters for VAD-supported adults from 2010 to 2017, to assess the relationship between MHDOs and outcomes in this population. MHDO diagnoses were present for 23% of encounters, and were associated with higher charges and rates of admission, but lower mortality.

Is There an Association Between COVID-19 Mortality and the Renin-Angiotensin System? A Call for Epidemiologic Investigations.

Mortality from coronavirus disease 2019 (COVID-19) is strongly associated with cardiovascular disease, diabetes, and hypertension. These disorders share underlying pathophysiology related to the renin-angiotensin system (RAS) that may be clinically insightful. In particular, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated in cardiovascular disease, and this enzyme is used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to initiate the infection. Cardiovascular disease and pharmacologic RAS inhibition both increase ACE2 levels, which may increase the virulence of SARS-CoV-2 within the lung and heart. Conversely, mechanistic evidence from related coronaviruses suggests that SARS-CoV-2 infection may downregulate ACE2, leading to toxic overaccumulation of angiotensin II that induces acute respiratory distress syndrome and fulminant myocarditis. RAS inhibition could mitigate this effect. With conflicting mechanistic evidence, we propose key clinical research priorities necessary to clarify the role of RAS inhibition in COVID-19 mortality that could be rapidly addressed by the international research community.

Thrombosis in COVID-19.

Thrombotic complications are frequent in COVID-19 and contribute significantly to mortality and morbidity. We review several mechanisms of hypercoagulability in sepsis that may be upregulated in COVID-19. These include immune-mediated thrombotic mechanisms, complement activation, macrophage activation syndrome, antiphospholipid antibody syndrome, hyperferritinemia, and renin-angiotensin system dysregulation. We highlight biomarkers within each pathway with potential prognostic value in COVID-19. Lastly, recent observational studies have evaluated a role for the expanded use of therapeutic anticoagulation in COVID-19. We review strengths and weaknesses of these studies, and we also discuss the hypothetical benefit and anticipated challenges of fibrinolytic therapy in COVID-19.

Relationship Between ACE2 and Other Components of the Renin-Angiotensin System.

PURPOSE OF THE REVIEW: Angiotensin-converting enzyme 2 (ACE2) is a key counter-regulatory component of the renin-angiotensin system. Here, we briefly review the mechanistic and target organ effects related to ACE2 activity, and the importance of ACE2 in SARS-CoV-2 infection. RECENT FINDINGS: ACE2 converts angiotensin (Ang) II to Ang-(1-7), which directly opposes the vasoconstrictive, proinflammatory, and prothrombotic effects of Ang II. ACE2 also facilitates SARS-CoV-2 viral entry into host cells. Drugs that interact with the renin-angiotensin system may impact ACE2 expression and COVID-19 pathogenesis; however, the magnitude and direction of these effects are unknown at this time. High quality research is needed to improve our understanding of how agents that act on the renin-angiotensin system impact ACE2 and COVID-19-related disease outcomes.

Left Ventricular Assist Device as Destination Therapy: a State of the Science and Art of Long-Term Mechanical Circulatory Support.

PURPOSE OF REVIEW: The purpose of this review is to synthesize and summarize recent developments in the care of patients with end-stage heart failure being managed with a left ventricular assist device (LVAD) as destination therapy. RECENT FINDINGS: Although the survival of patients treated with LVAD continues to improve, the rates of LVAD-associated complication, such as right ventricular failure, bleeding complications, and major infection, remain high, and management of these patients remains challenging. The durability and hemocompatibility of LVAD support have greatly increased in recent years as a result of new technologies and novel management strategies. Challenges remain in the comprehensive care of patients with destination therapy LVADs, including management of comorbidities and optimizing patient function and quality of life.

Retinal microvascular abnormalities predict progression of brain microvascular disease: an atherosclerosis risk in communities magnetic resonance imaging study.

BACKGROUND AND PURPOSE: Brain microvascular disease leads to leukoaraiosis and lacunar infarcts and contributes to risk of stroke and cognitive decline. Given a shared pathophysiology, retinal microvascular signs are expected to predict brain microvascular disease progression. We investigated if either leukoaraiosis volume progression measured continuously or combined with incident lacunar infarcts would better demonstrate expected associations with retinal disease than has previously been shown. METHODS: Eight hundred thirty participants in the Atherosclerosis Risk in Communities (ARIC) study aged ≥55 years and without previous stroke received an initial brain magnetic resonance imaging, retinal photography, and, 10 years later, a follow up magnetic resonance imaging. We evaluated retinal vascular sign phenotypes as predictors of (1) leukoaraiosis volume increase, and (2) a new score combining leukoaraiosis volume change and incident lacunar infarcts. Hypertension and diabetes mellitus were evaluated as confounders and effect modifiers. RESULTS: Individuals with any retinopathy (3.34 cm3; 95% confidence interval [CI], 0.74-5.96) or with arteriovenous nicking (2.61 cm3; 95% CI, 0.80-4.42) each had greater progression of leukoaraiosis compared with those without these conditions. Any retinopathy (odds ratio [OR], 3.18; 95% CI, 1.71-5.89) or its components-microaneurysms (OR, 3.06; 95% CI, 1.33-7.07) and retinal hemorrhage (OR, 3.02; 95% CI, 1.27-7.20)-as well as arteriovenous nicking (OR, 1.93; 95%, CI 1.24-3.02) and focal arteriolar narrowing (OR, 1.76; 95% CI, 1.19-2.59), were associated with a higher quartile of a novel brain microvascular disease score combining leukoaraiosis progression with incident subclinical lacunes. CONCLUSIONS: A novel scoring method revealed associations of retinal signs with leukoaraiosis progression and brain microvascular disease, which have not been shown before.

Hemodynamic management of cardiogenic shock in the intensive care unit.

Hemodynamic derangements are defining features of cardiogenic shock. Randomized clinical trials have examined the efficacy of various therapeutic interventions, from percutaneous coronary intervention to inotropes and mechanical circulatory support (MCS). However, hemodynamic management in cardiogenic shock has not been well-studied. This State-of-the-Art review will provide a framework for hemodynamic management in cardiogenic shock, including a description of the 4 therapeutic phases from initial 'Rescue' to 'Optimization', 'Stabilization' and 'de-Escalation or Exit therapy' (R-O-S-E), phenotyping and phenotype-guided tailoring of pharmacological and MCS support, to achieve hemodynamic and therapeutic goals. Finally, the premises that form the basis for clinical management and the hypotheses for randomized controlled trials will be discussed, with a view to the future direction of cardiogenic shock.

Evaluation of renal sodium handling in heart failure with preserved ejection fraction: A pilot study.

The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs.

Hospital Readmissions in Patients Supported with Durable Centrifugal-Flow Left Ventricular Assist Devices.

Background: Centrifugal-flow left ventricular assist devices (CF-LVADs) have improved morbidity and mortality for their recipients. Hospital readmissions remain common, negatively impacting quality of life and survival. We sought to identify risk factors associated with hospital readmissions among patients with CF-LVADs. Methods: Consecutive patients receiving a CF-LVAD between February 2011 and March 2021 were retrospectively evaluated using prospectively maintained institutional databases. Hospital readmissions within three years post-LVAD implantation were dichotomized into heart failure (HF)/LVAD-related or non-HF/LVAD-related readmissions. Multivariable Cox regression models augmented using a machine learning algorithm, the least absolute shrinkage and selection operator (LASSO) method, for variable selection were used to estimate associations between HF/LVAD-related readmissions and pre-, intra- and post-operative clinical variables. Results: A total of 204 CF-LVAD recipients were included, of which 138 (67.7%) had at least one HF/LVAD-related readmission. HF/LVAD-related readmissions accounted for 74.4% (436/586) of total readmissions. The main reasons for HF/LVAD-related readmissions were major bleeding, major infection, HF exacerbation, and neurological dysfunction. Using pre-LVAD variables, HF/LVAD-related readmissions were associated with substance use, previous cardiac surgery, HF duration, pre-LVAD inotrope dependence, percutaneous LVAD/VA-ECMO support, LVAD type, and the left ventricular ejection fraction in multivariable analysis (Harrell's concordance c-statistic; 0.629). After adding intra- and post-operative variables in the multivariable model, LVAD implant hospitalization length of stay was an additional predictor of readmission. Conclusions: Using machine learning-based techniques, we generated models identifying pre-, intra-, and post-operative variables associated with a higher likelihood of rehospitalizations among patients on CF-LVAD support. These models could provide guidance in identifying patients with increased readmission risk for whom clinical strategies to mitigate this risk may further improve LVAD recipient outcomes.

Heart failure related cardiogenic shock: An ISHLT consensus conference content summary.

In recent years, there have been significant advancements in the understanding, risk-stratification, and treatment of cardiogenic shock (CS). Despite improved pharmacologic and device-based therapies for CS, short-term mortality remains as high as 50%. Most recent efforts in research have focused on CS related to acute myocardial infarction, even though heart failure related CS (HF-CS) accounts for >50% of CS cases. There is a paucity of high-quality evidence to support standardized clinical practices in approach to HF-CS. In addition, there is an unmet need to identify disease-specific diagnostic and risk-stratification strategies upon admission, which might ultimately guide the choice of therapies, and thereby improve outcomes and optimize resource allocation. The heterogeneity in defining CS, patient phenotypes, treatment goals and therapies has resulted in difficulty comparing published reports and standardized treatment algorithms. An International Society for Heart and Lung Transplantation (ISHLT) consensus conference was organized to better define, diagnose, and manage HF-CS. There were 54 participants (advanced heart failure and interventional cardiologists, cardiothoracic surgeons, critical care cardiologists, intensivists, pharmacists, and allied health professionals), with vast clinical and published experience in CS, representing 42 centers worldwide. State-of-the-art HF-CS presentations occurred with subsequent breakout sessions planned in an attempt to reach consensus on various issues, including but not limited to models of CS care delivery, patient presentations in HF-CS, and strategies in HF-CS management. This consensus report summarizes the contemporary literature review on HF-CS presented in the first half of the conference (part 1), while the accompanying document (part 2) covers the breakout sessions where the previously agreed upon clinical issues were discussed with an aim to get to a consensus.

Consensus statements from the International Society for Heart and Lung Transplantation consensus conference: Heart failure-related cardiogenic shock.

The last decade has brought tremendous interest in the problem of cardiogenic shock. However, the mortality rate of this syndrome approaches 50%, and other than prompt myocardial revascularization, there have been no treatments proven to improve the survival of these patients. The bulk of studies have been in patients with acute myocardial infarction, and there is little evidence to guide the clinician in those patients with heart failure cardiogenic shock (HF-CS). An International Society for Heart and Lung Transplant consensus conference was organized to better define, diagnose, and manage HF-CS. There were 54 participants (advanced heart failure and interventional cardiologists, cardiothoracic surgeons, critical care cardiologists, intensivists, pharmacists, and allied health professionals) with vast clinical and published experience in CS, representing 42 centers worldwide. This consensus report summarizes the results of a premeeting survey answered by participants and the breakout sessions where predefined clinical issues were discussed to achieve consensus in the absence of robust data. Key issues discussed include systems for CS management, including the "hub-and-spoke" model vs a tier-based network, minimum levels of data to communicate when considering transfer, disciplines that should be involved in a "shock team," goals for mechanical circulatory support device selection, and optimal flow on such devices. Overall, the document provides expert consensus on some important issues facing practitioners managing HF-CS. It is hoped that this will clarify areas where consensus has been reached and stimulate future research and registries to provide insight regarding other crucial knowledge gaps.

Cardiac Reverse Remodeling Mediated by HeartMate 3 Left Ventricular Assist Device: Comparison to Older Generation Devices.

Currently, the fully magnetically levitated left ventricular assist device (LVAD) HeartMate 3 (HM3) is the only commercially available device for advanced heart failure (HF) patients. However, the left ventricular (LV) functional and structural changes following mechanical unloading and circulatory support (MCS) with the HM3 have not been investigated. We compared the reverse remodeling induced by the HM3 to older generation continuous-flow LVADs. Chronic HF patients (n = 405) undergoing MCS with HeartWare Ventricular Assist Device (HVAD, n = 115), HM3 (n = 186), and HeartMate II (HM2, n = 104) at four programs were included. Echocardiograms were obtained preimplant and at 1, 3, 6, and 12 months following LVAD implantation. There were no differences in the postimplant serial LV ejection fraction (LVEF) between the devices. The postimplant LV internal diastolic diameter (LVIDd) was significantly lower for HM2 at 3 and 6 months compared with HVAD and HM3. The proportion of patients achieving "cardiac reverse remodeling responder" status (defined as LVEF improvement to ≥40% and LVIDD ≤5.9 cm) was 11.9%, and was similar between devices. HeartMate 3 appears to result in similar cardiac reverse remodeling as older generation CF-LVADs, suggesting that the fully magnetically levitated device technology could provide an effective platform to further study and promote cardiac reverse remodeling.

Artificial intelligence predictive analytics in heart failure: results of the pilot phase of a pragmatic randomized clinical trial.

OBJECTIVES: We conducted an implementation planning process during the pilot phase of a pragmatic trial, which tests an intervention guided by artificial intelligence (AI) analytics sourced from noninvasive monitoring data in heart failure patients (LINK-HF2). MATERIALS AND METHODS: A mixed-method analysis was conducted at 2 pilot sites. Interviews were conducted with 12 of 27 enrolled patients and with 13 participating clinicians. iPARIHS constructs were used for interview construction to identify workflow, communication patterns, and clinician's beliefs. Interviews were transcribed and analyzed using inductive coding protocols to identify key themes. Behavioral response data from the AI-generated notifications were collected. RESULTS: Clinicians responded to notifications within 24 hours in 95% of instances, with 26.7% resulting in clinical action. Four implementation themes emerged: (1) High anticipatory expectations for reliable patient communications, reduced patient burden, and less proactive provider monitoring. (2) The AI notifications required a differential and tailored balance of trust and action advice related to role. (3) Clinic experience with other home-based programs influenced utilization. (4) Responding to notifications involved significant effort, including electronic health record (EHR) review, patient contact, and consultation with other clinicians. DISCUSSION: Clinician's use of AI data is a function of beliefs regarding the trustworthiness and usefulness of the data, the degree of autonomy in professional roles, and the cognitive effort involved. CONCLUSION: The implementation planning analysis guided development of strategies that addressed communication technology, patient education, and EHR integration to reduce clinician and patient burden in the subsequent main randomized phase of the trial. Our results provide important insights into the unique implications of implementing AI analytics into clinical workflow.