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.

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.

Integrating molecular and clinical variables to predict myocardial recovery.

Mechanical unloading and circulatory support with left ventricular assist devices (LVADs) mediate significant myocardial improvement in a subset of advanced heart failure (HF) patients. The clinical and biological phenomena associated with cardiac recovery are under intensive investigation. Left ventricular (LV) apical tissue, alongside clinical data, were collected from HF patients at the time of LVAD implantation (n=208). RNA was isolated and mRNA transcripts were identified through RNA sequencing and confirmed with RT-qPCR. To our knowledge this is the first study to combine transcriptomic and clinical data to derive predictors of myocardial recovery. We used a bioinformatic approach to integrate 59 clinical variables and 22,373 mRNA transcripts at the time of LVAD implantation for the prediction of post-LVAD myocardial recovery defined as LV ejection fraction (LVEF) ≥40% and LV end-diastolic diameter (LVEDD) ≤5.9cm, as well as functional and structural LV improvement independently by using LVEF and LVEDD as continuous variables, respectively. To substantiate the predicted variables, we used a multi-model approach with logistic and linear regressions. Combining RNA and clinical data resulted in a gradient boosted model with 80 features achieving an AUC of 0.731±0.15 for predicting myocardial recovery. Variables associated with myocardial recovery from a clinical standpoint included HF duration, pre-LVAD LVEF, LVEDD, and HF pharmacologic therapy, and LRRN4CL (ligand binding and programmed cell death) from a biological standpoint. Our findings could have diagnostic, prognostic, and therapeutic implications for advanced HF patients, and inform the care of the broader HF population.

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.

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.

Machine Learning Multicenter Risk Model to Predict Right Ventricular Failure After Mechanical Circulatory Support: The STOP-RVF Score.

Importance: The existing models predicting right ventricular failure (RVF) after durable left ventricular assist device (LVAD) support might be limited, partly due to lack of external validation, marginal predictive power, and absence of intraoperative characteristics. Objective: To derive and validate a risk model to predict RVF after LVAD implantation. Design, Setting, and Participants: This was a hybrid prospective-retrospective multicenter cohort study conducted from April 2008 to July 2019 of patients with advanced heart failure (HF) requiring continuous-flow LVAD. The derivation cohort included patients enrolled at 5 institutions. The external validation cohort included patients enrolled at a sixth institution within the same period. Study data were analyzed October 2022 to August 2023. Exposures: Study participants underwent chronic continuous-flow LVAD support. Main Outcome and Measures: The primary outcome was RVF incidence, defined as the need for RV assist device or intravenous inotropes for greater than 14 days. Bootstrap imputation and adaptive least absolute shrinkage and selection operator variable selection techniques were used to derive a predictive model. An RVF risk calculator (STOP-RVF) was then developed and subsequently externally validated, which can provide personalized quantification of the risk for LVAD candidates. Its predictive accuracy was compared with previously published RVF scores. Results: The derivation cohort included 798 patients (mean [SE] age, 56.1 [13.2] years; 668 male [83.7%]). The external validation cohort included 327 patients. RVF developed in 193 of 798 patients (24.2%) in the derivation cohort and 107 of 327 patients (32.7%) in the validation cohort. Preimplant variables associated with postoperative RVF included nonischemic cardiomyopathy, intra-aortic balloon pump, microaxial percutaneous left ventricular assist device/venoarterial extracorporeal membrane oxygenation, LVAD configuration, Interagency Registry for Mechanically Assisted Circulatory Support profiles 1 to 2, right atrial/pulmonary capillary wedge pressure ratio, use of angiotensin-converting enzyme inhibitors, platelet count, and serum sodium, albumin, and creatinine levels. Inclusion of intraoperative characteristics did not improve model performance. The calculator achieved a C statistic of 0.75 (95% CI, 0.71-0.79) in the derivation cohort and 0.73 (95% CI, 0.67-0.80) in the validation cohort. Cumulative survival was higher in patients composing the low-risk group (estimated <20% RVF risk) compared with those in the higher-risk groups. The STOP-RVF risk calculator exhibited a significantly better performance than commonly used risk scores proposed by Kormos et al (C statistic, 0.58; 95% CI, 0.53-0.63) and Drakos et al (C statistic, 0.62; 95% CI, 0.57-0.67). Conclusions and Relevance: Implementing routine clinical data, this multicenter cohort study derived and validated the STOP-RVF calculator as a personalized risk assessment tool for the prediction of RVF and RVF-associated all-cause mortality.

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.

Effect of Anesthesia Induction on Cardiac Hemodynamics in Patients Undergoing Durable Left Ventricular Assist Device Implantation: The EACH-LVAD Study.

Right ventricular (RV) dysfunction is common after left ventricular assist device (LVAD) implantation leading to clinical right heart failure (RHF) associated with worsened survival and quality of life. It is likely that intraoperative events such as anesthesia induction play a role in the development or unmasking of RV dysfunction in addition to known effects from hemodynamic changes that occur after LVAD implantation. The EACH-LVAD Study is a prospective, single-center, single-arm, observational cohort study of adult patients with advanced heart failure undergoing durable LVAD implantation with standard anesthesia induction. Intraoperative RV hemodynamics via central venous pressure, mean pulmonary artery pressure, pulmonary artery pulsatility index, and vasoactive-inotropic score (a simple weighted summation of standardized drug doses) and echocardiographic parameters (RV fractional area change, RV area in diastole, RV basal diameter, septum position, RV function, tricuspid regurgitation) were measured and compared at prespecified timepoints, including postinduction. Postoperative clinical RHF was determined based on published definitions. Forty-two patients receiving a first-time LVAD were included between September 2017 and March 2019. Propofol-based induction was used in 31 patients and etomidate-based induction in eight patients. A significant increase in central venous pressure (CVP; p < 0.001), mean pulmonary artery pressure (mPAP; p < 0.001), and vasoactive inotropic score (VIS; p < 0.001) with associated decrease in pulmonary artery pulsatility index (PAPi; p < 0.001) was observed. Right ventricular function worsened throughout. Right heart failure occurred in 70% of patients. Propofol-based induction was not associated with a higher risk of RHF (relative risk [RR], 1.01 [95% confidence interval {CI}, 0.64-1.61]). The EACH-LVAD study demonstrates an effect of anesthesia induction on worsened RV hemodynamics and echocardiographic changes which may have an effect on the development of RHF.

Trends and Outcomes of Cardiogenic Shock in Patients With End-Stage Renal Disease: Insights From USRDS Database.

BACKGROUND: There is a paucity of data regarding epidemiology, temporal trends, and outcomes of patients with cardiogenic shock (CS) and end-stage renal disease (chronic kidney disease stage V on hemodialysis). METHODS: This is a retrospective cohort study using the United States Renal Data System database from January 1, 2006 to December 31, 2019. We analyzed trends of CS, percutaneous mechanical support (intraaortic balloon pump, percutaneous ventricular assist device [Impella and Tandemheart], and extracorporeal membrane oxygenation) utilization, index mortality, 30-day mortality, and 1-year all-cause mortality in end-stage renal disease patients. RESULTS: A total of 43 825 end-stage renal disease patients were hospitalized with CS (median age, 67.8 years [IQR, 59.4-75.8] and 59.1% men). From 2006 to 2019, the incidence of CS increased from 275 to 578 per 100 000 patients (Ptrend<0.001). The index mortality rate declined from 54.1% in 2006 to 40.8% in 2019 (Ptrend=0.44), and the 1-year all-cause mortality decreased from 63% in 2006 to 61.8% in 2018 (Ptrend=0.73), but neither trend was statistically significant. There was a significantly decreased utilization of intra-aortic balloon pumps from 17 832 to 7992 (Ptrend<0.001), increased utilization of percutaneous ventricular assist device from 137 to 5201 (Ptrend<0.001) and increase in extracorporeal membrane oxygenation use from 69 to 904 per 100 000 patients (Ptrend<0.001). After adjusting for covariates, there was no significant difference in index mortality between CS patients requiring percutaneous mechanical support versus those not requiring percutaneous mechanical support (odds ratio, 0.97 [CI, 0.91-1.02]; P=0.22). On multivariable regression analysis, older age, peripheral vascular disease, diabetes, and time on dialysis were independent predictors of higher index mortality. CONCLUSIONS: The incidence of CS in end-stage renal disease patients has doubled without significant change in the trend of index mortality despite the use of percutaneous mechanical support.

The impact of obesity and LVAD-bridging on heart transplant candidate outcomes: a linked STS INTERMACS - OPTN/UNOS data analysis.

BACKGROUND: Limited data integrating waitlist and postheart transplant (HT) mortality have evaluated outcomes of left ventricular assist device (LVAD)-bridged strategy vs no LVAD according to patient characteristics. We evaluated waitlist and post-HT mortality in LVAD-bridged vs nonbridged patients based on body mass index (BMI). METHODS: We included linked adults listed for HT in Organ Procurement and Transplant Network/United Network for Organ Sharing and patients receiving durable LVAD as bridge to HT or candidacy in Society of Thoracic Surgeons/Interagency Mechanical Circulatory Support databases (2010-2019). Using BMI at listing or LVAD implant, we categorized patients as underweight (<18.5 kg/m2), normal weight (18.5-24.99 kg/m2), overweight (25-29.99 kg/m2), and obese (≥30 kg/m2). Kaplan-Meier analysis and multivariable Cox proportional hazards models informed the effect of LVAD-bridged and nonbridged strategy by BMI on waitlist, post-HT, and overall mortality (including waitlist and post-HT mortality). RESULTS: Among 11,216 LVAD-bridged and 17,122 nonbridged candidates, bridged candidates were more frequently obese (37.3% vs 28.6%) (p < 0.001). Multivariable analysis indicated increased waitlist mortality in LVAD-bridged vs nonbridged with overweight (Hazard ratio (HR) 1.18, 95% confidence interval (CI) 1.02-1.36) or obesity (HR 1.35, 95%CI 1.17-1.56) in comparison to normal weight candidates (HR 1.02, 95%CI 0.88-1.19) (p-interaction < 0.001). Post-transplant mortality was not statistically different in LVAD-bridged vs nonbridged patients across BMI categories (p-interaction = 0.26). There was a nonsignificant graded increase in overall mortality in LVAD-bridged with overweight (HR 1.53, 95%CI 1.39-1.68) or obesity (HR 1.61, 95%CI 1.46-1.78) compared to nonbridged patients (p-interaction = 0.13). CONCLUSIONS: LVAD-bridged candidates with obesity had higher waitlist mortality compared to nonbridged candidates with obesity. Post-transplant mortality was similar in LVAD-bridged and nonbridged patients, but obesity remained associated with increased mortality in both groups. This study may aid clinicians and advanced heart failure patients with obesity in decision-making.

Chronotropic Incompetence after Heart Transplantation Is Associated with Increased Mortality and Decreased Functional Capacity.

INTRODUCTION: The contribution of chronotropic incompetence to reduced exercise tolerance after a heart transplant is well known, but its role as a prognostic marker of post-transplant mortality is unclear. The aim of this study is to examine the relationship between post-transplant heart rate response (HRR) and survival. METHODS: We performed a retrospective analysis of all adult heart transplant recipients at the University of Pennsylvania between the years 2000 and 2011 who underwent a cardiopulmonary exercise test (CPET) within a year of transplant. Follow-up time and survival status were observed through October 2019, using data merged from the Penn Transplant Institute. HRR was calculated by subtracting the resting HR from the peak exercise HR. The association between HRR and mortality was analyzed using Cox proportional hazard models and Kaplan-Meier analysis. The optimal cut-off point for HRR was generated by Harrell's C statistic. Patients with submaximal exercise tests were excluded, defined by a respiratory exchange ratio (RER) cut-off of 1.05. RESULTS: Of 277 patients with CPETs performed within a year post-transplant, 67 were excluded for submaximal exercise. In the 210 included patients, the mean follow-up time was 10.9 years (Interquartile range (IQR) 7.8-14). Resting HR and peak HR did not significantly impact mortality after adjusting for covariates. In a multivariable linear regression analysis, each 10-beat increase in heart rate response was associated with a 1.3 mL/kg/min increase in peak VO2 and a 48 s increase in the total exercise time. Each beat/min increase in HRR was associated with a 3% reduction in the hazard of mortality (HR 0.97; 95% CI 0.96-0.99, p = 0.002). Using the optimal cut-off point generated by Harrell's C statistic, survival was significantly higher in patients with an HRR > 35 beats/min compared to those with an HRR < 35 beats/min (log rank p = 0.0012). CONCLUSION: In heart transplant patients, a low HRR is associated with increased all-cause mortality and decreased exercise capacity. Additional studies are needed to validate whether targeting HRR in cardiac rehabilitation may improve outcomes.

Left ventricular functional improvement appears to contribute to lower rates of device thrombosis in patients on durable mechanical circulatory support.

By unloading the failing heart, left ventricular (LV) assist devices (LVADs) provide a favorable environment for reversing adverse structural and functional cardiac changes. Prior reports have suggested that an improved native LV function might contribute to the development of LVAD thrombosis. We used the Interagency Registry for Mechanically Assisted Circulatory Support and found that LV functional improvement is associated with a lower risk for device thrombosis. The risk for cerebrovascular accident and transient ischemic attack was comparable across post-LVAD LV function subgroups, while the risk of hemolysis was lower in subgroups of patients with better LV function on LVAD support.

Durable Left Ventricular Assist Device Outflow Graft Obstructions: Clinical Characteristics and Outcomes.

PURPOSE: We report on the clinical course and management of patients supported with durable implantable LVADs who developed outflow graft obstructions at a large academic center. METHODS: We performed a retrospective review of patients receiving LVAD support from 2012 through 2020. Patients who developed an outflow graft obstruction diagnosed by computed tomography angiography (CTA) or angiogram were identified, and patient characteristics and outcomes were reported. RESULTS: Of the 324 patients supported by LVAD at our institution, 11 patients (3.4%) were diagnosed with outflow graft obstructions. The most common presentation was low flow alarms, which was present in 10/11 patients, and the remaining patient presented with lightheadedness. Patients had minimal LDH elevation with 8/11 presenting with less than 2-fold the upper limit of normal. Transthoracic echocardiograms were not diagnostic, but CTA enabled non-invasive diagnoses in 8/11 of the patients. Three patients with extrinsic compression of the outflow graft successfully underwent endovascular stent placement, and three patients with outflow cannula kinks received supportive care. Of the five patients diagnosed with intraluminal thromboses, one received a heart transplant, one underwent an outflow graft revision, and three received supportive care due to comorbidities. CONCLUSION: Outflow graft obstructions remain a rare, but serious complication. The true prevalence of this entity is likely underestimated due to the non-specific clinical presentation. CTA is a pivotal non-invasive diagnostic step. Patients with external compression were successfully treated with endovascular stenting.

Management of Cardiogenic Shock Unrelated to Acute Myocardial Infarction.

Cardiogenic shock is an extreme manifestation of acute decompensated heart failure. Cardiogenic shock is often caused by-and has traditionally been studied in the setting of-acute myocardial infarction (AMI CS); however, there is increasing incidence and recognition of cardiogenic shock not associated with acute myocardial infarction (non-AMI CS) as a distinct entity. Despite decades of study and technologic advancements, cardiogenic shock mortality remains as high as 50%, regardless of etiology. New approaches to shock phenotyping and classification have emerged, with a focus on appropriately matching patient physiology to a growing list of available interventions. Further study is needed to determine whether these efforts will lead to more nuanced use of mechanical circulatory support and improved patient outcomes, especially in non-AMI CS. In the meantime, models of care incorporating multidisciplinary decision making, such as shock teams, may improve patient selection and outcomes.

Left atrial enlargement is associated with pulmonary vascular disease in heart failure with preserved ejection fraction.

AIMS: Elevated left atrial (LA) pressure is a pathophysiologic hallmark of heart failure with preserved ejection fraction (HFpEF). Chronically elevated LA pressure leads to LA enlargement, which may impair LA function and increase pulmonary pressures. We sought to evaluate the relationship between LA volume and pulmonary arterial haemodynamics in patients with HFpEF. METHODS AND RESULTS: Data from 85 patients (aged 69 ± 8 years) who underwent exercise right heart catheterization and echocardiography were retrospectively analysed. All had symptoms of heart failure, left ventricular ejection fraction ≥50% and haemodynamic features of HFpEF. Patients were divided into LA volume index-based tertiles (≤34 ml/m2 , >34 to ≤45 ml/m2 , >45 ml/m2 ). A subgroup analysis was performed in patients with recorded LA global reservoir strain (n = 60), with reduced strain defined as ≤24%. Age, sex, body surface area and left ventricular ejection fraction were similar between volume groups. LA volume was associated with blunted increases in cardiac output with exercise (padjusted <0.001), higher resting mean pulmonary artery pressure (padjusted  = 0.003), with similar wedge pressure (padjusted  = 1). Pulmonary vascular resistance (PVR) increased with increasing LA volume (padjusted <0.001). Larger LA volumes featured reduced LA strain (padjusted <0.001), with reduced strain associated with reduced PVR-compliance time (0.34 [0.28-0.40] vs. 0.38 [0.33-0.43], p = 0.03). CONCLUSION: Increasing LA volume may be associated with more advanced pulmonary vascular disease in HFpEF, featuring higher PVR and pulmonary pressures. Reduced LA function, worse at increasing LA volumes, is associated with a disrupted PVR-compliance relationship, further augmenting impaired pulmonary haemodynamics.

Early Cardiopulmonary Fitness after Heart Transplantation as a Determinant of Post-Transplant Survival.

BACKGROUND: Decreased peak oxygen consumption during exercise (peak Vo2) is a well-established prognostic marker for mortality in ambulatory heart failure. After heart transplantation, the utility of peak Vo2 as a marker of post-transplant survival is not well established. METHODS AND RESULTS: We performed a retrospective analysis of adult heart transplant recipients at the Hospital of the University of Pennsylvania who underwent cardiopulmonary exercise testing within a year of transplant between the years 2000 to 2011. Using time-to-event models, we analyzed the hazard of mortality over nearly two decades of follow-up as a function of post-transplant percent predicted peak Vo2 (%Vo2). A total of 235 patients met inclusion criteria. The median post-transplant %Vo2 was 49% (IQR 42 to 60). Each standard deviation (±14%) increase in %Vo2 was associated with a 32% decrease in mortality in adjusted models (HR 0.68, 95% CI 0.53 to 0.87, p = 0.002). A %Vo2 below 29%, 64% and 88% predicted less than 80% survival at 5, 10, and 15 years, respectively. CONCLUSIONS: Post-transplant peak Vo2 is a highly significant prognostic marker for long-term post-transplant survival. It remains to be seen whether decreased peak Vo2 post-transplant is modifiable as a target to improve post-transplant longevity.

Heart waitlist survival in adults with an intra-aortic balloon pump relative to other Status 2, Status 1, and inotrope Status 3 patients.

BACKGROUND: Intra-aortic balloon pump (IABP) utilization has significantly outpaced other Status 2 eligibility criteria for heart transplant. The risk of waitlist mortality of IABP-supported patients relative to other Status 2 listed patients has not been described. METHODS: We performed a retrospective analysis of all adult patients listed Status 2 for heart transplantation under the current U.S. allocation policy, using data from the United Network for Organ Sharing. Patients listed status 1 and status 3 for high-dose inotropes were included for reference. Mortality and waitlist decompensation were modeled as a function of time-varying status in cause-specific Cox survival models. RESULTS: We identified 3638 Status 2 listings, of whom 1676 (46%) were Status 2 due to IABP. Relative to patients supported with IABP, status 2 patients with ventricular tachycardia/fibrillation [VT/VF] (HR 4.0, p < .001), right-or-biventricular assist device configurations (HR 2.3, p = .002), or temporary surgical left ventricular assist devices [LVAD] (HR 2.6, p = .003) had greater risk of waitlist mortality and decompensation. Other Status 2 subgroups had mortality comparable to IABP Status 2. Risk of waitlist mortality and decompensation for IABP Status 2 was similar to Status 3 patients listed for high-dose inotropes (HR 1.2, p = .27) and lower than Status 1 patients (HR 0.7, p = .002). CONCLUSIONS: Waitlist mortality varies significantly by Status 2 eligibility criteria and is highest among patients listed for VT/VF, right-or-biVAD configurations, or temporary surgical LVADs. IABP-supported patients were among those with the lowest Status 2 waitlist mortality risk and comparable to Status 3 inotrope-supported patients.

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.