Beta blockers are associated with lower all-cause mortality among HFpEF patients.

BACKGROUND: The evidence regarding beta blocker (BB) benefit in heart failure with preserved ejection fraction (HFpEF) remains inconclusive, leading to consideration of BB withdrawal in this population. OBJECTIVES: In this study, we retrospectively analyzed the association of BB on all-cause mortality in HFpEF patients. METHODS: This is a single-center retrospective cohort study of 20,206 patients with left ventricular ejection fraction (EF) ≥ 50% who were hospitalized with decompensated HF between January 2011 and March 2020. Survival is reported at 30 days, 1 year, and 3 years. A secondary analysis comparing mortality for patients on BB with additional indications including hypertension (HTN), coronary artery disease (CAD), and atrial fibrillation (AF) was completed. Mortality was compared between patients on BB and additional therapies of spironolactone or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs). RESULTS: BB showed lower all-cause mortality at 30 days, 1 year, and 3 years (p < 0.0001). This association with lower all-cause mortality was validated by a supplementary propensity score-matched analysis. At 3 years, there was significant mortality reduction with addition of BB to either spironolactone (p = 0.0359) or ACEi/ARBs (p < 0.0001). CONCLUSION: In a large single-center retrospective registry, BB use was associated with lower mortality in HFpEF patients with a recent decompensated HF hospitalization. The mortality benefit persisted in those treated with spironolactone or ACEi/ARBs, and in those with AF. This provocative data further highlights the uncertainty of the benefit of BB use in this cohort and calls for re-consideration of BB withdrawal, especially in those tolerating it well, without conclusive, large, and randomized trials showing lack of benefit or harm.

Impact of post-transplant stroke and subsequent functional independence on outcomes following heart transplantation under the 2018 United States heart allocation system.

BACKGROUND: This study evaluates the clinical trends, risk factors, and effects of post-transplant stroke and subsequent functional independence on outcomes following orthotopic heart transplantation under the 2018 heart allocation system. METHODS: The United Network for Organ Sharing registry was queried to identify adult recipients from October 18, 2018 to December 31, 2021. The cohort was stratified into 2 groups with and without post-transplant stroke. The incidence of post-transplant stroke was compared before and after the allocation policy change. Outcomes included post-transplant survival and complications. Multivariable logistic regression was performed to identify risk factors for post-transplant stroke. Sub-analysis was performed to evaluate the impact of functional independence among recipients with post-transplant stroke. RESULTS: A total of 9,039 recipients were analyzed in this study. The incidence of post-transplant stroke was higher following the policy change (3.8% vs 3.1%, p = 0.017). Thirty-day (81.4% vs 97.7%) and 1-year (66.4% vs 92.5%) survival rates were substantially lower in the stroke cohort (p < 0.001). The stroke cohort had a higher rate of post-transplant renal failure, longer hospital length of stay, and worse functional status. Multivariable analysis identified extracorporeal membrane oxygenation, durable left ventricular assist device, blood type O, and redo heart transplantation as strong predictors of post-transplant stroke. Preserved functional independence considerably improved 30-day (99.2% vs 61.2%) and 1-year (97.7% vs 47.4%) survival rates among the recipients with post-transplant stroke (p < 0.001). CONCLUSIONS: There is a higher incidence of post-transplant stroke under the 2018 allocation system, and it is associated with significantly worse post-transplant outcomes. However, post-transplant stroke recipients with preserved functional independence have improved survival, similar to those without post-transplant stroke.

Improved waitlist and comparable post-transplant outcomes in simultaneous heart-kidney transplantation under the 2018 heart allocation system.

OBJECTIVE: This study aimed to investigate the clinical trends and the impact of the 2018 heart allocation policy change on both waitlist and post-transplant outcomes in simultaneous heart-kidney transplantation in the United States. METHODS: The United Network for Organ Sharing registry was queried to compare adult patients before and after the allocation policy change. This study included 2 separate analyses evaluating the waitlist and post-transplant outcomes. Multivariable analyses were performed to determine the 2018 allocation system's risk-adjusted hazards for 1-year waitlist and post-transplant mortality. RESULTS: The initial analysis investigating the waitlist outcomes included 1779 patients listed for simultaneous heart-kidney transplantation. Of these, 1075 patients (60.4%) were listed after the 2018 allocation policy change. After the policy change, the waitlist outcomes significantly improved with a shorter waitlist time, lower likelihood of de-listing, and higher likelihood of transplantation. In the subsequent analysis investigating the post-transplant outcomes, 1130 simultaneous heart-kidney transplant recipients were included, where 738 patients (65.3%) underwent simultaneous heart-kidney transplantation after the policy change. The 90-day, 6-month, and 1-year post-transplant survival and complication rates were comparable before and after the policy change. Multivariable analyses demonstrated that the 2018 allocation system positively impacted risk-adjusted 1-year waitlist mortality (sub-hazard ratio, 0.66, 95% CI, 0.51-0.85, P < .001), but it did not significantly impact risk-adjusted 1-year post-transplant mortality (hazard ratio, 1.03; 95% CI, 0.72-1.47, P = .876). CONCLUSIONS: This study demonstrates increased rates of simultaneous heart-kidney transplantation with a shorter waitlist time after the 2018 allocation policy change. Furthermore, there were improved waitlist outcomes and comparable early post-transplant survival after simultaneous heart-kidney transplantation under the 2018 allocation system.

Reduction of HLA donor specific antibodies in heart transplant patients treated with proteasome inhibitors for antibody mediated rejection.

In this project, we describe proteasome inhibitor (PI) treatment of antibody-mediated rejection (AMR) in heart transplantation (HTX). From January 2018 to September 2021, 10 patients were treated with PI for AMR: carfilzomib (CFZ) n = 8; bortezomib (BTZ) n = 2. Patients received 1-3 cycles of PI. All patients had ≥1 strong donor-specific antibody (DSA) (mean fluorescence intensity [MFI] > 8000) in undiluted serum. Most DSAs (20/21) had HLA class II specificity. The MFI of strong DSAs had a median reduction of 56% (IQR = 13%-89%) in undiluted serum and 92% (IQR = 53%-95%) at 1:16 dilution. Seventeen DSAs in seven patients were reduced > 50% at 1:16 dilution after treatment. Four DSAs from three patients did not respond. DSA with MFI > 8000 at 1:16 dilution was less responsive to treatment. 60% (6/10) patients presented with graft dysfunction; 4/6 recovered ejection fraction > 40% after treatment. Pathologic AMR was resolved in 5/7 (71.4%) of patients within 1 year after treatment. 9/10 (90%) patients survived to 1 year after AMR diagnosis. Using PI in AMR resulted in significant DSA reduction with some resolution of graft dysfunction. Larger studies are needed to evaluate PI for AMR.

Implementing the EXPEDITE parenteral induction protocol: Rapid parenteral treprostinil titration and transition to oral treprostinil.

Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real-world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up-titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross-titration in an inpatient setting (median: 2 days) or gradual cross-titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short-term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil.

Clinical trends, risk factors, and temporal effects of post-transplant dialysis on outcomes following orthotopic heart transplantation in the 2018 United States heart allocation system.

BACKGROUND: This study evaluated the current clinical trends, risk factors, and temporal effects of post-transplant dialysis on outcomes following orthotopic heart transplantation after the 2018 United States adult heart allocation policy change. METHODS: The United Network for Organ Sharing (UNOS) registry was queried to analyze adult orthotopic heart transplant recipients after the October 18, 2018 heart allocation policy change. The cohort was stratified according to the need for post-transplant de novo dialysis. The primary outcome was survival. Propensity score-matching was performed to compare the outcomes between 2 similar cohorts with and without post-transplant de novo dialysis. The impact of post-transplant dialysis chronicity was evaluated. Multivariable logistic regression was performed to identify risk factors for post-transplant dialysis. RESULTS: A total of 7,223 patients were included in this study. Out of these, 968 patients (13.4%) developed post-transplant renal failure requiring de novo dialysis. Both 1-year (73.2% vs 94.8%) and 2-year (66.3% vs 90.6%) survival rates were lower in the dialysis cohort (p < 0.001), and the lower survival rates persisted in a propensity-matched comparison. Recipients requiring only temporary post-transplant dialysis had significantly improved 1-year (92.5% vs 71.6%) and 2-year (86.6 % vs 52.2%) survival rates compared to the chronic post-transplant dialysis group (p < 0.001). Multivariable analysis demonstrated low pretransplant estimated glomerular filtration (eGFR) and bridge with extracorporeal membrane oxygenation (ECMO) were strong predictors of post-transplant dialysis. CONCLUSIONS: This study demonstrates that post-transplant dialysis is associated with significantly increased morbidity and mortality in the new allocation system. Post-transplant survival is affected by the chronicity of post-transplant dialysis. Low pretransplant eGFR and ECMO are strong risk factors for post-transplant dialysis.

Basiliximab induction versus no induction in adult heart transplantation.

BACKGROUND: Induction immunosuppression in heart transplant recipients varies greatly by center. Basiliximab (BAS) is the most commonly used induction immunosuppressant but has not been shown to reduce rejection or improve survival. The objective of this retrospective study was to compare rejection, infection, and mortality within the first 12 months following heart transplant in patients who received BAS or no induction. METHODS: This was a retrospective cohort study of adult heart transplant recipients given BAS or no induction from January 1, 2017 to May 31, 2021. The primary endpoint was incidence of treated acute cellular rejection (ACR) at 12-months post-transplant. Secondary endpoints included ACR at 90 days post-transplant, incidence of antibody-mediated rejection (AMR) at 90 days and 1 year, incidence of infection, and all-cause mortality at 1 year. RESULTS: A total of 108 patients received BAS, and 26 patients received no induction within the specified timeframe. There was a lower incidence of ACR within the first year in the BAS group compared to the no induction group (27.7 vs. 68.2%, p < .002). BAS was independently associated with a lower probability of having a rejection event during the first 12-months post-transplant (hazard ratio (HR) .285, 95% confidence interval [CI] .142-.571, p < .001). There was no difference in the rate of infection and in mortality after hospital discharge at 1-year post-transplant (6% vs. 0%, p = .20). CONCLUSION: BAS appears to be associated with greater freedom from rejection without an increase in infections. BAS may be a preferred to a no induction strategy in patients undergoing heart transplantation.

Left ventricular assist device bridging to heart transplantation: Comparison of temporary versus durable support.

BACKGROUND: Since the revision of the United States heart allocation system, increasing use of mechanical circulatory support has been observed as a means to support acutely ill patients. We sought to compare outcomes between patients bridged to orthotopic heart transplantation (OHT) with either temporary (t-LVAD) or durable left ventricular assist devises (d-LVAD) under the revised system. METHODS: The United States Organ Network database was queried to identify all adult OHT recipients who were bridged to transplant with either an isolated t-LVAD or d-LVAD from 10/18/2018 to 9/30/2020. The primary outcome was 1-year post-transplant survival. Predictors of mortality were also modeled, and national trends of LVAD bridging were examined across the study period. RESULTS: About 1,734 OHT recipients were analyzed, 1,580 (91.1%) bridged with d-LVAD and 154 (8.9%) bridged with t-LVAD. At transplant, the t-LVAD cohort had higher total bilirubin levels and greater prevalence of pre-transplant intravenous inotrope usage and mechanical ventilation. Median waitlist time was also shorter for t-LVAD. At 1 year, there was a non-significant trend of increased survival in the t-LVAD cohort (94.8% vs 90.1%; p = 0.06). After risk adjustment, d-LVAD was associated with a 4-fold hazards for 1-year mortality (hazard ratio 3.96, 95% confidence interval 1.42-11.03; p = 0.009). From 2018 to 2021, t-LVAD bridging increased, though d-LVAD remained a more common bridging strategy. CONCLUSIONS: Since the 2018 allocation change, there has been a steady increase in t-LVAD usage as a bridge to OHT. Overall, patients bridged with these devices appear to have least equivalent 1-year survival compared to those bridged with d-LVAD.

Elucidating the Clinical Implications and Pathophysiology of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Call to Action: A Science Advisory From the American Heart Association.

This science advisory focuses on the need to better understand the epidemiology, pathophysiology, and treatment of pulmonary hypertension in patients with heart failure with preserved ejection fraction. This clinical phenotype is important because it is common, is strongly associated with adverse outcomes, and lacks evidence-based therapies. Our goal is to clarify key knowledge gaps in pulmonary hypertension attributable to heart failure with preserved ejection fraction and to suggest specific, actionable scientific directions for addressing such gaps. Areas in need of additional investigation include refined disease definitions and interpretation of hemodynamics, as well as greater insights into noncardiac contributors to pulmonary hypertension risk, optimized animal models, and further molecular studies in patients with combined precapillary and postcapillary pulmonary hypertension. We highlight translational approaches that may provide important biological insight into pathophysiology and reveal new therapeutic targets. Last, we discuss the current and future landscape of potential therapies for patients with heart failure with preserved ejection fraction and pulmonary vascular dysfunction, including considerations of precision medicine, novel trial design, and device-based therapies, among other considerations. This science advisory provides a synthesis of important knowledge gaps, culminating in a collection of specific research priorities that we argue warrant investment from the scientific community.

Understanding the Pathobiology of Pulmonary Hypertension Due to Left Heart Disease.

The development of pulmonary hypertension (PH) is common and has adverse prognostic implications in patients with heart failure due to left heart disease (LHD), and thus far, there are no known treatments specifically for PH-LHD, also known as group 2 PH. Diagnostic thresholds for PH-LHD, and clinical classification of PH-LHD phenotypes, continue to evolve and, therefore, present a challenge for basic and translational scientists actively investigating PH-LHD in the preclinical setting. Furthermore, the pathobiology of PH-LHD is not well understood, although pulmonary vascular remodeling is thought to result from (1) increased wall stress due to increased left atrial pressures; (2) hemodynamic congestion-induced decreased shear stress in the pulmonary vascular bed; (3) comorbidity-induced endothelial dysfunction with direct injury to the pulmonary microvasculature; and (4) superimposed pulmonary arterial hypertension risk factors. To ultimately be able to modify disease, either by prevention or treatment, a better understanding of the various drivers of PH-LHD, including endothelial dysfunction, abnormalities in vascular tone, platelet aggregation, inflammation, adipocytokines, and systemic complications (including splanchnic congestion and lymphatic dysfunction) must be further investigated. Here, we review the diagnostic criteria and various hemodynamic phenotypes of PH-LHD, the potential biological mechanisms underlying this disorder, and pressing questions yet to be answered about the pathobiology of PH-LHD.

Pulmonary Hypertension and Right Ventricular Failure: Lung Transplant Versus Heart-Lung Transplant.

Pulmonary arterial hypertension is a highly morbid disease with limited treatment options that improve survival and currently the only curative treatment is transplantation. There is a small body of literature comparing the efficacy of lung and heart-lung transplantation in this population. The bulk of evidence suggests that most patients with severe right ventricular failure undergoing transplant will have recovery of right ventricular function after lung transplantation. Existing data suggest that, in the absence of complex congenital heart disease or significant left ventricular dysfunction, double-lung transplant is the surgical procedure of choice.

Observational Study of Noninvasive Venous Waveform Analysis to Assess Intracardiac Filling Pressures During Right Heart Catheterization.

BACKGROUND: Outpatient monitoring and management of patients with heart failure (HF) reduces hospitalizations and health care costs. However, the availability of noninvasive approaches to assess congestion is limited. Noninvasive venous waveform analysis (NIVA) uses a unique physiologic signal, the morphology of the venous waveform, to assess intracardiac filling pressures. This study is a proof of concept analysis of the correlation between NIVA value and pulmonary capillary wedge pressure (PCWP) and the ability of the NIVA value to predict PCWP > 18 mmHg in subjects undergoing elective right heart catheterization (RHC). PCWP was also compared across common clinical correlates of congestion. METHODS AND RESULTS: A prototype NIVA device, which consists of a piezoelectric sensor placed over the skin on the volar aspect of the wrist, connected to a data-capture control box, was used to collect venous waveforms in 96 patients during RHC. PCWP was collected at end-expiration by an experienced cardiologist. The venous waveform signal was transformed to the frequency domain (Fourier transform), where a ratiometric algorithm of the frequencies of the pulse rate and its harmonics was used to derive a NIVA value. NIVA values were successfully captured in 83 of 96 enrolled patients. PCWP ranged from 4-40 mmHg with a median of 13 mmHg. NIVA values demonstrated a linear correlation with PCWP (r = 0.69, P < 0.05). CONCLUSIONS: This observational proof-of-concept study using a prototype NIVA device demonstrates a moderate correlation between NIVA value and PCWP in patients undergoing RHC. NIVA, thus, represents a promising developing technology for noninvasive assessment of congestion in spontaneously breathing patients.

Association of Mild Echocardiographic Pulmonary Hypertension With Mortality and Right Ventricular Function.

Importance: Current guidelines recommend evaluation for echocardiographically estimated right ventricular systolic pressure (RVSP) greater than 40 mm Hg; however, this threshold does not capture all patients at risk. Objectives: To determine if mild echocardiographic pulmonary hypertension (ePH) is associated with reduced right ventricular (RV) function and increased risk of mortality. Design, Setting, and Participants: In this cohort study, electronic health record data of patients who were referred for echocardiography at Vanderbilt University Medical Center, Nashville, Tennessee, from March 1997 to February 2014 and had recorded estimates of RVSP values were studied. Data were analyzed from February 2017 to May 2019. Exposures: Mild ePH was defined as an RVSP value of 33 to 39 mm Hg. Right ventricular function was assessed using tricuspid annular plane systolic excursion (TAPSE), and RV-pulmonary arterial coupling was measured using the ratio of TAPSE to RVSP. Main Outcomes and Measures: Associations of mild ePH with mortality adjusted for relevant covariates were examined using Cox proportional hazard models with restricted cubic splines. Results: Of the 47 784 included patients, 26 758 of 47 771 (56.0%) were female and 6040 of 44 763 (13.5%) were black, and the mean (SD) age was 59 (18) years. Patients with mild ePH had worse RV function compared with those with no ePH (mean [SD] TAPSE, 2.0 [0.6] cm vs 2.2 [0.5] cm; P < .001) and nearly double the prevalence of RV dysfunction (32.6% [92 of 282] vs 16.7% [170 of 1015]; P < .001). Compared with patients with RVSP less than 33 mm Hg, those with mild ePH also had reduced RV-pulmonary arterial coupling (mean [SD] ratio of TAPSE to RVSP, 0.55 [0.18] mm/mm Hg vs 0.93 [0.39] mm/mm Hg; P < .001). An increase in adjusted mortality began at an RVSP value of 27 mm Hg (hazard ratio, 1.32; 95% CI, 1.02-1.70). Female sex was associated with increased mortality risk at any given RVSP value. Conclusions and Relevance: Mild ePH was associated with RV dysfunction and worse RV-pulmonary arterial coupling in a clinical population seeking care. Future studies are needed to identify patients with mild ePH who are susceptible to adverse outcomes.

Early intervention: should we conduct therapeutic trials for mild pulmonary hypertension before onset of symptoms?

Pulmonary arterial hypertension (PAH) is a rare disease that carries a poor prognosis. For 45 years, the definition of pulmonary hypertension (PH) has been a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, based on expert opinion. Recent data indicate that the mortality risk starts in the mPAP range of 21-24 mmHg, which has recently been reflected in the World Symposium on PH consensus document defining PH as a mPAP > 20 mmHg. The mortality associated with these lower levels of pulmonary pressures suggests that these values reflect a more advanced disease stage than previously recognized. It is unknown whether interventions targeting patients with mPAP values in the range of 21-24 mmHg in the absence of left ventricular or hypoxic lung disease are of clinical benefit. Here we present historical perspective on the hemodynamic definition of PH, discuss recent epidemiologic data, and outline obstacles to enrolling and evaluating response to therapy in mild PAH patients, as well as potentially useful study designs.

Unbiased Phenome-Wide Association Studies of Red Cell Distribution Width Identifies Key Associations with Pulmonary Hypertension.

Rationale: Red cell distribution width (RDW) is a prognostic factor in many diseases; however, its clinical utility remains limited because the relative value of RDW as a biomarker across disease states has not been established. Objectives: To establish an unbiased RDW disease hierarchy to guide the clinical use of RDW and to assess its relationship to cardiovascular hemodynamic and structural parameters. Methods: We performed phenome-wide association studies for RDW in discovery and replication cohorts derived from a deidentified electronic health record in nonanemic individuals. RDW values obtained within 30 days of echocardiogram or right heart catheterization were tested for association with structural and hemodynamic variables. Results: RDW was associated with 263 phenotypes in both men and women in the discovery cohort (n = 121,530), 48 of which replicated in an independent cohort (n = 2,039). The strongest associations were observed with pulmonary arterial hypertension (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.9-2.3), chronic pulmonary heart disease (OR, 2.0; 95% CI, 1.9-2.2), and congestive heart failure (OR, 1.9; 95% CI, 1.8-2.0); P < 1 × 10-74 for all. By echocardiography, RDW was higher in the setting of right ventricular dysfunction than left ventricular dysfunction (P < 0.001). Measured invasively, mean pulmonary arterial pressure was associated with RDW (21 vs. 33 mm Hg at 25th vs. 75th percentile RDW; P < 1 × 10-7) and remained strongly significant even when controlling for mean pulmonary capillary wedge pressure (21 vs. 29 mm Hg at 25th vs. 75th percentile RDW; P < 1 × 10-7). Conclusions: Among 1,364 coded medical conditions, increased RDW was strongly associated with pulmonary hypertension and heart failure. Hemodynamic and echocardiographic phenotyping confirmed these associations and underscored that the most clinically relevant phenotype associated with RDW was pulmonary hypertension. These hypothesis-generating findings highlight the potential shared pathophysiology of pulmonary hypertension and elevated RDW. Elevated RDW in the absence of anemia should alert clinicians to the potential for underlying cardiopulmonary disease.

Right-to-left ventricular end diastolic diameter ratio in severe sepsis and septic shock.

PURPOSE: The ratio of right ventricular end-diastolic diameter (EDD) to left ventricular EDD (RV/LV) is a measure predictive of right ventricular failure. We hypothesized that an increase in RV/LV would be associated with poor prognosis in severe sepsis and septic shock. MATERIALS AND METHODS: This is a retrospective chart review of patients with severe sepsis and septic shock admitted to a medical intensive care unit (ICU) at a single tertiary care hospital. Patients were identified by ICD-9 codes: 995.92 for severe sepsis and 785.52 for septic shock; and had to have an echocardiogram within 48 h of ICU admission. Increased RV/LV was defined as RV/LV ≥ 0.9. Left and right-sided chamber dimensions were measured according to American Society of Echocardiography guidelines. RESULTS: We included 146 consecutive ICU patients admitted with septic shock (72) or severe sepsis (74). There was no significant difference in ICU mortality in patients with RV/LV ≥ 0.9 versus RV/LV < 0.9 (p = .49). CONCLUSIONS: An increased RV/LV does not predict mortality in severe sepsis or septic shock.