Variation in Hemodynamic Assessment and Interpretation: A Call to Standardize the Right Heart Catheterization.

BACKGROUND: Invasive hemodynamic measurement via right heart catheterization has shown divergent data in its role in the treatment of patients with heart failure (HF) and cardiogenic shock. We hypothesized that variation in data acquisition technique and interpretation might contribute to these observations. We sought to assess differences in hemodynamic acquisition and interpretation by operator subspecialty as well as level of experience. METHODS AND RESULTS: Individual-level responses to how physicians both collect and interpret hemodynamic data at the time of right heart catheterization was solicited via a survey distributed to international professional societies in HF and interventional cardiology. Data were stratified both by operator subspecialty (HF specialists or interventional cardiologists [IC]) and operator experience (early career [≤10 years from training] or late career [>10 years from training]) to determine variations in clinical practice. For the sensitivity analysis, we also look at differences in each subgroup. A total of 261 responses were received. There were 141 clinicians (52%) who self-identified as HF specialists, 99 (38%) identified as IC, and 20 (8%) identified as other. There were 142 early career providers (54%) and late career providers (119 [46%]). When recording hemodynamic values, there was considerable variation in practice patterns, regardless of subspecialty or level of experience for the majority of the intracardiac variables. There was no agreement or mild agreement among HF and IC as to when to record right atrial pressures or pulmonary capillary wedge pressures. HF cardiologists were more likely to routinely measure both Fick and thermodilution cardiac output compared with IC (51% vs 29%, P < .001), something mirrored in early career vs later career cardiologists. CONCLUSIONS: Significant variation exists between the acquisition and interpretation of right heart catheterization measurements between HF and IC, as well as those early and late in their careers. With the growth of the heart team approach to management of patients in cardiogenic shock, standardization of both assessment and management practices is needed.

Novel Acoustic Biomarker of Quality of Life in Left Ventricular Assist Device Recipients.

Background Although technological advances to pump design have improved survival, left ventricular assist device (LVAD) recipients experience variable improvements in quality of life. Methods for optimizing LVAD support to improve quality of life are needed. We investigated whether acoustic signatures obtained from digital stethoscopes can predict patient-centered outcomes in LVAD recipients. Methods and Results We followed precordial sounds over 6 months in 24 LVAD recipients (8 HeartWare HVAD™, 16 HeartMate 3 [HM3]). Subjects recorded their precordial sounds with a digital stethoscope and completed a Kansas City Cardiomyopathy Questionnaire weekly. We developed a novel algorithm to filter LVAD sounds from recordings. Unsupervised clustering of LVAD-mitigated sounds revealed distinct groups of acoustic features. Of 16 HM3 recipients, 6 (38%) had a unique acoustic feature that we have termed the pulse synchronized sound based on its temporal association with the artificial pulse of the HM3. HM3 recipients with the pulse synchronized sound had significantly better Kansas City Cardiomyopathy Questionnaire scores at baseline (median, 89.1 [interquartile range, 86.2-90.4] versus 66.1 [interquartile range, 31.1-73.7]; P=0.03) and over the 6-month study period (marginal mean, 77.6 [95% CI, 66.3-88.9] versus 59.9 [95% CI, 47.9-70.0]; P<0.001). Mechanistically, the pulse synchronized sound shares acoustic features with patient-derived intrinsic sounds. Finally, we developed a machine learning algorithm to automatically detect the pulse synchronized sound within precordial sounds (area under the curve, 0.95, leave-one-subject-out cross-validation). Conclusions We have identified a novel acoustic biomarker associated with better quality of life in HM3 LVAD recipients, which may provide a method for assaying optimized LVAD support.

Cardiac computed tomography improves the identification of cardiomechanical complications among patients with suspected left ventricular assist device malfunction.

BACKGROUND: Left ventricular assist devices (LVAD) are increasingly used for durable mechanical circulatory support in advanced heart failure. While LVAD therapy provides substantial improvement in mortality and quality of life, long-term therapy confers increased risk for device complications. We evaluated if cardiac computed tomography (CCT) improves the detection of cardiomechanical complications among patients with LVAD and suspected device malfunction. METHODS: In this study, we compared the diagnostic performance of CCT and transthoracic echocardiography (TTE) for the identification of cardiomechanical LVAD complications, including thrombus or neointimal hyperplasia, inflow cannula malposition with dynamic obstruction, fixed outflow obstruction, device infection, and severe aortic regurgitation. Complications were confirmed with surgical evaluation, pathologic assessment, or response to therapeutic intervention. RESULTS: Among 58 LVAD patients, who underwent CCT and TTE for suspected LVAD dysfunction, there were 49 confirmed cardiomechanical LVAD complications among 43 (74.1%) patients. The most common LVAD complication was thrombus or neointimal hyperplasia (65.3%), followed by dynamic obstruction (26.5%). Individually, CCT identified 29 of the 49 (59.2%) confirmed LVAD cardiomechanical complications, whereas TTE alone identified a complication in 11 cases (22.4%). However, diagnostic performance was greatest when the two modalities were used in combination, yielding a sensitivity of 67%, specificity of 93%, PPV of 97%, NPV of 47% and diagnostic accuracy of 73%. CONCLUSION: The novel and complementary use of CCT with TTE for the evaluation of suspected device malfunction improves the accurate identification of cardiomechanical LVAD complication compared to either modality alone.

Clinical applications of machine learning in the diagnosis, classification, and prediction of heart failure.

Machine learning and artificial intelligence are generating significant attention in the scientific community and media. Such algorithms have great potential in medicine for personalizing and improving patient care, including in the diagnosis and management of heart failure. Many physicians are familiar with these terms and the excitement surrounding them, but many are unfamiliar with the basics of these algorithms and how they are applied to medicine. Within heart failure research, current applications of machine learning include creating new approaches to diagnosis, classifying patients into novel phenotypic groups, and improving prediction capabilities. In this paper, we provide an overview of machine learning targeted for the practicing clinician and evaluate current applications of machine learning in the diagnosis, classification, and prediction of heart failure.

Association between systolic ejection time and outcomes in heart failure by ejection fraction.

AIMS: Worsening heart failure (HF) is associated with shorter left ventricular systolic ejection time (SET), but there are limited data describing the relationship between SET and clinical outcomes. Thus, the objective was to describe the association between SET and clinical outcomes in an ambulatory HF population irrespective of ejection fraction (EF). METHODS AND RESULTS: We identified ambulatory patients with HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) who had an outpatient transthoracic echocardiogram performed between August 2008 and July 2010 at a tertiary referral centre. Multivariable logistic regression was used to evaluate the association between SET and 1-year outcomes. A total of 545 HF patients (171 HFrEF, 374 HFpEF) met eligibility criteria. Compared with HFpEF, HFrEF patients were younger [median age 60 years (25th-75th percentiles 50-69) vs. 64 years (25th-75th percentiles 53-74], with fewer females (30% vs. 56%) and a similar percentage of African Americans (36% vs. 35%). Median (25th-75th percentiles) EF with HFrEF was 30% (25-35%) and with HFpEF was 54% (48-58%). Median SET was shorter (280 ms vs. 315 ms, P < 0.001), median pre-ejection period was longer (114 ms vs. 89 ms, P < 0.001), and median relaxation time was shorter (78.7 ms vs. 93.3 ms, P < 0.001) among patients with HFrEF vs. HFpEF. Death or HF hospitalization occurred in 26.9% (n = 46) HFrEF and 11.8% (n = 44) HFpEF patients. After adjustment, longer SET was associated with lower odds of the composite of death or HF hospitalization at 1 year among HFrEF but not HFpEF patients. CONCLUSION: Longer SET is independently associated with improved outcomes among HFrEF patients but not HFpEF patients, supporting a potential role for normalizing SET as a therapeutic strategy with systolic dysfunction.

Heart Transplantation and Mechanical Circulatory Support in Adults with Congenital Heart Disease.

PURPOSE OF REVIEW: To assess current management strategies for advanced heart failure in adults with congenital heart disease, including heart transplantation and mechanical circulatory support. RECENT FINDINGS: Current data demonstrate that adults with CHD generally experience higher short-term mortality after heart transplantation and MCS implantation, but enjoy superior long-term survival. Such patients are nonetheless less likely to receive a transplant than non-ACHD peers due to a variety of factors, including lack of applicability of current listing criteria to HF in ACHD. MCS is underutilized in ACHD, but provides similar quality of life benefits for ACHD and non-ACHD patients alike. Heart failure in ACHD is complex and difficult to treat, and both heart transplantation and mechanical circulatory support are often challenging to implement in this patient population. However, long-term results are encouraging, and existing data supports increasing use of MCS and transplant earlier in their disease course. Multidisciplinary care is critical to success in these complex patients.

Medical Management of Patients With a Left Ventricular Assist Device for the Non-Left Ventricular Assist Device Specialist.

More than 2,400 continuous-flow left ventricular assist devices (LVADs) are implanted each year in the United States alone. Both the number of patients living with LVADs and the life expectancy of these patients are increasing. As a result, patients with LVADs are increasingly encountered by non-LVAD specialists who do not have training in managing advanced heart failure for general medical care, cardiovascular procedures, and other subspecialty care. An understanding of the initial evaluation and management of patients with LVADs is now an essential skill for many health care providers. In this State-of-the-Art Review, we discuss current LVAD technology, summarize our clinical experience with LVADs, and review the current data for the medical management of patients living with LVADs.

Antihyperglycemic Medication Use Among Medicare Beneficiaries With Heart Failure, Diabetes Mellitus, and Chronic Kidney Disease.

BACKGROUND: Diabetes mellitus, heart failure (HF), and chronic kidney disease are common comorbidities, but overall use and safety of antihyperglycemic medications (AHMs) among patients with these comorbidities are poorly understood. METHODS AND RESULTS: Using Get With the Guidelines-Heart Failure and linked Medicare Part D data, we assessed AHM use within 90 days of hospital discharge among HF patients with diabetes mellitus discharged from Get With the Guidelines-Heart Failure hospitals between January 1, 2006, and October 1, 2011. We further summarized use by renal function and assessed renal contraindicated AHM use for patients with estimated glomerular filtration rate <30 mL/min/1.73m(2). Among 8791 patients meeting inclusion criteria, the median age was 77 (interquartile range 71-83), 62.3% were female, median body mass index was 29.7 (interquartile range 25.5-35.3), median hemoglobin A1c was 6.8 (interquartile range 6.2-7.8), and 34% had ejection fraction <40%. 74.9% of patients filled a prescription for an AHM, with insulin (39.5%), sulfonylureas (32.4%), and metformin (17%) being the most commonly used AHMs. Insulin use was higher and sulfonylurea/metformin use was lower among patients with lower renal function classes. Among 1512 patients with estimated glomerular filtration rate <30 mL/min/1.73m(2), 35.4% filled prescriptions for renal contraindicated AHMs per prescribing information, though there was a trend toward lower renal contraindicated AHM use over time (Cochran-Mantel-Haenszel row-mean score test P=0.048). Although use of other AHMs was low overall, thiazolidinediones were used in 6.6% of HF patients, and dipeptidyl peptidase-4 inhibitors were used in 5.1%, with trends for decreasing thiazolidinedione use and increased dipeptidyl peptidase-4 inhibitor use over time (P<0.001). CONCLUSIONS: Treatment of diabetes mellitus in patients with HF and chronic kidney disease is complex, and these patients are commonly treated with renal contraindicated AHMs, including over 6% receiving a thiazolidinedione, despite known concerns regarding HF. More research regarding safety and efficacy of various AHMs among HF patients is needed.

Novel Oral Anticoagulant Use Among Patients With Atrial Fibrillation Hospitalized With Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND: Novel oral anticoagulants (NOACs) have been shown to be at least as good as warfarin for preventing stroke or transient ischemic attack in patients with atrial fibrillation, yet diffusion of these therapies and patterns of use among atrial fibrillation patients with ischemic stroke and transient ischemic attack have not been well characterized. METHODS AND RESULTS: Using data from Get With The Guidelines-Stroke, we identified a cohort of 61 655 atrial fibrillation patients with ischemic stroke or transient ischemic attack hospitalized between October 2010 and September 2012 and discharged on warfarin or NOAC (either dabigatran or rivaroxaban). Multivariable logistic regression was used to identify factors associated with NOAC versus warfarin therapy. In our study population, warfarin was prescribed to 88.9%, dabigatran to 9.6%, and rivaroxaban to 1.5%. NOAC use increased from 0.04% to a 16% to 17% plateau during the study period, although anticoagulation rates among eligible patients did not change appreciably (93.7% versus 94.1% from first quarter 2011 to second quarter 2012), suggesting a trend of switching from warfarin to NOACs rather than increased rates of anticoagulation among eligible patients. Several bleeding risk factors and CHA2DS2-VASc scores were lower among those discharged on NOAC versus warfarin therapy (47.9% versus 40.9% with CHA2DS2-VASc ≤5, P<0.001 for difference in CHA2DS2-VASc). CONCLUSIONS: NOACs have had modest but growing uptake over time among atrial fibrillation patients hospitalized with stroke or transient ischemic attack and are prescribed to patients with lower stroke risk compared with warfarin.

Hypotension during hospitalization for acute heart failure is independently associated with 30-day mortality: findings from ASCEND-HF.

BACKGROUND: Outcomes associated with episodes of hypotension while hospitalized with acute decompensated heart failure are not well understood. METHODS AND RESULTS: Using data from Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), we assessed factors associated with in-hospital hypotension and subsequent 30-day outcomes. Patients were classified as having symptomatic or asymptomatic hypotension. Multivariable logistic regression was used to determine factors associated with in-hospital hypotension, and Cox proportional hazards models were used to assess the association between hypotension and 30-day outcomes. We also tested for treatment interaction with nesiritide on 30-day outcomes and the association between in-hospital hypotension and renal function at hospital discharge. Overall, 1555 of 7141 (21.8%) patients had an episode of hypotension, of which 73.1% were asymptomatic and 26.9% were symptomatic. Factors strongly associated with in-hospital hypotension included randomization to nesiritide (odds ratio, 1.98; 95% confidence interval [CI], 1.76-2.23; P<0.001), chronic metolazone therapy (odds ratio, 1.74; 95% CI, 1.17-2.60; P<0.001), and baseline orthopnea (odds ratio, 1.31; 95% CI, 1.13-1.52; P=0.001) or S3 gallop (odds ratio, 1.21; 95% CI, 1.06-1.40; P=0.006). In-hospital hypotension was associated with increased hazard of 30-day mortality (hazard ratio, 2.03; 95% CI, 1.57-2.61; P<0.001), 30-day heart failure hospitalization or mortality (hazard ratio, 1.58; 95% CI, 1.34-1.86; P<0.001), and 30-day all-cause hospitalization or mortality (hazard ratio, 1.40; 95% CI, 1.22-1.61; P<0.001). Nesiritide had no interaction on the relationship between hypotension and 30-day outcomes (interaction P=0.874 for death, P=0.908 for death/heart failure hospitalization, P=0.238 death/all-cause hospitalization). CONCLUSIONS: Hypotension while hospitalized for acute decompensated heart failure is an independent risk factor for adverse 30-day outcomes, and its occurrence highlights the need for modified treatment strategies. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852.

Targeting anti-beta-1-adrenergic receptor antibodies for dilated cardiomyopathy.

Anti-beta-1-adrenergic receptor antibodies (anti-ß1AR Abs) have long been implicated in the pathogenesis of dilated cardiomyopathy (DCM). It is believed that these autoantibodies bind to and constitutively stimulate the ß1AR to promote pathological cardiac remodelling and ß1AR desensitization and downregulation. The prevalence of anti-ß1AR Abs in patients with DCM ranges from 26% to 60%, and the presence of these autoantibodies correlates with a poor prognosis. Several small studies have shown improvements in functional status, haemodynamics, and biomarkers of heart failure upon removal or neutralization of these antibodies from the sera of affected patients. Traditionally, removal of anti-ß1AR Abs required immunoadsorption therapy with apheresis columns directed against human immunoglobulins (Igs) and subsequent i.v. Ig infusion, thereby essentially performing a plasma exchange transfusion. However, recent advances have allowed the development of small peptides and nucleotide sequences that specifically target and neutralize anti-ß1AR Abs, providing a hopeful avenue for future drug development to treat DCM. Herein, we briefly review the clinical literature of therapy directed against anti-ß1AR Abs and highlight the opportunity for further research and development in this area.

beta-Arrestin mediates beta1-adrenergic receptor-epidermal growth factor receptor interaction and downstream signaling.

beta1-Adrenergic receptor (beta1AR) stimulation confers cardioprotection via beta-arrestin-de pend ent transactivation of epidermal growth factor receptors (EGFRs), however, the precise mechanism for this salutary process is unknown. We tested the hypothesis that the beta1AR and EGFR form a complex that differentially directs intracellular signaling pathways. beta1AR stimulation and EGF ligand can each induce equivalent EGFR phosphorylation, internalization, and downstream activation of ERK1/2, but only EGF ligand causes translocation of activated ERK to the nucleus, whereas beta1AR-stimulated/EGFR-transactivated ERK is restricted to the cytoplasm. beta1AR and EGFR are shown to interact as a receptor complex both in cell culture and endogenously in human heart, an interaction that is selective and undergoes dynamic regulation by ligand stimulation. Although catecholamine stimulation mediates the retention of beta1AR-EGFR interaction throughout receptor internalization, direct EGF ligand stimulation initiates the internalization of EGFR alone. Continued interaction of beta1AR with EGFR following activation is dependent upon C-terminal tail GRK phosphorylation sites of the beta1AR and recruitment of beta-arrestin. These data reveal a new signaling paradigm in which beta-arrestin is required for the maintenance of a beta1AR-EGFR interaction that can direct cytosolic targeting of ERK in response to catecholamine stimulation.

Physiologic and cardiac roles of beta-arrestins.

Beta-arrestin1 and beta-arrestin2 were initially identified by sequence homology to visual arrestins and by their ability to bind to and inactivate signaling of the beta-2-adrenergic receptor in a process known as desensitization. While the role of beta-arrestins in desensitization has been known for some time, more recent evidence has revealed that beta-arrestins are multifunctional scaffolding proteins that are involved in numerous aspects of G protein-coupled receptor (GPCR) signaling. Interestingly, exciting new data shows that beta-arrestins can mediate signaling in their own right independent of classical second messenger mediated signaling, and that this beta-arrestin-mediated signaling may be cardioprotective. Identifying novel ligands for GPCRs that can block G protein-mediated signaling while simultaneously promoting beta-arrestin-mediated signaling could provide powerful new therapies for cardiac disease.

Beta-arrestin-mediated signaling in the heart.

Beta-arrestin is a multifunctional adapter protein well known for its role in G-protein-coupled receptor (GPCR) desensitization. Exciting new evidence indicates that beta-arrestin is also a signaling molecule capable of initiating its own G-protein-independent signaling at GPCRs. One of the best-studied beta-arrestin signaling pathways is the one involving beta-arrestin-dependent activation of a mitogen-activated protein kinase cascade, the extracellular regulated kinase (ERK). ERK signaling, which is classically activated by agonist stimulation of the epidermal growth factor receptor (EGFR), can be activated by a number of GPCRs in a beta-arrestin-dependent manner. Recent work in animal models of heart failure suggests that beta-arrestin-dependent activation of EGFR/ERK signaling by the beta-1-adrenergic receptor, and possibly the angiotensin II Type 1A receptor, are cardioprotective. Hence, a new model of signaling at cardiac GPCRs has emerged and implicates classical G-protein-mediated signaling with promoting harmful remodeling in heart failure, while concurrently linking beta-arrestin-dependent, G-protein-independent signaling with cardioprotective effects. Based on this paradigm, a new class of drugs could be identified, termed "biased ligands", which simultaneously block harmful G-protein signaling, while also promoting cardioprotective beta-arrestin-dependent signaling, leading to a potential breakthrough in the treatment of chronic cardiac disease.