Introduction Although patients with stage D/ advanced heart failure (HF) share a similar clinical syndrome of refractory HF symptoms limiting daily life despite attempts to optimize recommended therapies, their clinical characteristics, pathophysiology, and outcomes are exceptionally diverse. Our goal was to assess the prevalence of clinically recognized phenotypes in a population-based cohort of patients with advanced HF. Hypothesis The prevalence of advanced HF phenotypes varies by ejection fraction (EF). Methods We included all adult residents of Olmsted County Minnesota with advanced HF, identified using ESC criteria, from 2007-2018 (n=936). Advanced HF phenotypes were proposed by a 2022 NHLBI advanced HF workshop in the following areas: 1) cardiorenal, 2) hepatic dysfunction, 3) right HF, 4) low cardiac output, 5) frailty, and 6) adverse social determinants of health. The prevalence of phenotypes was examined using data available from the time of advanced HF diagnosis. Results Among patients with advanced HF (mean age 77 years, 45% women), 42% had HFrEF, 14% HFmrEF, 43% HFpEF with phenotypes shown (Figure), Phenotypes more common in HFrEF than HFpEF were hepatic dysfunction (p=0.006), right HF (p<0.001), and low cardiac output (p<0.001), while frailty (p<0.001) was less common in patients with advanced HFrEF. Conclusions This is the first assessment of the prevalence of clinically recognized advanced HF phenotypes. Further work is needed to: 1) explore heterogeneity using robust analytical approaches, and 2) examine how therapeutic response and outcomes differ by phenotype.

Background and Aims:Genetic testing is recommended for select patients with atrial fibrillation (AF). The aims of this study were to define the results of genetic evaluation and its therapeutic impact for patients referred to a dedicated AF precision medicine clinic. Methods:Patients diagnosed with AF before age 60 were candidates for referral. In addition to standard evaluation with history, physical exam, and ECG, genetic evaluation included a 3-generation pedigree, cardiac imaging, ambulatory monitoring, and clinical genetic testing with a cardiomyopathy/arrhythmia panel. Results:264 participants were referred: the median age was 47 years (Q1, Q3: 38, 55), 77 (29%) were female, and 236 (89%) were White. Median age at AF diagnosis was 39 years (Q1, Q3: 31, 48) and median time from AF diagnosis to evaluation was 3.7 years (Q1, Q3: 0.9, 10). 242 patients (92%) underwent genetic testing, which identified a pathogenic or likely pathogenic variant in 48 (20%). The strongest predictors of positive genetic testing were history of cardiomyopathy, infranodal conduction disease, and elevated T1 or late gadolinium enhancement on cardiac MRI (all p<0.05). The strongest predictors of negative genetic testing were obstructive sleep apnea and a normal 12-lead ECG (both p<0.04). Overall, genetic testing changed clinical management in 52% of patients with positive genetic testing, highlighted by 7 new ICD placements and initiation of disease modifying therapy in 16 patients. Conclusions:Genetic testing was positive in 20% of patients with early-onset AF referred to a dedicated AF precision medicine clinic. Genetic testing results changed clinical management in approximately half of genotype-positive patients. STRUCTURED GRAPHICAL ABSTRACT:Key Question: Does genetic evaluation of patients with early-onset atrial fibrillation (AF) change their clinical management?Key Finding: Among 246 participants that completed genetic evaluation in a dedicated AF precision medicine clinic, 20% had positive genetic testing with identification of a pathogenic cardiomyopathy or channelopathy variant. These findings led to changes in clinical management in 52% of patients with positive genetic testing.Take-home Message: Genetic evaluation of patients with early-onset AF consists of detailed phenotyping and genetic testing to identify previously undiagnosed genetic disorders. This facilitates earlier diagnosis and clinical intervention.

AIMS:This study investigated Class III heart failure patient experience with pulmonary artery pressure (PAP) monitoring over 24 months including (1) changes in reported quality of life (QoL), (2) changes in HF illness perception and sense of control (control), (3) patient evaluation of PAP-guided therapy as a modality and (4) behavioural adherence to remote monitoring. METHODS AND RESULTS:A 272 patient subgroup from the N = 1200 patient CardioMEMS™ Post-Approval Study completed 3 questionnaires including HF-related QoL, illness perception and control, and PAP therapy evaluation. Patient measurement frequency was also collected as a behavioural adherence index. Patient perception of illness was assessed via a general linear mixed model to account for all data available at all time points (n = 272). A paired analysis of patients with 24-month questionnaires (n = 135) was performed to further evaluate patients who completed follow-up. Patients reported significant improvement in overall QoL scores from baseline (44.5 ± 24.0) to 6 months (58.8 ± 25.2) which was maintained through 2 years (all P < 0.0001). Patients described their sense of control as strong (4.3 ± 0.9, 5 is strongly agree), positively evaluated PAP-guided therapy (4.1 ± 1.0, 5 is strongly agree), and 90% actively transmitted device data weekly with a significant reduction in patient perceived illness throughout 2 years of follow-up. CONCLUSIONS:Two-year follow up of the patient experience of PAP-guided therapy indicated that patients reported increased QoL, perceptions of control, device acceptability and continued remote monitoring over the 24 month follow-up. These results suggest that knowledge of PA pressures is associated with positive patient experience and engagement in HF care.

Background The Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12), a patient-reported outcome measure for adults with heart failure, is associated with hospitalizations and mortality in clinical trials. Curated data sets from controlled trials differ substantially from pragmatic data collected from real-world settings, however, and few data exist on the KCCQ-12's predictive utility in clinical practice. Objectives This study sought to evaluate the predictive utility of the KCCQ-12 for hospitalizations and mortality when administered during outpatient heart failure care. Methods We conducted a cohort study of patients assigned the KCCQ-12 in heart failure clinics from July 2019 through March 2024. The primary exposure was KCCQ-12 Overall Summary (KCCQ-OS) score. The primary outcomes were 90-day hospitalization and cumulative mortality. Multivariable-adjusted associations were assessed using logistic regression and Cox proportional hazards models. Gradient boosting (XGBoost) and random survival forest machine learning models were used to evaluate KCCQ-OS feature importance in predicting 90-day hospitalizations and cumulative mortality, respectively. Results Among 4,406 patients assigned the KCCQ-12, 2,888 (66%) completed at least 1 questionnaire. The median KCCQ-OS score was 59.4 (Q1-Q3: 35.4-81.8). Patients with KCCQ-OS scores <25 had higher adjusted risks of 90-day hospitalization (OR: 3.49; 95% CI: 2.50-4.90) and cumulative mortality (HR: 3.09; 95% CI: 2.29-4.17) compared with those with scores ≥75. The KCCQ-OS score was the most important feature for predicting 90-day hospitalizations in the XGBoost model (area under the receiver-operating characteristic curve: 0.760; 95% CI: 0.706-0.811) and the most important feature for predicting cumulative mortality in the random survival forest model (C-index 0.783; 95% CI: 0.742-0.824) compared with other clinical, demographic, and laboratory variables. KCCQ-12 noncompletion was independently associated with increased 90-day hospitalization (OR: 1.72; 95% CI: 1.46-2.02) and 1-year mortality (HR: 1.52; 95% CI: 1.25-1.84) after adjusting for all variables in the primary analysis. Conclusions In outpatient heart failure care, lower KCCQ-OS scores were strongly associated with increased hospitalizations and mortality, with the greatest risk among patients with scores <25. Noncompletion of the KCCQ-12 was itself associated with worse outcomes. The KCCQ-OS score was the dominant predictor of 90-day hospitalizations and cumulative mortality in machine learning models, supporting the KCCQ-12 as a prognostic tool in routine clinical practice.

INTRODUCTION:Ambulatory hemodynamic monitoring (AHM) of heart failure (HF) using pulmonary artery pressure (PAP) is marked by frequent changes in HF medications. We are beginning to learn how medication titrations during AHM affect mean PAP (mPAP) measured in the seated position, which reflects most waking hours. METHOD:We analyzed the 12-month data from the PROACTIVE-HF trial of the Cordella Cordella, Endotronix Inc, Naperville, Illinois, United States) PAP sensor system. Seated mPAP was examined in the 14-days before and after isolated changes in medications; only those medications with ≥10 titrations were analyzed. Dependent sample Wilcoxon-signed rank test was used to compare changes in mPAP with titrations. RESULTS:We analyzed 456 subjects (age: 64 years, females: 40%, Black: 18%, HF with reduced ejection fraction: 46%). Loop diuretics (LD) were up-titrated 176 times in 133 patients and down-titrated 113 times in 96 patients. Before LD up-titration, mPAP increased by 1.6 ± 1.0 mm Hg; afterwards, it decreased by 2.3 ± 1.0 mm Hg (P < 0.001), with most reduction occurring within 1 week. Down-titration of LD was followed by an increase of 1.8 ± 1.3 mm Hg (P = 0.004) over the next several days. Similar trends were observed across categories of ejection fraction (≤40% and >40%). Angiotensin receptor neprilysin inhibitor (ARNI) up-titration decreased mPAP by 1.8 ± 1.9 mm Hg (P = 0.042), whereas down-titration increased mPAP by 1.5 ± 1.4 (P = 0.094). Mineralocorticoid receptor antagonist (MRA) up-titration tended to decrease mPAP (1.6 ± 2.5 mm Hg, P = 0.286,) whereas down-titration was followed by a significant increase in mPAP of 3.2 ± 1.6 mm Hg (P = 0.001). CONCLUSION:The AHM platform using seated mPAP data provided valuable insights into its short-term responses to isolated changes in HF medications. The seated mPAP changed expectedly in response to the titration of LD, whereas the degree of response varied for ARNI and MRA. Ongoing investigation will further characterize the timing and variability of responses to inform algorithms for ambulatory management of PAP.

BACKGROUND:Hemodynamically guided management of patients with chronic heart failure (HF), using a remote, ambulatory pulmonary artery (PA) pressure monitor, has been shown to reduce mortality and morbidity. These improved outcomes were associated with a reduction in PA pressure. However, several pivotal questions remain unanswered: do systolic, diastolic, or mean PA pressures each predict all-cause mortality? Do PA pressures predict mortality across the ejection fraction (EF) spectrum? Do increases or decreases in PA pressure over time predict increases or decreases in mortality? METHODS:Retrospective analyses of data from CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients; n=550), GUIDE-HF (Hemodynamic-GUIDEed management of Heart Failure; n=2358), US PAS (CardioMEMS HF System Post Approval Study; n=1200), and MEMS-HF (CardioMEMS Monitoring Study for Heart Failure; n=234) were performed, including all enrolled patients regardless of treatment assignments (Total N=4342). PA systolic, PA diastolic, and PA mean pressures were examined in patients with HF and reduced EF (<50%, n=2562) and preserved EF (≥50%, n=1454). Baseline pressure (averaged over 14 days after implantation) and change in pressure (increase/decrease/no change) from baseline to 6 months (averaged over 14 days just before the 6-month time point) were related to all-cause mortality over a 2-year follow-up period. RESULTS:Baseline PA diastolic, independent of other covariates, was a significant predictor of mortality (hazard ratio, 1.04 [95% CI, 1.03-1.05]; P<0.0001). Change in PA diastolic from baseline to 6 months (assessed as a continuous variable) was an independent predictor of mortality after 6 months (landmark analysis; hazard ratio, 1.03 [95% CI, 1.01-1.05]; P=0.0042). Change in PA diastolic from baseline to 6 months(assessed as a categorical variable) decrease or increase of >2 mm Hg compared with no change predicted a 14.7% decrease and 26.7% increase in mortality, respectively (P=0.0237). PA systolic and PA mean pressures in both HF with reduced EF and HF with preserved EF patients, for both baseline and change from baseline to 6 months, were also predictive of all-cause mortality. CONCLUSIONS:Baseline PAP (systolic, diastolic, and mean) and change in PAP (systolic, diastolic, and mean) from baseline to 6 months were independent predictors of 2-year mortality in patients with chronic HF in both preserved and reduced EF. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifiers: CHAMPION, NCT00531661; GUIDE-HF, NCT03387813; USPAS, NCT02279888; MEMS-HF, NCT02693691.

Background: Genetic testing is now recommended for select patients with early-onset atrial fibrillation (AF). Hemochromatosis is an autosomal recessive syndrome that occurs in patients who carry two pathogenic or likely-pathogenic (P/LP) variants in HFE. HFE is included on some genetic testing panels used for patients with AF. Hemochromatosis causes cardiomyopathy due to iron overload in the ventricle; however, it is unknown whether AF can be an early manifestation that is identified by genetic testing. Methods: A total of 347 patients were referred to a dedicated AF precision medicine clinic. The clinical diagnostic evaluation included an H&P, 12-lead ECG, ambulatory ECG monitoring, and cardiac imaging (cardiac MRI and/or TTE). Genetic testing was performed using CLIA-approved laboratories: Labcorp/Invitae, GeneDx, or Vanderbilt University Medical Center. HFE was included on the cardiomyopathy panel used by 2 of the 3 laboratories. Results: HFE was tested in 165 participants (median age 46 years [IQR 35-55], 115 [70%] male, 149 [90%] White). Six participants (4%) had two pathogenic variants in HFE. All of them were C282Y/H63D compound heterozygotes. Forty-one participants (25%) were heterozygous carriers of one pathogenic HFE variant. Among the 6 participants with 2 pathogenic HFE variants, the median ferritin level was 346 mcg/L [IQR 262, 496] (normal <300 mcg/L males, <200 mcg/L females). Three participants (50%) met laboratory criteria for iron overload. One individual had isolated ferritin elevation with normal transferrin saturation. All 6 underwent cardiac MRI as part of the genetic evaluation for early onset AF, and there was no evidence of cardiac siderosis based on cardiac T1 mapping, median 990 ms [IQR 968-1024] (normal 960-1030 ms). Dedicated sequences to evaluate for iron overload demonstrated short hepatic T2* in one individual, indicating presence of hepatic iron overload (9 ms, normal >11.4 ms; liver iron concentration 3.4 mg/g, normal <2 mg/g). Three out of 6 participants were referred for a hematology evaluation and 2 out of 6 were started on therapeutic phlebotomy. Conclusion: Genetic testing can identify patients with early-onset AF who are genetically susceptible to hemochromatosis, have evidence of iron overload, and receive early intervention with therapeutic phlebotomy. These results suggest HFE should be sequenced as part of genetic testing for early-onset AF, but larger sample sizes are needed to confirm these results.

BACKGROUND Left ventricular assist device (LVAD) use remains uncommon in advanced heart failure (HF) patients not dependent on inotropes. OBJECTIVES Before considering a randomized trial comparing a strategy of earlier use of LVAD to continued medical therapy, a better understanding is needed of the clinical trajectory of ambulatory patients with advanced systolic HF on optimal guideline-directed medical therapy (GDMT). METHODS REVIVAL enrolled 400 patients with advanced ambulatory systolic HF, >= 1 HF mortality risk marker (>= 2 HF hospitalizations past year; or HF hospitalization and high natriuretic peptide; or no HF hospitalizations but low peak oxygen consumption, 6-minute walk, serum sodium, HF survival score or Seattle HF model predicted survival), and no LVAD contraindication at 21 LVAD centers from July 2015 to June 2016. Patients were followed for 2 years or until a primary outcome (death, durable ventricular assist device, or urgent transplant). Clinical outcomes and health-related quality of life were evaluated. RESULTS Mean baseline left ventricular ejection fraction was 21%, median 6-minute walk was 341 m, and 92% were Interagency Registry for Mechanically Assisted Circulatory Support profiles 5 to 7. Adherence to GDMT and electrical device therapies was robust. Composite primary outcome occurred in 22% and 37% at 1 and 2 years, with death alone in 8% and 16%, respectively. Patients surviving for 2 years maintained GDMT intensity and had no decline in health-related quality of life. CONCLUSIONS Structured, serial follow-up at programs with expertise in caring for advanced ambulatory systolic HF patients facilitates triage for advanced therapies. Better strategies are still needed to avoid deaths in a small but significant group of patients who die without advanced therapies. REVIVAL patients not selected for VAD or transplant have robust survival and patient-reported outcomes, which challenges advocacy for earlier VAD implantation. (Registry Evaluation of Vital Information for VADs in Ambulatory Life [REVIVAL]; NCT01369407) (JACC Heart Fail. 2024;12:1734-1746) (c) 2024 the American College of Cardiology Foundation. Published by Elsevier. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Background TTN encodes a sarcomeric protein called titin. Pathogenic rare variants in TTN are the most common finding in patients with atrial fibrillation (AF) and positive genetic testing. Objectives This study sought to define the characteristics and outcomes in patients with AF and pathogenic TTN variants compared with genotype-negative patients with AF. Methods Patients who presented initially with AF were enrolled in an AF registry. Retrospectively they underwent research sequencing for cardiomyopathy and arrhythmia genes. TTN(+) AF cases were defined as participants with pathogenic or likely pathogenic (P/LP) rare variants located in exons with high cardiac expression. They were matched 1:2 with control subjects with no P/LP variants. Phenotyping used retrospective manual chart review. Results Among 2794 participants; 57 (2.0%) TTN(+) AF cases were identified and matched with 114 control subjects. Low QRS complex voltage was present more often in TTN(+) AF cases (18% vs 5%; P < 0.01), with no difference in PR, QRS interval, or QTc. More TTN(+) AF cases had persistent AF at enrollment (44% vs 30%; P = 0.028) and had undergone multiple cardioversions (61% vs. 37%; P < 0.01). By end of follow-up (median 8.3 years; Q1, Q3: 4.5, 13.7 years), 11% of TTN(+) AF cases developed sustained ventricular tachycardia/ventricular fibrillation, 44% left ventricular (LV) systolic dysfunction (LV ejection fraction <50%), and 47% met a combined endpoint of sustained ventricular tachycardia/ventricular fibrillation or LV systolic dysfunction. Conclusions TTN(+) AF patients undergo more cardioversions and have more persistent forms of AF. Approximately 50% develop LV systolic dysfunction and/or malignant ventricular arrhythmias. These results highlight the need for diagnostic evaluation and management in TTN(+) patients beyond the usual care for AF.

BACKGROUND:An angiotensin receptor-neprilysin inhibitor (ARNI) is the preferred renin-angiotensin system (RAS) inhibitor for heart failure with reduced ejection fraction (HFrEF). Among eligible patients, insurance status and prescriber concern regarding out-of-pocket costs may constrain early initiation of ARNI and other new therapies. OBJECTIVES:In this study, the authors sought to evaluate the association of insurance and other social determinants of health with ARNI initiation at discharge from HFrEF hospitalization. METHODS:The authors analyzed ARNI initiation from January 2017 to June 2020 among patients with HFrEF eligible to receive RAS inhibitor at discharge from hospitals in the Get With The Guidelines-Heart Failure registry. The primary outcome was the proportion of ARNI prescription at discharge among those prescribed RAS inhibitor who were not on ARNI on admission. A logistic regression model was used to determine the association of insurance status, U.S. region, and their interaction, as well as self-reported race, with ARNI initiation at discharge. RESULTS:From 42,766 admissions, 24,904 were excluded for absolute or relative contraindications to RAS inhibitors. RAS inhibitors were prescribed for 16,817 (94.2%) of remaining discharges, for which ARNI was prescribed in 1,640 (9.8%). Self-reported Black patients were less likely to be initiated on ARNI compared to self-reported White patients (OR: 0.64; 95% CI: 0.50-0.81). Compared to Medicare beneficiaries, patients with third-party insurance, Medicaid, or no insurance were less likely to be initiated on ARNI (OR: 0.47 [95% CI: 0.31-0.72], OR: 0.41 [95% CI: 0.25-0.67], and OR: 0.20 [95% CI: 0.08-0.47], respectively). ARNI therapy varied by hospital region, with lowest utilization in the Mountain region. An interaction was demonstrated between the impact of insurance disparities and hospital region. CONCLUSIONS:Among patients hospitalized between 2017 and 2020 for HFrEF who were prescribed RAS inhibitor therapy at discharge, insurance status, geographic region, and self-reported race were associated with ARNI initiation.

Background: Psychosocial evaluations to assess candidacy for advanced heart failure therapies are not standardized across institutions, potentially contributing to disparities in approval for advanced therapies. Remediation rates of psychosocial stressors among patients with advanced HF and reconsideration for advanced therapies have not been well- described. Methods and Results: We performed a retrospective, single-center study of 647 adults evaluated for heart transplant and ventricular assist device implantation between 2014 and 2020, of whom 89 (14%) were denied for psychosocial stressors, including caregiver, substance use, housing, financial, or mental health concerns. Later reevaluation occurred in 32 patients (36%), of whom 23 were then approved. Patients initially declined were mostly male (76%), White (74%), and urban (79%). Reevaluation occurred in more women than men (43% vs 34%), Black patients than White (43% vs 37%), and urban patients than rural (39% vs 28%). Patients had fewer psychosocial stressors at reevaluation (median 0.5) than at initial denial (median 2.0). Caregiver and substance use concerns were the most prevalent stressors in patients never returning for or subsequently denied at reevaluation. Conclusions: Caregiver and substance use concerns were common in patients denied for psychosocial reasons. Future efforts should focus on early screening for these stressors and the implementation of a systematic reevaluation process.

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple approaches have been tried to achieve adequate decongestion rapidly while minimizing adverse effects, no single diuretic strategy has shown superiority, and there is a paucity of data and guidelines to utilize in making these decisions. Observational cohort studies have shown associations between urine sodium excretion and outcomes after hospitalization for ADHF. Urine chemistries (urine sodium ± urine creatinine) may guide diuretic titration during ADHF, and multiple randomized clinical trials have been designed to compare a strategy of urine chemistry–guided diuresis to usual care. This review will summarize current literature for diuretic monitoring and titration strategies, outline evidence gaps, and describe the recently completed and ongoing clinical trials to address these gaps in patients with ADHF with a particular focus on the utility of urine sodium–guided strategies.

Background: Ambulatory inotropic infusions can be used as a palliative therapy (PT) or bridge to advanced therapies in end-stage heart failure (ESHF) patients, many of whom have implantable cardioverter defibrillators (ICDs). Research Questions: How often do patients receive ICD therapies after initiation of outpatient inotropic support and how often is defibrillation inactivated? Methods: We conducted a retrospective review of all patients discharged from an academic tertiary medical center with a new prescription for inotropic therapy between November 2017 and March 2023. Clinical data, Palliative Care consultation, and ICD interrogations before and after inotrope initiation were extracted from the electronic health record. Results: The cohort comprised 45 patients discharged on new inotropic support, including 22 (49%) with intent of PT and 23 (51%) as a bridge to advanced therapies (Figure). Among PT patients, 15 (68%) had an ICD in place with only 4 having ICD therapies deactivated at discharge. Only 2 additional PT patients had a documented discussion regarding ongoing ICD therapies. By 1 year, 4 (18%) PT patients were transitioned to hospice and 13 (59%) had died, with only 1 additional patient having ICD deactivation. Of 28 patients discharged on inotropic infusions with ICD therapies on (both PT and bridge patients), only 4 patients had ICD therapies turned off later and no ICD shocks were reported for the year following initiation of inotropic support. Conclusion: In a series of 45 patients initiated on inotropic support for PT or bridge to advanced therapies, the majority (77%) had an active ICD, but therapies were rarely delivered. Notably, there were very few documented discussions regarding ICD therapies in PT patients even with specialty Palliative Care consultation. In patients with ESHF initiated on inotropic support as PT, most patients chose to leave ICD therapies in place. For those patients, there was a low rate of ICD therapies delivered.

Clinical outcomes for patients who have heart failure with reduced ejection fraction continue to improve with the selection of effective therapies and their increasing duration of use. Randomized, controlled trials usually measure the efficacy of a therapy for a limited time, after which its longer-term efficacy is blurred by the crossover of patients to the active treatment after the trial has been completed. If a therapy is tested in patients who have advanced heart failure, its benefits may soon be obvious during the trial. However, earlier initiation of therapy, before symptoms of heart failure have become severe, may have a . . .