Metabolomic Association and Risk Prediction With Heart Failure in Older Adults.

BACKGROUND: Older adults have markedly increased risks of heart failure (HF), specifically HF with preserved ejection fraction (HFpEF). Identifying novel biomarkers can help in understanding HF pathogenesis and improve at-risk population identification. This study aimed to identify metabolites associated with incident HF, HFpEF, and HF with reduced ejection fraction and examine risk prediction in older adults. METHODS: Untargeted metabolomic profiling was performed in Black and White adults from the ARIC study (Atherosclerosis Risk in Communities) visit 5 (n=3719; mean age, 75 years). We applied Cox regressions to identify metabolites associated with incident HF and its subtypes. The metabolite risk score (MRS) was constructed and examined for associations with HF, echocardiographic measures, and HF risk prediction. Independent samples from visit 3 (n=1929; mean age, 58 years) were used for replication. RESULTS: Sixty metabolites (hazard ratios range, 0.79-1.49; false discovery rate, <0.05) were associated with incident HF after adjusting for clinical risk factors, eGFR, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Mannonate, a hydroxy acid, was replicated (hazard ratio, 1.36 [95% CI, 1.19-1.56]) with full adjustments. MRS was associated with an 80% increased risk of HF per SD increment, and the highest MRS quartile had 8.7× the risk of developing HFpEF than the lowest quartile. High MRS was also associated with unfavorable values of cardiac structure and function. Adding MRS over clinical risk factors and NT-proBNP improved 5-year HF risk prediction C statistics from 0.817 to 0.850 (∆C, 0.033 [95% CI, 0.017-0.047]). The association between MRS and incident HF was replicated after accounting for clinical risk factors (P<0.05). CONCLUSIONS: Novel metabolites associated with HF risk were identified, elucidating disease pathways, specifically HFpEF. An MRS was associated with HF risk and improved 5-year risk prediction in older adults, which may assist at at-risk population identification.

Long-term predictors of morbidity and mortality in patients following LVAD replacement.

BACKGROUND: As heart transplant guidelines evolve, the clinical indication for 73% of durable left ventricular assist device (LVAD) implants is now destination therapy. Although completely magnetically levitated LVAD devices have demonstrated improved durability relative to previous models, LVAD replacement procedures are still required for a variety of indications. Thus, the population of patients with a replaced LVAD is growing. There is a paucity of data regarding the outcomes and risk factors for those patients receiving first-time LVAD replacements. METHODS: The study cohort consisted of all consecutive patients between 2006 and 2020 that received a first-time LVAD replacement at a single institution. Preoperative clinical and laboratory variables were collected retrospectively. The primary endpoint was death or need for an additional LVAD replacement. Data were subjected to Kaplan-Meier, univariate, and multivariate Cox hazard ratio analyses. RESULTS: In total, 152 patients were included in the study, of which 101 experienced the primary endpoint. On multivariate analysis, patients receiving HeartMate 3 (HM3) LVADs as the replacement device showed superior outcomes (HR 0.15, 95% CI 0.065-0.35, p < 0.0001). Independent risk factors for death or need for additional replacement included preoperative extracorporeal membrane oxygenation (ECMO) (HR 4.44, 95% CI 1.87-14.45, and p = 0.00042), increased number of sternotomies (HR 5.20, 95% CI 1.87-14.45, and p = 0.0016), and preoperative mechanical ventilation (HR 1.98, 95% CI 1.01-3.86, and p = 0.045). CONCLUSIONS: Replacement with HM3 showed superior outcomes compared to all other pump types when controlling for both initial pump type and other independent predictors of death or LVAD replacement. Preoperative ECMO, mechanical ventilation, and multiple sternotomies also increased the odds for death or the need for subsequent replacement.

Beyond Stage C: Considerations in the Management of Patients With Heart Failure Progression and Gaps in Evidence.

Despite treatment with contemporary medical therapies for chronic heart failure (HF), there has been an increase in the prevalence of patients progressing to more advanced disease. Patients progressing to and living at the interface of severe stage C and stage D HF are underrepresented in clinical trials, and there is a lack of high-quality evidence to guide clinical decision making. For patients with severe HF phenotypes, the medical therapies used for patients with less advanced stages of illness are often no longer tolerated or provide inadequate clinical stability. The limited data on these patients highlights the need to increase formal research characterizing this high-risk population. This review summarizes existing clinical trial data and incorporates our considerations for approaches to the medical management of patients advanced "beyond stage C" HF.

Atrial fibrillation is an independent risk factor for heart failure hospitalization in heart failure with preserved ejection fraction.

AIMS: Atrial fibrillation (AF) is a common comorbid condition in heart failure with preserved ejection fraction (HFpEF). The effect of AF on heart failure (HF) exacerbation in HFpEF has not been well described. This study investigated how AF modifies the clinical trajectory of HFpEF patients after hospitalization for decompensated HF. METHODS AND RESULTS: We stratified HFpEF subjects by AF diagnosis and performed longitudinal analysis to compare risk for HF hospitalization after index hospitalization for decompensated HF. All-cause mortality, 30 day all-cause readmissions, and response to inpatient diuresis were also evaluated. Of 90 subjects enrolled, 35.6% (n = 32) had AF. Subjects with AF were older (72.5 vs. 60.5 years; P < 0.01), more often male (46.9% vs. 24.1%; P = 0.03), and had greater left atrial diameter (4.9 vs. 3.8 cm; P < 0.01) compared with those without AF. Subjects with AF had a higher risk for HF hospitalization than their counterparts without AF (P = 0.02); this relationship remained significant following multivariable competing risk regression with propensity score weighting (hazard ratio 2.53, P = 0.04 and hazard ratio 2.91, P = 0.04, with overlap and inverse probability weighting, respectively). Although having AF appeared to increase the risk of all-cause hospital readmission within 30 days of discharge (37.5% vs. 17.5%; P = 0.036), this relationship failed to remain significant following propensity score adjustment for clinical covariates. CONCLUSIONS: Atrial fibrillation is an independent risk factor for HF rehospitalization in HFpEF. Further understanding of the interplay between AF and HFpEF will be critical to guide the selection of appropriate rhythm management strategies in this population.

Nonplatelet thromboxane generation is associated with impaired cardiovascular performance and mortality in heart failure.

Nonplatelet thromboxane generation, stimulated largely by oxidative stress, is a novel mortality risk factor in individuals with coronary artery disease. Though inversely associated with left ventricular ejection fraction (LVEF), a potential role in the pathobiology of heart failure (HF) remains poorly defined. Nonplatelet thromboxane generation and oxidative stress were assessed by measuring urine thromboxane-B2 metabolites (TXB2-M) and 8-isoPGF2α by ELISA in 105 subjects taking aspirin and undergoing right heart catheterization for evaluation of HF, valve disease, or after transplantation. Multivariable logistic regression and survival analyses were used to define associations of TXB2-M to invasive measures of cardiovascular performance and 4-year clinical outcomes. TXB2-M was elevated (>1,500 pg/mg creatinine) in 46% of subjects and correlated with HF severity by New York Heart Association (NYHA) functional class and brain natriuretic peptide level, modestly with LVEF, but not with HF etiology. There was no association of oxidative stress to HF type or etiology but a trend with NYHA functional class. Multiple invasive hemodynamic parameters independently associated with TXB2-M after adjustment for oxidative stress, age, sex, and race with pulmonary effective arterial elastance (Ea pulmonary), reflective of right ventricular afterload, being the most robust on hierarchical analysis. Similar to Ea pulmonary, elevated urinary TXB2-M is associated with increased risk of death (adjusted HR = 2.15, P = 0.037) and a combination of death, transplant, or mechanical support initiation (adjusted HR = 2.0, P = 0.042). Nonplatelet TXA2 thromboxane generation is independently associated with HF severity reflected by invasive measures of cardiovascular performance, particularly right ventricular afterload, and independently predicted long-term mortality risk.NEW & NOTEWORTHY Nonplatelet thromboxane generation in heart failure is independently associated with risk of death, transplant, or need for mechanical support. Measurement of urine thromboxane metabolites using a clinically available assay may be a useful surrogate for invasive measurement of cardiovascular hemodynamics and performance that could provide prognostic information and facilitate tailoring of therapy in patients with heart failure. Inhibiting thromboxane generation or its biological effects is a potential strategy for improving cardiovascular performance and outcomes in heart failure.

Cardiovascular Disease Risk Among Cancer Survivors: The Atherosclerosis Risk In Communities (ARIC) Study.

BACKGROUND: More than 80% of adult patients diagnosed with cancer survive long term. Long-term complications of cancer and its therapies may increase the risk of cardiovascular disease (CVD), but prospective studies using adjudicated cancer and CVD events are lacking. OBJECTIVES: The aim of this study was to assess the risk of CVD in cancer survivors in a prospective community-based study. METHODS: We included 12,414 ARIC (Atherosclerosis Risk In Communities) study participants. Cancer diagnoses were ascertained via linkage with state registries supplemented with medical records. Incident CVD outcomes were coronary heart disease (CHD), heart failure (HF), stroke, and a composite of these. We used multivariable Poisson and Cox regressions to estimate the association of cancer with incident CVD. RESULTS: Mean age was 54 years, 55% were female, and 25% were Black. A total of 3,250 participants (25%) had incident cancer over a median 13.6 years of follow-up. Age-adjusted incidence rates of CVD (per 1,000 person-years) were 23.1 (95% CI: 24.7-29.1) for cancer survivors and 12.0 (95% CI: 11.5-12.4) for subjects without cancer. After adjustment for cardiovascular risk factors, cancer survivors had significantly higher risks of CVD (HR: 1.37; 95% CI: 1.26-1.50), HF (HR: 1.52; 95% CI: 1.38-1.68), and stroke (HR: 1.22; 95% CI: 1.03-1.44), but not CHD (HR: 1.11; 95% CI: 0.97-1.28). Breast, lung, colorectal, and hematologic/lymphatic cancers, but not prostate cancer, were significantly associated with CVD risk. CONCLUSIONS: Compared with persons without cancer, adult cancer survivors have significantly higher risk of CVD, especially HF, independent of traditional cardiovascular risk factors. There is an unmet need to define strategies for CVD prevention in this high-risk population.

Progression of aortic valve insufficiency during centrifugal versus axial flow left ventricular assist device support.

OBJECTIVES: Long-term left ventricular assist device (LVAD) support can cause accelerated progression of aortic insufficiency (AI). The MOMENTUM trial has led to increased use of the HeartMate 3 (HM3) LVAD, due to greater hemocompatibility. However, the differential effect on the rate of progression of AI during HM3 support versus HeartMate 2 (HM2) has not been extensively studied. This analysis compares the rates of progression to moderate or severe AI (MSAI) comparing a cohort of patients supported with the HM2 versus HM3. METHODS: A retrospective review was performed on all consecutive patients implanted with HM2 or HM3 between May 2005 and June 2020. Follow-up time was limited to the first 6 years after LVAD implantation. Demographics and 4005 echocardiograms were assessed for 536 HM2 and 300 HM3 patients. The primary end point was progression to MSAI. Univariable and multivariable Cox proportional hazard regression and landmark analyses were performed. RESULTS: Progression to MSAI was greater in the HM2 (17%) versus HM3 (9.9%) cohort. On the univariable analysis, the hazard ratio for HM3 was 0.581 (95% confidence interval 0.370-0.909, P = 0.02) whereas on multivariable analysis hazard ratio was 0.624 (95% confidence interval 0.386-1.008, P = 0.0537). Preoperative AI, female sex and body surface area <2 were significantly associated with progression to MSAI. Landmark analysis suggests that LVAD type has the most significant effect on progression to MSAI between 1 and 2 years post-implantation. CONCLUSIONS: Current practice strategies achieved low rates of progression to MSAI. Preoperative AI, female sex and body surface area <2 were the most important predictors of progression to MSAI. Pump type appears to be of secondary importance.

Race- and Gender-Based Differences in Cardiac Structure and Function and Risk of Heart Failure.

BACKGROUND: Although heart failure (HF) risk and cardiac structure/function reportedly differ according to race and gender, limited data exist in late life when risk of HF is highest. OBJECTIVES: The goal of this study was to evaluate race/gender-based differences in HF risk factors, cardiac structure/function, and incident HF in late life. METHODS: This analysis included 5,149 HF-free participants from ARIC (Atherosclerosis Risk In Communities), a prospective epidemiologic cohort study, who attended visit 5 (2011-2013) and underwent echocardiography. Participants were subsequently followed up for a median 5.5 years for incident HF/death. RESULTS: Patients' mean age was 75 ± 5 years, 59% were women, and 20% were Black. Male gender and Black race were associated with lower mean left ventricular ejection fraction. Black race was also associated with greater left ventricular wall thickness and concentricity, differences that persisted after adjusting for cardiovascular comorbidities. After adjusting for cardiovascular comorbidities, men were at higher risk for HF and heart failure with reduced ejection fraction (HFrEF) in Black participants compared with White participants (HF: HR of 2.36 [95% CI: 1.37-4.08] vs 1.16 [95% CI: 0.89-1.51], interaction P = 0.016; HFrEF: HR of 3.70 [95% CI: 1.72-7.95] vs 1.55 [95% CI: 1.01-2.37] respectively, interaction P = 0.039). Black race was associated with a higher incidence of HF overall and HFrEF in men only (HF: 1.65 [95% CI: 1.07-2.53] vs 0.76 [95% CI: 0.49-1.17]; HFrEF: HR of 2.55 [95% CI: 1.46-4.44] vs 0.91 [95% CI: 0.46-1.83]). No race/gender-based differences were observed in risk of incident heart failure with preserved ejection fraction. CONCLUSIONS: Among older persons free of HF, men and Black participants exhibit worse systolic performance and are at heightened risk for HFrEF, whereas the risk of heart failure with preserved ejection fraction is similar across gender and race groups.

Pericardial Adipose Tissue Volume and Left Ventricular Assist Device-Associated Outcomes.

BACKGROUND: Pericardial adipose tissue (PAT) is associated with adverse cardiovascular outcomes in those with and without established heart failure (HF). However, it is not known whether PAT is associated with adverse outcomes in patients with end-stage HF undergoing left ventricular assist device (LVAD) implantation. This study aimed to evaluate the associations between PAT and LVAD-associated outcomes. METHODS AND RESULTS: We retrospectively measured computed tomography-derived PAT volumes in 77 consecutive adults who had available chest CT imaging prior to HeartMate 3 LVAD surgery between October 2015 and March 2019 at Duke University Hospital. Study groups were divided into above-median (≥219 cm3) and below-median (<219 cm3) PAT volume. Those with above-median PAT had a higher proportion of atrial fibrillation, chronic kidney disease and ischemic cardiomyopathy. Groups with above-median vs below-median PAT had similar Kaplan-Meier incidence rates over 2 years for (1) composite all-cause mortality, redo-LVAD surgery and cardiac transplantation (35.9 vs 32.2%; log-rank P = 0.65) and (2) composite incident hospitalizations for HF, gastrointestinal bleeding, LVAD-related infection, and stroke (61.5 vs 60.5%; log-rank P = 0.67). CONCLUSIONS: In patients with end-stage HF undergoing LVAD therapy, PAT is not associated with worse 2-year LVAD-related outcomes. The significance of regional adiposity vs obesity in LVAD patients warrants further investigation.

Acute Diuretic-Sparing Effects of Sacubitril-Valsartan: Staying in the Loop.

BACKGROUND: Previous literature has suggested a potential diuretic sparing effect as early as 6 months following sacubitril-valsartan initiation in patients with heart failure with reduced ejection fraction (HFrEF); however, whether this effect manifests earlier after initiation is unclear. Objective: To evaluate the acute diuretic-sparing effects of sacubitril-valsartan. METHODS: This was a single-center, retrospective analysis of outpatients with HFrEF initiated on sacubitril-valsartan with follow up within 90 ± 30 days and a concomitant loop diuretic prescription. The primary outcome was the percent of patients with an increase, decrease or no change in loop diuretic total daily dose (TDD). Key secondary outcomes included change in loop diuretic TDD (mg furosemide equivalents) and hospital admissions or emergency department (ED) visits. RESULTS: A total of 145 patients were included (overall cohort) with 120 continuing sacubitril-valsartan at follow up (on-treatment cohort). In the on-treatment cohort, 20% (n = 24) had a reduction in loop diuretic TDD and 10% had an increase (n = 12). Median change in loop diuretic TDD was unchanged from baseline to follow up (p 0.13). In patients on >80 mg TDD of furosemide at baseline (n = 9), mean change was-53 ± 44 mg (p 0.006). Hospitalizations (6.2%) and ED visits (0.7%) for heart failure were infrequent. CONCLUSION: Patients may require a loop diuretic dose reduction within 2-3 months following sacubitril-valsartan initiation. This diuretic-sparing effect appears larger in those on higher baseline loop diuretic doses, and closer follow up may be warranted for these patients.

Surgical Treatment of Tricuspid Valve Regurgitation in Patients Undergoing Left Ventricular Assist Device Implantation: Interim analysis of the TVVAD trial.

OBJECTIVES: Right heart failure remains a serious complication of left ventricular assist device therapy. Many patients presenting for left ventricular assist device implantation have significant tricuspid regurgitation. It remains unknown whether concurrent tricuspid valve surgery reduces postoperative right heart failure. The primary aim was to identify whether concurrent tricuspid valve surgery reduced the incidence of moderate or severe right heart failure within the first 6 months after left ventricular assist device implantation. METHODS: Patients with moderate or severe tricuspid regurgitation on preoperative echocardiography were randomized to left ventricular assist device implantation alone (no tricuspid valve surgery) or with concurrent tricuspid valve surgery. Randomization was stratified by preoperative right ventricular dysfunction. The primary end point was the frequency of moderate or severe right heart failure within 6 months after surgery. RESULTS: This report describes a planned interim analysis of the first 60 randomized patients. The tricuspid valve surgery group (n = 32) had mild or no tricuspid regurgitation more frequently on follow-up echocardiography studies compared with the no tricuspid valve surgery group (n = 28). However, at 6 months, the incidence of moderate and severe right heart failure was similar in each group (tricuspid valve surgery: 46.9% vs no tricuspid valve surgery: 50%, P = .81). There was no significant difference in postoperative mortality or requirement for right ventricular assist device between the groups. There were also no significant differences in secondary end points of functional status and adverse events. CONCLUSIONS: The presence of significant tricuspid regurgitation before left ventricular assist device is associated with a high incidence of right heart failure within the first 6 months after surgery. Tricuspid valve surgery was successful in reducing postimplant tricuspid regurgitation compared with no tricuspid valve surgery but was not associated with a lower incidence of right heart failure.

Guidance for Timely and Appropriate Referral of Patients With Advanced Heart Failure: A Scientific Statement From the American Heart Association.

Among the estimated 6.2 million Americans living with heart failure (HF), ≈5%/y may progress to advanced, or stage D, disease. Advanced HF has a high morbidity and mortality, such that early recognition of this condition is important to optimize care. Delayed referral or lack of referral in patients who are likely to derive benefit from an advanced HF evaluation can have important adverse consequences for patients and their families. A 2-step process can be used by practitioners when considering referral of a patient with advanced HF for consideration of advanced therapies, focused on recognizing the clinical clues associated with stage D HF and assessing potential benefits of referral to an advanced HF center. Although patients are often referred to an advanced HF center to undergo evaluation for advanced therapies such as heart transplantation or implantation of a left ventricular assist device, there are other reasons to refer, including access to the infrastructure and multidisciplinary team of the advanced HF center that offers a broad range of expertise. The intent of this statement is to provide a framework for practitioners and health systems to help identify and refer patients with HF who are most likely to derive benefit from referral to an advanced HF center.

Endothelial Stromal PD-L1 (Programmed Death Ligand 1) Modulates CD8+ T-Cell Infiltration After Heart Transplantation.

BACKGROUND: The role of checkpoint axes in transplantation has been partially addressed in animal models but not in humans. Occurrence of fulminant myocarditis with allorejection-like immunologic features in patients under anti-PD1 (programmed death cell protein 1) treatment suggests a key role of the PD1/PD-L1 (programmed death ligand 1) axis in cardiac immune homeostasis. METHODS: We cross-sectionally studied 23 heart transplant patients undergoing surveillance endomyocardial biopsy. Endomyocardial tissue and peripheral blood mononuclear cells were analyzed by flow cytometry. Multivariate logistic regression analyses including demographic, clinical, and hemodynamic parameters were performed. Murine models were used to evaluate the impact of PD-L1 endothelial graft expression in allorejection. RESULTS: We found that myeloid cells dominate the composition of the graft leukocyte compartment in most patients, with variable T-cell frequencies. The CD (cluster of differentiation) 4:CD8 T-cell ratios were between 0 and 1.5. The proportion of PD-L1 expressing cells in graft endothelial cells, fibroblasts, and myeloid leukocytes ranged from negligible up to 60%. We found a significant inverse logarithmic correlation between the proportion of PD-L1+HLA (human leukocyte antigen)-DR+ endothelial cells and CD8+ T cells (slope, -18.3 [95% CI, -35.3 to -1.3]; P=0.030). PD-L1 expression and leukocyte patterns were independent of demographic, clinical, and hemodynamic parameters. We confirmed the importance of endothelial PD-L1 expression in a murine allogeneic heart transplantation model, in which Tie2Crepdl1fl/fl grafts lacking PD-L1 in endothelial cells were rejected significantly faster than controls. CONCLUSIONS: Loss of graft endothelial PD-L1 expression may play a role in regulating CD8+ T-cell infiltration in human heart transplantation. Murine model results suggest that loss of graft endothelial PD-L1 may facilitate alloresponses and rejection.

Prognostic Value of Peak Oxygen Uptake in Patients Supported With Left Ventricular Assist Devices (PRO-VAD).

OBJECTIVES: The purpose of this study was to examine whether peak oxygen uptake (pVO2) and other cardiopulmonary exercise test (CPET)-derived variables could predict intermediate-term mortality in stable continuous flow LVAD recipients. BACKGROUND: pVO2 is a cornerstone in the selection of patients for heart transplantation, but the prognostic power of pVO2 obtained in patients treated with a left ventricular assist device (LVAD) is unknown. METHODS: We collected data for pVO2 and outcomes in adult LVAD recipients in a retrospective, multicenter study and evaluated cutoff values for pVO2 including: 1) values above or below medians; 2) grouping patients in tertiles; and 3) pVO2 ≤14 ml/kg/min if the patient was not treated with beta-blockers (BB) or pVO2 ≤12 ml/kg/min if the patient was taking BB therapy. RESULTS: Nine centers contributed data from 450 patients. Patients were 53 ± 13 years of age; 78% were male; body mass index was 25 ± 5 kg/m2 with few comorbidities (stroke: 11%; diabetes: 18%; and peripheral artery disease: 4%). The cause of heart failure (HF) was most often nonischemic (66%). Devices included were the HeartMate II and 3 (Abbott); and Heartware ventricular assist devices Jarvik and Duraheart (Medtronic). The index CPET was performed at a median of 189 days (154-225 days) after LVAD implantation, and mean pVO2 was 14.1 ± 5 ml/kg/min (47% ± 14% of predicted value). Lower pVO2 values were strongly associated with poorer survival regardless of whether patients were analyzed for absolute pVO2 in ml/kg/min, pVO2 ≤12 BB/14 ml/kg/min, or as a percentage of predicted pVO2 values (P ≤ 0.001 for all). For patients with pVO2 >12 BB/14 and ventilation/carbon dioxide relationship (VE/VCO2) slope <35, the 1-year survival was 100%. CONCLUSIONS: Even after LVAD implantation, pVO2 has prognostic value, similar to HF patients not supported by mechanical circulatory support devices. (PROgnostic Value of Exercise Capacity Measured as Peak Oxygen Uptake [pVO2] in Recipients of Left Ventricular Assist Devices [PRO-VAD]; NCT04423562).

Caregiver Health-Related Quality of Life, Burden, and Patient Outcomes in Ambulatory Advanced Heart Failure: A Report From REVIVAL.

Background Heart failure (HF) imposes significant burden on patients and caregivers. Longitudinal data on caregiver health-related quality of life (HRQOL) and burden in ambulatory advanced HF are limited. Methods and Results Ambulatory patients with advanced HF (n=400) and their participating caregivers (n=95) enrolled in REVIVAL (Registry Evaluation of Vital Information for VADs [Ventricular Assist Devices] in Ambulatory Life) were followed up for 24 months, or until patient death, left ventricular assist device implantation, heart transplantation, or loss to follow-up. Caregiver HRQOL (EuroQol Visual Analog Scale) and burden (Oberst Caregiving Burden Scale) did not change significantly from baseline to follow-up. At time of caregiver enrollment, better patient HRQOL by Kansas City Cardiomyopathy Questionnaire was associated with better caregiver HRQOL (P=0.007) and less burden by both time spent (P<0.0001) and difficulty (P=0.0007) of caregiving tasks. On longitudinal analyses adjusted for baseline values, better patient HRQOL (P=0.034) and being a married caregiver (P=0.016) were independently associated with better caregiver HRQOL. Patients with participating caregivers (versus without) were more likely to prefer left ventricular assist device therapy over time (odds ratio, 1.43; 95% CI, 1.03-1.99; P=0.034). Among patients with participating caregivers, those with nonmarried (versus married) caregivers were at higher composite risk of HF hospitalization, death, heart transplantation or left ventricular assist device implantation (hazard ratio, 2.99; 95% CI, 1.29-6.96; P=0.011). Conclusions Patient and caregiver characteristics may impact their HRQOL and other health outcomes over time. Understanding the patient-caregiver relationship may better inform medical decision making and outcomes in ambulatory advanced HF.

Acute cardiovascular hospitalizations and illness severity before and during the COVID-19 pandemic.

BACKGROUND: Cardiovascular disease (CVD) hospitalizations declined worldwide during the COVID-19 pandemic. It is unclear how shelter-in-place orders affected acute CVD hospitalizations, illness severity, and outcomes. HYPOTHESIS: COVID-19 pandemic was associated with reduced acute CVD hospitalizations (heart failure [HF], acute coronary syndrome [ACS], and stroke [CVA]), and worse HF illness severity. METHODS: We compared acute CVD hospitalizations at Duke University Health System before and after North Carolina's shelter-in-place order (January 1-March 29 vs. March 30-August 31), and used parallel comparison cohorts from 2019. We explored illness severity among admitted HF patients using ADHERE ("high risk": >2 points) and GWTG-HF (">10%": >57 points) in-hospital mortality risk scores, as well as echocardiography-derived parameters. RESULTS: Comparing hospitalizations during January 1-March 29 (N = 1618) vs. March 30-August 31 (N = 2501) in 2020, mean daily CVD hospitalizations decreased (18.2 vs. 16.1 per day, p = .0036), with decreased length of stay (8.4 vs. 7.5 days, p = .0081) and no change in in-hospital mortality (4.7 vs. 5.3%, p = .41). HF hospitalizations decreased (9.0 vs. 7.7 per day, p = .0019), with higher ADHERE ("high risk": 2.5 vs. 4.5%; p = .030), but unchanged GWTG-HF (">10%": 5.3 vs. 4.6%; p = .45), risk groups. Mean LVEF was lower (39.0 vs. 37.2%, p = .034), with higher mean LV mass (262.4 vs. 276.6 g, p = .014). CONCLUSIONS: CVD hospitalizations, HF illness severity, and echocardiography measures did not change between admission periods in 2019. Evaluating short-term data, the COVID-19 shelter-in-place order was associated with reductions in acute CVD hospitalizations, particularly HF, with no significant increase in in-hospital mortality and only minor differences in HF illness severity.

Racial Differences and Temporal Obesity Trends in Heart Failure with Preserved Ejection Fraction.

BACKGROUND/OBJECTIVES: Obesity increases with age, is disproportionately prevalent in black populations, and is associated with heart failure with preserved ejection fraction (HFpEF). An "obesity paradox," or improved survival with obesity, has been reported in patients with HFpEF. The aim of this study was to examine whether racial differences exist in the temporal trends and outcomes associated with obesity among older patients with HFpEF. DESIGN: Community surveillance of acute decompensated heart failure (ADHF) hospitalizations, sampled by stratified design from 2005 to 2014. SETTING: Atherosclerosis Risk in Communities Study (NC, MS, MD, MN). PARTICIPANTS: A total of 10,147 weighted hospitalizations for ADHF (64% female, 74% white, mean age 77 years), with ejection fraction ≥50%. MEASUREMENTS: ADHF classified by physician review, HFpEF defined by ejection fraction ≥50%. Body mass index (BMI) calculated from weight at hospital discharge. Obesity defined by BMI ≥30 kg/m2 , class III obesity by BMI ≥40 kg/m2 . RESULTS: When aggregated across 2005-2014, the mean BMI was higher for black compared to white patients (34 vs 30 kg/m2 ; P < .0001), as was prevalence of obesity (56% vs 43%; P < .0001) and class III obesity (24% vs 13%; P < .0001). Over time, the annual mean BMI and prevalence of class III obesity remained stable for black patients, but steadily increased for white patients, with annual rates statistically differing by race (P-interaction = .04 and P = .03, respectively). For both races, a U-shaped adjusted mortality risk was observed across BMI categories, with the highest risk among patients with a BMI ≥40 kg/m2 . CONCLUSION: Black patients were disproportionately burdened by obesity in this decade-long community surveillance of older hospitalized patients with HFpEF. However, temporal increases in mean BMI and class III obesity prevalence among white patients narrowed the racial difference in recent years. For both races, the worst survival was observed with class III obesity. Effective strategies are needed to manage obesity in patients with HFpEF.

Ambulatory Management of Worsening Heart Failure: Current Strategies and Future Directions.

Heart failure (HF) is a highly prevalent and morbid disease in the USA. The chronic, progressive course of HF is defined by periodic exacerbations of symptoms, described as 'worsening heart failure' (WHF). Previously, episodes of WHF have required hospitalization for intravenous diuretics; however, recent innovations in care delivery models for patients with HF have allowed a transition from the acute care setting to the ambulatory setting. The development of remote monitoring strategies, including device-based algorithms and implantable haemodynamic monitoring systems, has facilitated more advanced surveillance of patients, aiming to prevent the clinical deterioration that leads to hospitalization. Additionally, the establishment of multidisciplinary HF clinics has provided the setting and resources for the outpatient treatment of WHF, specifically the administration of intravenous diuretics. Here we review the current state of ambulatory HF management, including mechanisms for patient monitoring and treatment, and outline future opportunities for outpatient management of this patient population.

Management of heart failure in cardiac amyloidosis using an ambulatory diuresis clinic.

BACKGROUND: Recurrent congestion in cardiac amyloidosis (CA) remains a management challenge, often requiring high dose diuretics and frequent hospitalizations. Innovative outpatient strategies are needed to effectively manage heart failure (HF) in patients with CA. Ambulatory diuresis has not been well studied in restrictive cardiomyopathy. Therefore, we aimed to examine the outcomes of an ambulatory diuresis clinic in the management of congestion related to CA. METHODS AND RESULTS: We retrospectively studied patients with CA seen in an outpatient HF disease management clinic for (1) safety outcomes of ambulatory intravenous (IV) diuresis and (2) health care utilization. Forty-four patients with CA were seen in the clinic a total of 203 times over 6 months. Oral diuretics were titrated at 96 (47%) visits. IV diuretics were administered at 56 (28%) visits to 17 patients. There were no episodes of severe acute kidney injury or symptomatic hypotension. There was a significant decrease in emergency department and inpatient visits and associated charges after index visit to the clinic. The proportion of days hospitalized per 1000 patient days of follow-up decreased as early as 30 days (147.3 vs 18.1/1000 patient days of follow-up, P< .001) and persisted through 180 days (33.6 vs 22.9/1000 patient days of follow-up, P< .001) pre- vs post-index visit to the clinic. CONCLUSIONS: We demonstrate the feasibility of ambulatory IV diuresis in patients with CA. Our findings also suggest that use of a HF disease management clinic may reduce acute care utilization in patients with CA. Leveraging multidisciplinary outpatient HF clinics may be an effective alternative to hospitalization in patients with HF due to CA, a population who otherwise carries a poor prognosis and contributes to high health care burden.