BACKGROUND:Hypertension is present in 90% of individuals with heart failure with preserved ejection fraction (HFpEF) and is a major modifiable risk factor for the development of HFpEF. However, randomized controlled trial evidence for hypertension management in HFpEF is limited. METHODS:In a double-blind, randomized, crossover trial, we studied the effect of amlodipine 5 to 10 mg versus metoprolol succinate 100 to 200 mg (doses previously demonstrated to have comparable antihypertensive efficacy) for 4 weeks among adults with HFpEF and hypertension, without contraindications to initiating or withholding either drug. The primary outcome was the difference in mean home systolic blood pressure (BP) during the final week of each treatment. RESULTS:The mean age of the 50 enrolled participants was 72±9 years, 34 (68%) were female, 33 (66%) were of Black race, mean blood pressure was 144±15/78±9 mm Hg, and 23 (46%) were receiving β-blockers before enrollment. Compared with metoprolol, systolic BP was 4 (95% CI, -7 to -1; P=0.017) mm Hg lower with amlodipine. In addition, peak oxygen uptake during exercise was 1.2 (95% CI, 0.3-2.0; P=0.008) mL/min per kg higher, physical activity was 0.1 (95% CI, 0.01-0.1; P=0.019) metabolic equivalents of task/d higher, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) was 200 (95% CI, -291 to -109; P<0.0001) pg/mL lower with amlodipine versus metoprolol. There was no significant difference in septal E/e', myocardial strain, or systemic vasodilatory reserve. The frequency and severity of adverse events were similar across treatments. CONCLUSIONS:Our findings support the use of dihydropyridine calcium channel blockers as a preferred alternative to β-blockers for the management of hypertension in HFpEF. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04434664.

Importance Nitric oxide deficiency may contribute to exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Prior pilot studies have shown improvements in exercise tolerance with single-dose and short-term inorganic nitrate administration. Objective To assess the impact of chronic inorganic nitrate administration on exercise tolerance in a larger trial of participants with HFpEF. Design, Setting, and Participants This multicenter randomized double-blinded crossover trial was conducted at the University of Pennsylvania, the Philadelphia Veterans Affairs Medical Center, and Northwestern University between October 2016 and July 2022. Participants included patients with symptomatic (New York Heart Association class II/III) HFpEF who had objective signs of elevated left ventricular filling pressures. Image quantification, physiological data modeling and biochemical measurements, unblinding, and statistical analyses were completed in 2024. Intervention Potassium nitrate (KNO3) (6 mmol 3 times daily) vs equimolar doses of potassium chloride (KCl) for 6 weeks, each with a 1-week washout in between. MAIN OUTCOMES AND MEASURES The coprimary end points included peak oxygen uptake and total work performed during a maximal effort incremental cardiopulmonary exercise test. Secondary end points included the exercise systemic vasodilatory reserve (ie, reduction in systemic vascular resistance with exercise) and quality of life assessed using the Kansas City Cardiomyopathy Questionnaire. Results Eighty-four participants were enrolled. Median age was 68 years and 58 participants were women (69.0%). Most participants had NYHA class II disease (69%) with a mean 6-minute walk distance of 335.5 (SD, 97.3) m. Seventy-seven participants received the KNO3 intervention and 74 received the KCl intervention. KNO3 increased trough levels of serum nitric oxide metabolites after 6 weeks (KNO3, 418.4 [SD, 26.9] uM vs KCl, 40.1 [SD, 28.3] uM; P < .001). KNO3 did not improve peak oxygen uptake (KNO3, 10.23 [SD, 0.43] mL/min/kg vs KCl, 10.17 [SD, 0.43] mL/min/kg; P = .73) or total work performed (KNO3, 25.9 [SD, 3.65] kilojoules vs KCl, 23.63 [SD, 3.63] kilojoules; P = .29). KNO3 nitrate did not improve the vasodilatory reserve or quality of life, though it was well-tolerated. Conclusions and Relevance In this study, potassium nitrate did not improve aerobic capacity, total work, or quality of life in participants with HFpEF.

AIMS:Acute decompensated heart failure (ADHF) is associated with a high degree of morbidity and mortality. Dynamic lung ultrasound artefact called B-lines can be obtained at the bedside and directly correlate with pulmonary vascular congestion. Obtaining patient-performed lung ultrasound images in the outpatient setting is novel. We assessed the feasibility of patients recently hospitalized for ADHF to self-perform a limited lung ultrasound using a handheld ultrasound probe and upload the images to a secure cloud for physician interpretation. METHODS:This was a prospective observational convenience sample. Patients were enrolled from an urban academic tertiary care centre and were eligible if they had chronic left-sided heart failure regardless of ejection fraction. While hospitalized, patients were educated for 20 min on a six-lung-zone image protocol, how to use the cloud archival system and given a handheld ultrasound transducer and smart tablet. A brief instructional video was also available to patients on the smart tablet throughout the study (https://www.dropbox.com/scl/fi/bii7ovdcv21ps7yxyqsy1/120-21080-00-Rev-01-BNI-041-UPENN-IN-APP-TRAINING-VIDEO.mp4?rlkey=f5vu55xbnugdoz6jzyb8lv872&st=56es4qif&dl=0). Patients were asked to upload images three times weekly, for 3 weeks, for a total of nine studies. All images were reviewed and a B-line score was calculated for each lung zone, and a total B-line score for the entire exam. Additionally, patients completed a survey to assess the patient-centred experience. RESULTS:A total of 15 patients were enrolled, all of whom completed seven or more studies (10 patients completed all 9). Median patient age was 63 years (range: 28 -86 years), the majority were male (73%), white (60%) and average body mass index was 33 kg/m2. Of them,33.3% had an ejection fraction >50%, average hospital length of stay was 6.3 days. Of the 792 potential images, 788 were obtained (99.5%). Of these, a total of 637 scans were interpretable (80.8%). The right upper apical lung zone (zone 1R) was most often adequate for interpretation (96.2%), where left lower mid-axillary (zone 3L) was least often interpretable (69.5%). The average number of B-lines per six-image scan was three (with a range of 0-13). Patient survey data identified zone 3L as the most challenging to obtain with overall high satisfaction with the study educational materials. CONCLUSIONS:This pilot study demonstrates that patients with hospitalized ADHF can be taught to use a handheld portable ultrasound device and obtain and upload high quality lung ultrasound images. Compliance with the study protocol and ability to obtain some images were excellent. Further studies are needed to determine if patient-performed lung ultrasound can help detect and manage acute worsening HF in this patient population.

BACKGROUND:The etiology of exercise intolerance in heart failure with preserved ejection fraction (HFpEF) is multifactorial. Several contributing pathways may be improved by ketone ester (KE). OBJECTIVES:This study aims to determine whether KE improves exercise tolerance in HFpEF. METHODS:KETO-HFpEF (Ketogenic Exogenous Therapies in HFpEF) is a randomized, crossover, placebo-controlled trial of acute KE dosing in 20 symptomatic HFpEF participants. Coprimary endpoints include peak oxygen consumption (VO2) during incremental cardiopulmonary exercise testing and time to exhaustion during an additional constant-intensity exercise (75% peak workload) bout. RESULTS:The average age was 71 ± 8 years, 60% were women, and 65% were White. KE did not improve peak VO2 (KE: 10.4 ± 3.6 vs placebo: 10.5 ± 4.0 mL/kg/min; P = 0.75). At rest, heart rate, biventricular systolic function, and cardiac output (0.6 L/min [95% CI: 0.3-1.0 L/min]) were greater with KE vs placebo, whereas total peripheral resistance (-3.2 WU [95% CI: -5.2 to -1.2 WU]) and the arteriovenous oxygen content difference (-0.7 mL of O2/dL blood [95% CI: -1.2 to -0.2 mL]) were lower. These differences mostly disappeared during incremental exercise. KE did not improve exercise endurance during the constant-intensity protocol (9.7 ± 7.3 minutes vs 8.7 ± 4.4 minutes; P = 0.51). In 6 participants receiving 6,6-2H2-glucose infusions during constant-intensity exercise, plasma glucose appearance rate before and during exercise was lower with KE (-0.24 mg/kg/min; P < 0.001). During both exercise protocols, KE lowered: 1) respiratory exchange ratios, demonstrating decreased systemic carbohydrate use; 2) nonesterified fatty acids and glucose; and 3) estimated left ventricular filling pressures (E/e'). CONCLUSIONS:Despite robust ketosis, shifting substrate use away from carbohydrates, and decreasing estimated left ventricular filling pressures, acute KE supplementation did not improve peak VO2 or constant-intensity exercise in HFpEF. (Ketogenic Exogenous Therapies in HFpEF [KETO-HFpEF]; NCT04633460).

While heart failure with preserved ejection fraction (HFpEF) is associated with the presence of obstructive sleep apnea (OSA), few studies have examined the association between scoring systems used to predict HFpEF risk, such as the H2FPEF and HFA-PEFF scores, and OSA prevalence and severity. We performed chart review on all patients who underwent both an echocardiogram and sleep study at the University of Pennsylvania between July 1, 2020, and June 30, 2022. There were 277 patients in the final cohort after excluding patients with relevant comorbidities. Associations between echocardiographic parameters and OSA severity, as well as between H2FPEF score and OSA severity, were examined using linear tests of trend. The association between H2FPEF score and prevalent OSA was examined with logistic regression. OSA severity was associated with echocardiographic markers, including left atrial volume index (P = .03) and left ventricular relative thickness (P = .008). Patients with high H2FPEF risk scores had over 17-fold higher odds of prevalent OSA compared with those with low-risk scores (17.7; 95

Background: While heart failure with preserved ejection fraction (HFpEF) is highly associated with the presence of sleep apnea, few studies have examined the association between diagnostic scoring systems used to predict HFpEF risk, such as the H 2 FPEF score, and OSA prevalence and severity. Methods: We performed a retrospective chart review on all patients (N = 434) who underwent both an echocardiogram and a sleep study at the University of Pennsylvania between July 1, 2020, and June 30, 2022. Associations between echocardiographic parameters and OSA severity, as well as between H 2 FPEF score and OSA severity, were examined using linear tests of trend. The association between H 2 FPEF score categorization and odds of prevalent OSA was examined with logistic regression. Results: OSA severity was associated with echocardiographic markers of diastolic dysfunction including greater LV mass index (p = 0.04), left atrial volume index (p = 0.03), and LV relative thickness (p = 0.008). Patients with intermediate H 2 FPEF risk scores had 4.3 times greater odds of prevalent OSA compared with those patients with low risk H 2 FPEF scores (95% CI 2.2, 8.7, p < 0.001). Patients with high H2FPEF risk scores had over 17-fold higher odds of prevalent OSA compared to those with low-risk scores (17.7, 95% CI 4.3, 120.7, p < 0.001) (Figure 1). Increasing risk of HFpEF according to H 2 FPEF categorization was strongly correlated with OSA severity as measured by apnea-hypopnea index (p < 0.001) and oxygen desaturation index (p = 0.002). Conclusions: In an ambulatory population referred for both sleep study and echocardiogram, markers of diastolic dysfunction were associated with OSA severity. OSA prevalence and severity were strongly associated with increased H 2 FPEF scores. Clinicians should have a low threshold for referring OSA patients with dyspnea for cardiac workup, as well as a low threshold for referring HFpEF patients for sleep study.

Limited venous access and lateral left ventricular scar are impediments to traditional cardiac resynchronization therapy. We present a case where placement of an implantable cardioverter-defibrillator from a femoral approach while using left bundle branch area pacing led to clinical improvement. (Level of Difficulty: Intermediate.)

We present a case of cardiac sarcoidosis with persistent, focal fluorodeoxyglucose uptake at the left ventricular apical aneurysm concerning for ongoing active inflammatory injury, prompting aggressive immunosuppressive therapy. This case highlights the importance of understanding the various clinical entities that may resemble disease activity on fluorodeoxyglucose positron emission tomography/computed tomography imaging. (Level of Difficulty: Intermediate.).

Introduction: Acute Decompensated Heart Failure (ADHF) is associated with a high degree of morbidity and mortality. Dynamic lung ultrasound artifact called B-lines directly correlate with pulmonary vascular congestion (PVC) and can be seen on a limited lung ultrasound. Hypothesis: We assessed the ability of a recently hospitalized patient with ADHF to self-perform a lung ultrasound using a hand-held ultrasound and store images for physician interpretation. Methods: This was a prospective observational convenience sample of patients with known chronic heart failure admitted to an urban academic tertiary care center. The patient was educated on a 6 lung-zone image protocol, how to use the cloud archival system, and given a hand-held ultrasound transducer and iPad. The patients were asked to upload images three times a week, for 3 weeks. A B-line score for each interpretable lung zone was calculated. Results: Fifteen patients were enrolled, all of whom completed 7 or more scans. Average patient age was 60 years (range: 28- 86 years), 73% male, 60% white, and 47% obese. Five patients had ejection fraction >50%, and average length of hospital stay was 6.3 days. Of the 792 potential images, 784 were obtained (99%) and 637 (81%) were interpretable. The right upper zone was most often interpretable (97%), whereas the left lateral zone was least (70%). Median patient B line score when indexed to 6 interpretable scans was 3.00. Indexed B line scores are shown for all 15 patients (Figure 1). Patient survey data identified the left lateral zone as the most challenging to obtain. Conclusions: This pilot study shows that patients with ADHF can be taught how to use a hand-held portable ultrasound device and obtain and upload lung ultrasound images to a cloud. Compliance with the study protocol was excellent. Further studies are needed to determine if patient-performed lung ultrasound can be useful to clinicians to detect and manage PVC in this patient population.

Introduction: Pulmonary hypertension (PH) in the setting of heart failure with preserved ejection fraction (PH-HFpEF) is further characterized as isolated post-capillary PH (IpcPH) or combined pre- & post-capillary PH (CpcPH). This is distinguished by pulmonary vascular resistance (PVR) cut-off of 3 WU. Prior definitions used a diastolic pulmonary gradient (DPG) cut-off of 7mmHg to distinguish PH subtype. Studies have examined echocardiographic right ventricular outflow tract Doppler notching (RVOT-notch) as a correlate for pulmonary vascular disease, though its role in distinguishing PH-HFpEF subtype by current vs. prior definition has never been described. Hypothesis: Our study explores the ability of RVOT-notch to distinguish CpcPH from IpcPH in patients with PH-HFpEF, in the context of current PVR & prior DPG cutpoints. Methods: We retrospectively reviewed patients with PH-HFpEF referred to our PH program who underwent right heart catheterization and echo (later reviewed independently by blinded cardiologists to assess RVOT-notch). Results: 86 patients with PH-HFpEF were reviewed with a mean age of 66 and female predominance. Patients with RVOT-notch had signs of worsening right heart function both via echocardiography (higher estimated PASP, more severe TR, lower TAPSE) & hemodynamically (higher DPG, higher PVR, and lower pulmonary arterial compliance). RVOT-notch was able to distinguish CpcPH from IpcPH, with current PVR cut-off ≥3 WU (sensitivity 91%, specificity 68%, PPV 76%, NPV 88%) and prior DPG cut-off ≥7mmHg (sensitivity of 94%, specificity 58%, PPV 57%, NPV 94%). Conclusions: In PH-HFpEF, RVOT-notch is a sensitive marker of CpcPH, and notably better reflects the current PVR-based definition (PVR≥3) with better specificity than prior DPG-based definition. This could have implications as non-invasive screening for CpcPH in patients with PH-HFpEF. Further work is needed to validate this marker in larger cohorts.

Background: Cardiac point of care ultrasound (POCUS) is increasingly utilized by trainees across various specialties and can rapidly assess the cardiac status of unstable patients. However, the quality of trainee performed cardiac examinations has been reported only in controlled studies. In this study we aimed to assess the quality of all cardiac POCUS performed by internal medicine trainees at a major academic medical center over a three-year period. Methods: 256 studies were included and were graded by experts blinded to postgraduate year (PGY) using a previously validated scoring metric. Results: We found significant improvement in overall quality of resident performed cardiac POCUS from PGY 1 to 3 (10.8, 10.2, 13.2, p = 0.012). Assessment of left ventricular function was possible in 82% of studies and increased from PGY 1 to PGY 3 (77%, 76%, 88%, p = 0.025). Similar trends were seen in the assessment of the pericardial space (67%, 71%, 84%, p = 0.012). Images sufficient for right ventricular and volume status assessment were less commonly found (65%, 60%, 75% and 60%, 49%, 57%, respectively). Conclusions: This study provides a real world experience of the level of diagnostic accuracy that can be expected from IM trainees with minimal hands-on supervision.

Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p < 0.001) of the association between DM and the risk of cardiovascular death, aborted cardiac arrest, and heart failure hospitalization. (C) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

AbstractAimsSkeletal muscle (SkM) abnormalities may impact exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF). We sought to quantify differences in SkM oxidative phosphorylation capacity (OxPhos), fibre composition, and the SkM proteome between HFpEF, hypertensive (HTN), and healthy participants.Methods and resultsFifty‐nine subjects (20 healthy, 19 HTN, and 20 HFpEF) performed a maximal‐effort cardiopulmonary exercise test to define peak oxygen consumption (VO2, peak), ventilatory threshold (VT), and VO2 efficiency (ratio of total work performed to O2 consumed). SkM OxPhos was assessed using Creatine Chemical‐Exchange Saturation Transfer (CrCEST, n = 51), which quantifies unphosphorylated Cr, before and after plantar flexion exercise. The half‐time of Cr recovery (t1/2, Cr) was taken as a metric of in vivo SkM OxPhos. In a subset of subjects (healthy = 13, HTN = 9, and HFpEF = 12), percutaneous biopsy of the vastus lateralis was performed for myofibre typing, mitochondrial morphology, and proteomic and phosphoproteomic analysis. HFpEF subjects demonstrated lower VO2,peak, VT, and VO2 efficiency than either control group (all P < 0.05). The t1/2, Cr was significantly longer in HFpEF (P = 0.005), indicative of impaired SkM OxPhos, and correlated with cycle ergometry exercise parameters. HFpEF SkM contained fewer Type I myofibres (P = 0.003). Proteomic analyses demonstrated (a) reduced levels of proteins related to OxPhos that correlated with exercise capacity and (b) reduced ERK signalling in HFpEF.ConclusionsHeart failure with preserved ejection fraction patients demonstrate impaired functional capacity and SkM OxPhos. Reductions in the proportions of Type I myofibres, proteins required for OxPhos, and altered phosphorylation signalling in the SkM may contribute to exercise intolerance in HFpEF.

Background: Focused cardiac ultrasound (FCU) is a safe and efficient diagnostic intervention for internal medicine physicians. FCU is a highly teachable skill, but is used in routine cardiac assessment in only 20% of surveyed training programs. We developed an FCU curriculum for internal medicine residents and an assessment tool to evaluate the impact of the curriculum on trainee knowledge and confidence. Methods: Internal medicine residents rotating through clinical cardiology services underwent 30 minutes of didactic and 60 minutes of hands-on teaching on acquisition and interpretation of FCU. A 20 item pre and post-curriculum online survey was administered (November 2018-December 2019) to assess confidence and knowledge in FCU. Results: 79 of 116 (68%) residents completed the pre-survey and 50 completed the post-survey, of whom 34 received the curriculum. The mean change in confidence score in those who received versus did not receive the curriculum was 0.99 versus 0.39 (p=0.046) on a 5-point Likert scale. Among 33 residents who had paired pre- and post-surveys the mean change in confidence score was 1.2 versus 0.85 (p<0.001) in those who received versus did not receive the curriculum. The mean increase in knowledge score was 13% versus 7% respectively (p<0.0001). Conclusions: We instituted a novel curriculum for internal medicine residents to gain experience in image acquisition and interpretation. Both confidence and knowledge in FCU improved following the curriculum, indicating that this is a highly teachable skill. Additional analysis of the of the FCU study images will be useful for informing future interventions.

Case Presentation: A 29-year-old male with LVH diagnosed in childhood was admitted with acute HF. TTE showed LVEF 5-10% and LV thrombi for which he was anticoagulated. He received inappropriate ICD shocks due to T wave oversensing, leading to cardiogenic shock requiring VA-ECMO support. Serum lactate peaked at 17 mmol/L due to cardiac and metabolic decompensation. He underwent heart transplantation (HT) on hospital day (HD) 8 and tolerated standard immunosuppression. First endomyocardial biopsy showed acute cellular rejection requiring pulse steroids. He was discharged on HD 33. Trio whole exome and mitochondrial genome sequencing revealed biallelic variants in complement component 1Q subcomponent-binding protein ( C1QBP ), due to a maternally inherited likely pathogenic variant c.612C>G (p.F204L in exon 5) and an apparently de novo deletion of 17p13.2, spanning exons 4-6 of C1QBP and exon 6 of the RPAIN gene. Mitochondrial genome sequencing of the explanted heart revealed multiple large-scale mitochondrial DNA deletions at 33% heteroplasmy. Discussion: C1QBP variants are associated with mitochondrial and multi-organ dysfunction. Only 12 patients exhibiting biallelic C1QBP variants are reported. Four died in the peripartum period due to fetal hydrops or HF; 5 exhibited early-onset cardiomyopathy (CM); 3 others had late-onset ophthalmoplegia without CM. The p.F204L variant has been reported in 1 patient with compound C1QBP p.F204L/p.C186S heterozygosity who died from hydrops fetalis and a second with p.F204L homozygosity with late-onset ophthalmoplegia and skeletal myopathy without CM. Differences in the size, heteroplasmy, and tissue distribution of mitochondrial genome secondary deletions may explain variability in disease onset and progression. We present the first patient with biallelic pathogenic C1QBP gene variants with mitochondrial CM to undergo HT and highlight the diagnosis and management of an exceptionally uncommon genetic disorder.

OBJECTIVES:This study sought to assess if clinical phenogroups differ in comprehensive biomarker profiles, cardiac and arterial structure/function, and responses to spironolactone therapy. BACKGROUND:Previous studies identified distinct subgroups (phenogroups) of patients with heart failure with preserved ejection fraction (HFpEF). METHODS:Among TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial) participants, we performed latent-class analysis to identify HFpEF phenogroups based on standard clinical features and assessed differences in multiple biomarkers measured from frozen plasma; cardiac and arterial structure/function measured with echocardiography and arterial tonometry; prognosis; and response to spironolactone. RESULTS:Three HFpEF phenogroups were identified. Phenogroup 1 (n = 1,214) exhibited younger age, higher prevalence of smoking, preserved functional class, and the least evidence of left ventricular (LV) hypertrophy and arterial stiffness. Phenogroup 2 (n = 1,329) was older, with normotrophic concentric LV remodeling, atrial fibrillation, left atrial enlargement, large-artery stiffening, and biomarkers of innate immunity and vascular calcification. Phenogroup 3 (n = 899) demonstrated more functional impairment, obesity, diabetes, chronic kidney disease, concentric LV hypertrophy, high renin, and biomarkers of tumor necrosis factor-alpha-mediated inflammation, liver fibrosis, and tissue remodeling. Compared with phenogroup 1, phenogroup 3 exhibited the highest risk of the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest (hazard ratio [HR]: 3.44; 95% confidence interval [CI]: 2.79 to 4.24); phenogroups 2 and 3 demonstrated similar all-cause mortality (phenotype 2 HR: 2.36; 95% CI: 1.89 to 2.95; phenotype 3 HR: 2.26, 95% CI: 1.77 to 2.87). Spironolactone randomized therapy was associated with a more pronounced reduction in the risk of the primary endpoint in phenogroup 3 (HR: 0.75; 95% CI: 0.59 to 0.95; p for interaction = 0.016). Results were similar after excluding participants from Eastern Europe. CONCLUSIONS:We identified important differences in circulating biomarkers, cardiac/arterial characteristics, prognosis, and response to spironolactone across clinical HFpEF phenogroups. These findings suggest distinct underlying mechanisms across clinically identifiable phenogroups of HFpEF that may benefit from different targeted interventions.

In December 2019, an outbreak of a severe respiratory viral illness was first identified in the Hubei province of China. The illness was later discovered to be caused by infection with a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To the best of our knowledge, we present here the first confirmed case of COVID-19 in a patient on left ventricular assist device (LVAD) support. Our case patient is a 66-year-old man with a history of end-stage ischemic cardiomyopathy, on HeartMate II (Abbott Laboratories, Abbott Park, IL) LVAD as destination therapy, hypertension, atrial flutter, and ischemic stroke who presented with a 4-day history of fever, cough, and shortness of breath after recent 2-month travel to Egypt. Initial physical examination revealed a body temperature of 100.9°F (38.3°C), normal mean arterial pressure by Doppler, and oxygen saturation of 70% on room air. Arterial blood gas revealed a partial pressure of oxygen in arterial blood of 46 mm Hg despite delivery of 100% fraction of inspired oxygen via nonrebreather ventilation. LVAD parameters were stable on presentation. A chest radiograph showed bilateral pulmonary infiltrates suggestive of multifocal pneumonia (Fig. 1a). The patient seemed to be in moderate respiratory distress, with tachypnea and accessory muscle use. Owing to concern for developing respiratory muscle fatigue and impending respiratory failure, the decision was made to pursue intubation and mechanical ventilation. Testing for novel coronavirus returned positive for SARS-CoV-2 by polymerase chain reaction. Salient features of the patient's initial clinical laboratory trend include lymphocytopenia, transaminitis, and hyperbilirubinemia, as well as elevated creatinine, lactate dehydrogenase, d-dimer, and ferritin levels. In the following days, the patient developed progressive hypotension requiring initiation of vasopressor agents, acute oliguric renal failure requiring continuous renal replacement therapy, and refractory hypoxemia consistent with acute respiratory distress syndrome (ARDS). Right ventricular failure was considered as a potential etiology of hypotension in the setting of LVAD and inflammatory surge. The patient was unable to be transferred to the catheterization laboratory for invasive hemodynamic assessment owing to COVID-19. Pulmonary artery catheterization was attempted at the bedside, but placement was unsuccessful. A central line was used to measure central venous pressure (17 mm Hg) and oxygen saturation (central venous oxygen saturation of 75%). Transthoracic echocardiogram revealed baseline moderate right ventricular dysfunction. LVAD parameters otherwise remained stable. Management of ARDS was further complicated by refractory hypoxemia despite mechanical ventilation. Implementation of prone positioning was considered to assist with oxygenation; however, the presence of LVAD was determined to be a relative contraindication. Although it has previously been shown that prone positioning unloads the right ventricle in ARDS owing to improved pulmonary pressures,1Zochios V. Parhar K. Vieillard-baron A. Protecting the right ventricle in ARDS: the role of prone ventilation.J Cardiothorac Vasc Anesth. 2018; 32: 2248-2251Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar the use of this maneuver in the setting of LVAD has not been well-described and may be adversely associated with increase in right ventricular pressures and subsequent right ventricular failure. The patient's clinical course was later complicated by septic shock in the setting of Escherichia coli and Lactobacillus species bacteremia, hyperbilirubinemia secondary to acalculous cholecystitis with requirement for percutaneous cholecystostomy, and acute blood loss anemia secondary to gastrointestinal bleed requiring blood transfusion. Owing to prolonged ventilator-dependent respiratory failure, the patient underwent placement of tracheostomy. The patient was treated with hydroxychloroquine 600 mg twice daily after the initial diagnosis. Oseltamivir 75 mg twice daily was added and, once liquid lopinavir-ritonavir was available at our institution, the patient was switched to lopinavir–ritonavir 400–100 mg twice daily on treatment day 5, but was discontinued in the setting of hyperbilirubinemia on treatment day 9. He was transitioned back to hydroxychloroquine 200 mg twice daily to complete a total 14-day course. The patient was deemed not a candidate for the compassionate use of remdesivir owing to poor creatinine clearance. This report describes the first known presentation of illness secondary to SARS-CoV-2 in a patient with long-term LVAD support. At the time of writing, the patient remains critically ill; however, there has been clinical improvement. Recent evidence suggests that patients with cardiovascular comorbidities seem to be at increased risk of morbidity and mortality with COVID-19.2Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18526) Google Scholar Notably, prior studies have shown that cellular immunity is compromised among long-term LVAD recipients.3Ankersmit H.J. Tugulea S. Spanier T. Weinberg A.D. Artrip J.H. Burke E.M. et al.Activation-induced T-cell death and immune dysfunction after implantation of left-ventricular assist device.Lancet. 1999; 354: 550-555Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar,4Kimball P.M. Flattery M. Mcdougan F. Kasirajan V. Cellular immunity impaired among patients on left ventricular assist device for 6 months.Ann Thorac Surg. 2008; 85: 1656-1661Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar This "functionally immunocompromised state" may in part explain the patient's rapid clinical deterioration and prolonged critical illness after infection with SARS-CoV-2. Increased susceptibility to viral infections, particularly COVID-19, in the setting of LVAD has not been reported previously in the literature. Furthermore, this case highlights an important consideration for the management of ARDS, as the safety and efficacy of prone positioning in the presence of LVAD is currently unknown. Finally, we propose the establishment of a COVID-LVAD registry to further understand the impact of COVID-19 on this advanced heart failure population.

BACKGROUND:Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF).OBJECTIVES:The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF.METHODS:In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156).RESULTS:Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro-B-type natriuretic peptide. A machine-learning-derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score.CONCLUSIONS:Various novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.