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Our goal in writing this review was to provide a comprehensive appraisal of current therapies for idiopathic recurrent pericarditis with a particular focus on the newest therapeutic agents. We sought to understand the role of the inflammasome in the pathophysiology of pericarditis and how it informs the use of interleukin-1 (IL-1)-directed therapies.The latest research on this topic has focused on the critical role of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein) inflammasome. Very recently, components of the NLRP3 inflammasome were detected by immune staining in pericardial tissue from patients with recurrent idiopathic pericarditis. In a mouse model of pericarditis, anti-IL-1 agents anakinra and rilonacept reduced NLRP3 immunostaining. Subsequent study of these drugs in human subjects with idiopathic recurrent pericarditis demonstrated their efficacy. Recurrent idiopathic pericarditis, while relatively rare, poses a continued treatment challenge and contributes to a diminished quality of life for those patients who are afflicted. Recent developments, including an animal model of the disease and the use of IL-1-directed therapies, represent an exciting leap forward in our understanding of treatment targets. These advances offer not only new tools in our fight against this disease, but also the promise of earlier intervention and attenuation of disease morbidity. As our experience with these new agents expands, we can address questions about the ideal timing of introduction of anti-IL-1 therapy and duration of therapy and better understand the potential side effect profile.

To obtain a nationally representative annualized estimate of the prevalence of pericarditis (inflammation of the pericardium) in the United States (US) in order to better understand the potential burden on the health care system. Three nationally representative datasets were used to estimate the annualized period prevalence and prevalence rate of pericarditis from 2007 to 2016: the National Ambulatory Medical Care Survey (NAMCS), the National Hospital Ambulatory Medical Care Survey (NHAMCS), and the Nationwide Inpatient Sample (NIS). Across all data sources, ICD-9/10 codes were used to identify healthcare encounters with ≥1 primary or secondary diagnosis related to pericarditis irrespective of duration or etiology. The prevalence of pericarditis in 2020 was extrapolated by multiplying the average annualized prevalence rate from 2007 to 2016 by the total US population as of March 2020. Data from NAMCS/NHAMCS (2007–2016) yielded an average annualized estimate of 125,209 patients with pericarditis, resulting in a pooled average annualized prevalence estimate of 40 patients with pericarditis per 100,000 persons. Data from NIS (2007–2016) yielded an average annualized estimate of 34,441 patients with pericarditis, resulting in a pooled average annualized prevalence estimate of 11 hospitalized patients with pericarditis per 100,000 persons. Extrapolation of these results based on the March 2020 population estimates from the US Census Bureau of 329,436,928 resulted in an estimated US prevalence of pericarditis to be approximately160,000. Despite certain methodologic limitations, our analysis of data from nationally representative sources support that pericarditis is a rare disease affecting substantially fewer than 200,000 persons in the US.

Anti-interleukin (IL)-1 agents have been developed for the treatment of autoinflammatory and rheumatic conditions, where overproduction of IL-1 is an important pathophysiologic process. IL-1α and IL-1β are the most studied members of the IL-1 family of cytokines and have the strongest proinflammatory effects. A naturally occurring antagonist (IL-1Ra) mitigates their proinflammatory effects. Overproduction of both IL-1α (released by inflamed/damaged pericardial cells) and IL-1β (released by inflammatory cells) is now a well-recognized therapeutic target in patients with recurrent idiopathic pericarditis. Currently, there are three available anti-IL-1 agents: anakinra (recombinant human IL-1Ra), rilonacept (a soluble decoy receptor ‘trap’, binding both IL-1α and IL-1β), and canakinumab (human monoclonal anti-IL-1β antibody). For patients with corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation, as evidenced by elevated C-reactive protein, the efficacy and safety of anakinra (2 mg/kg/day up to 100 mg/day subcutaneously usually for at least 6 months, then tapered) and rilonacept (320 mg subcutaneously for the first day followed by 160 mg subcutaneously weekly) have been clearly demonstrated in observational studies and randomized controlled clinical trials. Severe side effects are rare and discontinuation rates are very low (50% of patients). In this article, we describe the historical and pathophysiological background and provide a comprehensive review of these agents, which appear to be the most significant advance in medical therapy of recurrent pericarditis in the last 5 years.

The interaction of phospholamban (PLB) and the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) is a key regulator of cardiac contractility and a therapeutic target in heart failure (HF). PLB-mediated increases in SERCA2a activity improve cardiac function and HF. Clinically, this mechanism can only be exploited by a general activation of the proteinkinase A (PKA), which is associated with side effects and adverse clinical outcomes. A selective interference of the PLB-SERCA2a interaction is desirable but will require novel tools that allow for an integrated assessment of this interaction under both physiological and pathophysiological conditions. A circularly permutated green fluorescent protein (cpGFP) was interposed between SERCA2a and PLB to result into a single SERCA2a-cpGFP-PLB recombinant protein (SGP). Expression, phosphorylation, fluorescence, and function of SGP were evaluated. Expression of SGP-cDNA results in a functional recombinant protein at the predicted molecular weight. The PLB domain of SGP retains its ability to polymerize and can be phosphorylated by PKA activation. This increases the fluorescent yield of SGP by between 10% and 165% depending on cell line and conditions. In conclusion, a single recombinant fusion protein that combines SERCA2a, a circularly permutated green fluorescent protein, and PLB can be expressed in cells and can be phosphorylated at the PLB domain that markedly increases the fluorescence yield. SGP is a novel cellular SERCA2a-PLB interaction monitor. NEW & NOTEWORTHY This study describes the design and characterization of a novel biosensor that can visualize the interaction of SERCA2a and phospholamban (PLB). The biosensor combines SERCA2a, a circularly permutated green fluorescent protein, and PLB into one recombinant protein (SGP). Proteinkinase A activation results in phosphorylation of the PLB domain and is associated with a marked increase in the fluorescence yield to allow for real-time monitoring of the SERCA2a and PLB interaction in cells.

Background: Post-episode tapering of Standard of Care (SoC) medication in patients with recurrent pericarditis (RP) varies considerably. Gradual tapering of corticosteroids (CS) is recommended in ESC guidelines (decreasing by 1-2.5 mg/day every 2-6 weeks over 1-2 years) to prevent recurrence. We describe successful faster tapering of SoC treatment onto rilonacept monotherapy during RHAPSODY, a Phase 3, placebo-controlled, randomized-withdrawal (RW) trial in RP. Methods: Patients with acute symptomatic RP despite stable doses of NSAIDs, colchicine, and/or CS in any combination enrolled in a 12-week run-in period in which weekly rilonacept was initiated. After 1-week of stabilization, tapering of CS began at a rate dependent on baseline dose, to be completed by Week 10 for randomization at Week 12 when clinical response was confirmed by reduced pain and normalized CRP levels. Colchicine tapering/discontinuation was initiated no earlier than Week 4. This analysis evaluates time to rilonacept monotherapy in subgroups receiving different combinations of background therapies. Results: 79 of 86 patients were receiving pharmacotherapy at run-in baseline. Median (95% CI) time to monotherapy (n=79) was 7.9 (7.0-8.1) weeks. Of the patients receiving CS at baseline (41/86 [48%]), 39 (95%) tapered to rilonacept monotherapy, and median time to monotherapy was 7.9 (7.1-8.1) weeks. Of the patients receiving colchicine at baseline (65/86 [76%]), 61 (94%) patients achieved rilonacept monotherapy, and median time to monotherapy was 8.0 (7.1-8.3) weeks. Patients receiving only one SoC therapy achieved rilonacept monotherapy faster (6.1 [0.4-8.1] weeks) than those receiving 2 (8.0 [6.7-9.9] weeks) or 3 (7.7 [7.0-8.3] weeks) therapies. All patients who did not achieve monotherapy had withdrawn from the study for reasons unrelated to pericarditis. Conclusion: All patients randomized in the RHAPSODY trial discontinued SoC and transitioned to rilonacept monotherapy (median time 7.9 weeks) without a recurrent pericarditis episode during run-in. With rilonacept, time to successful discontinuation of SoC, including high dose CS, was substantially more rapid than current treatment practices. RHAPSODY data helped support FDA approval of the first therapy for RP.

ImportancePatients with heart failure with preserved ejection fraction (HFpEF) with a pacemaker may benefit from a higher, more physiologic backup heart rate than the nominal 60 beats per minute (bpm) setting.ObjectiveTo assess the effects of a moderately accelerated personalized backup heart rate compared with 60 bpm (usual care) in patients with preexisting pacemaker systems that limit pacemaker-mediated dyssynchrony.Design, Setting, and ParticipantsThis blinded randomized clinical trial enrolled patients with stage B and C HFpEF from the University of Vermont Medical Center pacemaker clinic between June 2019 and November 2020. Analysis was modified intention to treat.InterventionsParticipants were randomly assigned to personalized accelerated pacing or usual care and were followed up for 1 year. The personalized accelerated pacing heart rate was calculated using a resting heart rate algorithm based on height and modified by ejection fraction.Main Outcomes and MeasuresThe primary outcome was the serial change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score. Secondary end points were changes in N-terminal pro–brain natriuretic peptide (NT-proBNP) levels, pacemaker-detected physical activity, atrial fibrillation from baseline, and adverse clinical events.ResultsOverall, 107 participants were randomly assigned to the personalized accelerated pacing (n = 50) or usual care (n = 57) groups. The median (IQR) age was 75 (69-81) years, and 48 (48%) were female. Over 1-year follow-up, the median (IQR) pacemaker-detected heart rate was 75 (75-80) bpm in the personalized accelerated pacing arm and 65 (63-68) bpm in usual care. MLHFQ scores improved in the personalized accelerated pacing group (median [IQR] baseline MLHFQ score, 26 [8-45]; at 1 month, 15 [2-25]; at 1 year, 9 [4-21]; P P = .03). In addition, personalized accelerated pacing led to improved changes in NT-proBNP levels (mean [SD] decrease of 109 [498] pg/dL vs increase of 128 [537] pg/dL with usual care; P = .02), activity levels (mean [SD], +47 [67] minutes per day vs −22 [35] minutes per day with usual care; P P = .04) over 1-year of follow-up. Adverse clinical events occurred in 4 patients in the personalized accelerated pacing group and 11 patients in usual care.Conclusions and RelevanceIn this study, among patients with HFpEF and pacemakers, treatment with a moderately accelerated, personalized pacing rate was safe and improved quality of life, NT-proBNP levels, physical activity, and atrial fibrillation compared with the usual 60 bpm setting.Trial RegistrationClinicalTrials.gov Identifier: NCT04721314

RationaleImpaired cardiac energetics in hypertrophic cardiomyopathy (HCM) is thought to result from increased ATP utilization at the sarcomere and is believed to be central to pathophysiology. However, the precise defects in cardiac metabolism and substrate availability in human HCM have not been defined.ObjectiveThe purpose of this study is to define major disease pathways and determine the pool sizes of intermediary metabolites in human HCM.Methods and ResultsWe conducted paired proteomic and metabolomic analyses of septal myectomy samples from patients with HCM and compared results to non-failing control human hearts. Increased abundance of extracellular matrix and intermediate filament / Z-disc proteins, and decreased abundance of proteins involved in fatty acid oxidation and cardiac energetics was evident in HCM compared to controls. Acyl carnitines, byproducts of fatty acid oxidation, were markedly depleted in HCM samples. Conversely, the ketone body 3-hydroxybutyrate, lactate, and the 3 branched chain amino acids, were all significantly increased in HCM hearts, suggesting that they may serve as alternate fuel sources for the production of ATP. ATP, nicotinamide adenine dinucleotide (NADH), NADP and NADPH, and acetyl CoA were also severely depleted in HCM hearts. Based on measurements from human skinned muscle fibers, the magnitude of observed reduction in ATP content in the HCM hearts would be expected to decrease the rate of cross-bridge detachment, implying a direct effect of energy depletion on myofilament function that could contribute to diastolic dysfunction.ConclusionsHCM hearts display profound deficits in cardiac energetics, marked by depletion of fatty acid derivatives and compensatory increases in other metabolites that could serve as alternate fuel sources. These results lend support to the paradigm that energy depletion contributes to the pathophysiology of HCM and also have important therapeutic implications for the future design of metabolic modulators to treat HCM.

To identify renin-angiotensin system (RAS) inhibition utilization and discontinuation after transcatheter aortic valve replacement (TAVR) and identify predictors of use and discontinuation.RAS inhibition after TAVR has been associated with lower cardiac mortality and heart failure readmissions.We analyzed 735 consecutive TAVR patients (2014-2019) who survived to hospital discharge at a high-volume TAVR center to determine the utilization and discontinuation of RAS inhibition after TAVR and identify predictors of use and discontinuation. Clinical characteristics, procedural variables, and hospital outcomes were compared between patients receiving vs not receiving discharge RAS inhibitors. Data were compared using t-test and Chi-square test. Multivariable analysis was used to determine independent clinical predictors.Of the 735 patients, 41.9% were discharged with at least 1 RAS inhibitor. In TAVR patients with heart failure with reduced ejection fraction (HFrEF), defined as EF ≤40%, the utilization of RAS inhibitors at discharge was 51.1%. Patients receiving discharge RAS inhibitors had lower incidences of acute kidney injury (AKI) post procedure (8.1% vs 17.8%; P.01). Discontinuation of RAS inhibition was observed in approximately 1 in 3 patients and was associated with AKI and pacemaker requirement. Three predictors of RAS inhibitor utilization were higher systolic blood pressure, RAS inhibitor use prior to TAVR, and HFrEF. Conversely, new pacemaker and AKI were associated with less utilization of RAS inhibitors; patients developing AKI were 74% less likely to receive RAS inhibitors than those without AKI.Decreased RAS inhibition provides a potential mechanism for worse outcomes in TAVR patients who develop AKI.

The 2017 American College of Cardiology/American Heart Association guideline proposes an aggressive approach to hypertension (HTN) management ([1][1]). The NHANES (National Health and Nutrition Examination Survey) study suggested that HTN-related cardiovascular disease (CVD) deaths in the United

Background Impact of recurrent pericarditis (RP) on patient health-related quality of life (HRQoL) was evaluated through qualitative patient interviews and as an exploratory endpoint in a Phase 2 trial evaluating the efficacy and safety of rilonacept (IL-1α/IL-1β cytokine trap) to treat RP. Methods Qualitative interviews were conducted with ten adults with RP to understand symptoms and HRQoL impacts, and the 10-item Patient-Reported Outcomes Measurement Information System Global Health (PROMIS GH) v1.2 was evaluated to determine questionnaire coverage of patient experience. The Phase 2 trial enrolled participants with active symptomatic RP (A-RP, n = 16) and corticosteroid-dependent participants with no active recurrence at baseline (CSD-RP, n = 9). All participants received rilonacept weekly during a 6-week base treatment period (TP) plus an optional 18-week extension period (EP). Tapering of concomitant medications, including corticosteroids (CS), was permitted during EP. HRQoL was assessed using the PROMIS GH, and patient-reported pain and blood levels of c-reactive protein (CRP) were collected at Baseline and follow-up periods. A secondary, descriptive analysis of the Phase 2 trial efficacy results was completed using HRQoL measures to characterize both the impact of RP and the treatment effect of rilonacept. Results Information from qualitative interviews demonstrated that PROMIS GH concepts are relevant to adults with RP. From the Phase 2 trial, both participant groups showed impacted HRQoL at Baseline (mean PROMIS Global Physical Health [GPH] and Global Mental Health [GMH], were lower than population norm average). In A-RP, GPH/MPH improved by end of base TP and were sustained through EP (similar trends were observed for pain and CRP). Similarly, in CSD-RP, GPH/MPH improved by end of TP and further improved during EP, during CS tapering or discontinuation, without disease recurrence (low pain scores and CRP levels continued during the TP and EP). Conclusion This is the first study demonstrating impaired HRQoL in RP. Rilonacept treatment was associated with HRQoL improvements using PROMIS GH scores. Maintained/improved HRQoL during tapering/withdrawal of CS without recurrence suggests that rilonacept may provide an alternative to CS. Trial registration: ClinicalTrials.Gov; NCT03980522; 5 June 2019, retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT03980522.

Background Recurrent pericarditis (RP) is characterized by recurrence of symptoms of pericarditis after the original episode has ceased for 4–6 weeks. Though RP is associated with significant morbidity, there is little information regarding the impact of RP on patients' health-related quality of life (HRQOL). Purpose To describe clinical characteristics of and HRQOL burden in patients with RP in the United States. Methods An IRB-approved web-based survey was conducted among patients ≥18 years old with RP who experienced ≥1 recurrence during the prior 12 months. Respondents were recruited from the RHAPSODY clinical trial recruitment database. Patients who met the survey inclusion criteria were asked to provide information on their demographic/clinical characteristics, treatments for RP, and to complete an 11-point pericarditis pain numerical rating scale, the Patient Global Impression of Pericarditis Severity scale, the Patient-Reported Outcomes Measurement Information System® (PROMIS®) Global Health and Sleep Disturbance scales, and questions about the impact of RP on daily life. Results Of the 83 respondents with RP included in the study, 25% responded while experiencing a recurrence. Most respondents were Caucasian (76%) and 55% were female, with mean (standard deviation [SD]) age of 49.3 (13.7) years. Patients frequently reported history of hypertension (39%), anxiety (37%), and depression (34%); 16% and 15% of patients reported having pre-existing autoimmune disease and diabetes, respectively. About half (49%) of patients reported ≥3 recurrences in the prior year, and 40% visited the ER and 25% were hospitalized for their most recent recurrence. Among patients not actively experiencing a recurrence, 37% reported that the duration of their prior episode lasted ≥8 days. Medications most frequently used for RP and pain in the prior year included non-steroidal anti-inflammatory drugs (82%), colchicine (63%), and corticosteroids (29%). Commonly reported symptoms included chest pain (93%), shortness of breath (66%), weakness/fatigue (64%), and heart palpitations (52%). Two-thirds of patients rated the severity of symptoms during the most recent RP episode as moderately severe to very severe, and 48% reported “quite a bit” or “very much” fear of pericarditis recurrence. The mean (SD) value for worst pericarditis pain (0–10 scale) during the recent recurrence was 6.1 (2.3), with 48% reporting severe pain (≥7 on the scale). Patients had substantially worse mean [SD] T scores for PROMIS physical health (37.6 [8.6]), mental health (42.8 [9.9]), and sleep disturbance (60.6 [8.3]) than the general population (50 [10]). Conclusions RP is a burden on the daily lives of patients, resulting in severe pain and impaired quality-of-life including poor physical and mental health, sleep disturbance, and fear of recurrence. This study demonstrates the unmet need for therapies that can rapidly resolve symptoms and prevent recurrences. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Kiniksa Pharmaceuticals Corp.

Background Increases in heart rate are thought to result in incomplete left ventricular (LV) relaxation and elevated filling pressures in patients with heart failure with preserved ejection fraction (HFpEF). Experimental studies in isolated human myocardium have suggested that incomplete relaxation is a result of cellular Ca 2+ overload caused by increased myocardial Na + levels. We tested these heart rate paradigms in patients with HFpEF and referent controls without hypertension. Methods and Results In 22 fully sedated and instrumented patients (12 controls and 10 patients with HFpEF) in sinus rhythm with a preserved ejection fraction (≥50%) we assessed left‐sided filling pressures and volumes in sinus rhythm and with atrial pacing (95 beats per minute and 125 beats per minute) before atrial fibrillation ablation. Coronary sinus blood samples and flow measurements were also obtained. Seven women and 15 men were studied (aged 59±10 years, ejection fraction 61%±4%). Patients with HFpEF had a history of hypertension, dyspnea on exertion, concentric LV remodeling and a dilated left atrium, whereas controls did not. Pacing at 125 beats per minute lowered the mean LV end‐diastolic pressure in both groups (controls −4.3±4.1 mm Hg versus patients with HFpEF −8.5±6.0 mm Hg, P =0.08). Pacing also reduced LV end‐diastolic volumes. The volume loss was about twice as much in the HFpEF group (controls −15%±14% versus patients with HFpEF −32%±11%, P =0.009). Coronary venous [Ca 2+ ] increased after pacing at 125 beats per minute in patients with HFpEF but not in controls. [Na + ] did not change. Conclusions Higher resting heart rates are associated with lower filling pressures in patients with and without HFpEF. Incomplete relaxation and LV filling at high heart rates lead to a reduction in LV volumes that is more pronounced in patients with HFpEF and may be associated with myocardial Ca 2+ retention.

The extent to which recurrences of pericarditis episodes impact patients’ health-related quality of life (HRQOL) remains poorly understood. This study aimed to evaluate HRQOL and work productivity in patients with recurrent pericarditis (RP). Adult patients from a centralized recruitment database for the rilonacept Phase 2/3 clinical trials were invited to participate in a survey. Inclusion criteria were confirmed RP diagnosis and ≥1 recurrence within the previous 12 months. The 11-Point Pain Numeric Rating Scale, Patient Global Impression of Pericarditis Severity, Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health v1.2, PROMIS Short Form Sleep Disturbance 8b, Work Productivity and Activity Impairment v2.0, and customized questions about fear and economic impact were used. In total, 83 patients (55% female, average age = 49.3 years) completed the survey. The median time since pericarditis diagnosis was 3.0 years at the time of survey completion; 49% experienced ≥3 recurrences in the previous 12 months. Forty percent had an emergency room visit, and 25% were hospitalized for their most recent recurrence. Sixty-six percent of participants rated the symptoms of their last recurrence as severe. The mean value for worst pericarditis pain (0 to 10 scale) during the most recent recurrence was 6.1. The average T-scores for PROMIS physical and mental health were 37.6 and 42.8, respectively, compared with 50 in the general population. Participants reported 50% of overall work impairment and 62% of activity impairment due to RP. In conclusion, patients with RP experienced a high number of recurrences with severe symptoms that substantially reduced their HRQOL and work productivity.

ObjectiveRecurrent pericarditis (RP) incurs significant morbidity. Rilonacept inhibits both interleukin-1 alpha (IL-1α) and IL-1β; these cytokines are thought to play a major role in RP. This phase II study evaluated rilonacept efficacy and safety in RP.MethodsThis multicentre, open-label study enrolled adult patients with idiopathic or postpericardiotomy RP, symptomatic (≥2 pericarditis recurrences) or corticosteroid (CS) dependent (≥2 recurrences prior).Patients received rilonacept 320 mg SC load/160 mg SC weekly maintenance in a 6-week base treatment period (TP) followed by an optional 18-week on-treatment extension period (EP) (option to wean background therapy).ResultsOutcomes: pericarditis pain (numeric rating scale (NRS)) and inflammation (C reactive protein (CRP)) for symptomatic patients; disease activity after CS taper for CS-dependent patients. Secondary outcomes: health-related quality of life (HRQOL), pericarditis manifestations and additional medications. 25 unique patients enrolled, while 23 completed the EP (seven colchicine failures and five CS failures). In symptomatic patients, NRS and CRP decreased; response was observed after first rilonacept dose. NRS decreased from 4.5 at baseline to 0.7, and CRP decreased from 4.62 mg/dL at baseline to 0.38 mg/dL at end of TP. Median time to CRP normalisation: 9 days. Pericarditis manifestations resolved. 13 patients on CS at baseline completed the EP; 11 (84.6%) discontinued CS, and 2 tapered; CRP and NRS remained low without recurrence. Mean HRQOL scores improved in symptomatic patients. One serious adverse event (SAE) resulted in discontinuation of rilonacept.ConclusionsRilonacept led to rapid and sustained improvement in pain, inflammation (CRP and pericarditis manifestations) and HRQOL. CSs were successfully tapered or discontinued; safety was consistent with known rilonacept safety profile.Trial registration numberNCT03980522.

Background: Recurrent pericarditis (RP) episodes and conventional treatments result in morbidity, but the impact on patient health-related quality of life (HRQoL) has not been quantified. The Phase 2 trial NCT03980522 of rilonacept (IL-1α/IL-1β inhibitor) evaluated HRQoL. Methods: Patients with active RP who were symptomatic at Baseline (A-RP, n=16) and RP patients who were not currently experiencing a recurrence but were corticosteroid-dependent at Baseline (CSD-RP, n=9) were enrolled. All received rilonacept weekly for 6 weeks to end of base treatment period (TP) plus an optional 18-week extension treatment period (EP). Corticosteroid tapering occurred in the EP. Physical and mental HRQoL (PROMIS Global Health v1.2 Physical and Mental Component Scores [PCS/MCS]) were assessed at baseline and follow-up. Results: Figure 1 presents the PROMIS PCS/MCS and pain scale scores (both patient-reported) as well as C-reactive protein levels over time. Mean PCS/MCS scores at baseline were 39.9/44.5 and 43.3/46.5 for A-RP and CSD-RP groups respectively (versus the norm mean of 50). In A-RP, PCS/MCS scores improved by 11.4/5.6 points by end of base TP, and this improvement was sustained throughout the EP (increase of 11.4/6.0 points from baseline at end of EP). In CSD-RP, PCS/MCS scores increased by 1.8/1.4 points by end of TP and improved by 3.5/4.2 points at end of study, after tapering or discontinuation of corticosteroid without disease recurrence. Conclusion: Impaired baseline HRQoL suggests negative impact of RP. For A-RP, rilonacept rapidly improved pericarditis signs and symptoms which was associated with HRQoL improvements. For CSD-RP, rilonacept supported tapering/withdrawal of corticosteroids without recurrence, with maintained/improved HRQoL. These results suggest rilonacept can improve RP patient HRQoL while providing an alternative to corticosteroids.

Palmer et al. demonstrate that a stretch-induced enhancement of the myosin crossbridge detachment rate is sufficient to explain the force response of cardiac muscle to a quick stretch and would benefit diastolic function in a beating heart., The force response of cardiac muscle undergoing a quick stretch is conventionally interpreted to represent stretching of attached myosin crossbridges (phase 1) and detachment of these stretched crossbridges at an exponential rate (phase 2), followed by crossbridges reattaching in increased numbers due to an enhanced activation of the thin filament (phases 3 and 4). We propose that, at least in mammalian cardiac muscle, phase 2 instead represents an enhanced detachment rate of myosin crossbridges due to stretch, phase 3 represents the reattachment of those same crossbridges, and phase 4 is a passive-like viscoelastic response with power-law relaxation. To test this idea, we developed a two-state model of crossbridge attachment and detachment. Unitary force was assigned when a crossbridge was attached, and an elastic force was generated when an attached crossbridge was displaced. Attachment rate, f(x), was spatially distributed with a total magnitude f0. Detachment rate was modeled as g(x) = g0 + g1x, where g0 is a constant and g1 indicates sensitivity to displacement. The analytical solution suggested that the exponential decay rate of phase 2 represents (f0 + g0) and the exponential rise rate of phase 3 represents g0. The depth of the nadir between phases 2 and 3 is proportional to g1. We prepared skinned mouse myocardium and applied a 1% stretch under varying concentrations of inorganic phosphate (Pi). The resulting force responses fitted the analytical solution well. The interpretations of phases 2 and 3 were consistent with lower f0 and higher g0 with increasing Pi. This novel scheme of interpreting the force response to a quick stretch does not require enhanced thin-filament activation and suggests that the myosin detachment rate is sensitive to stretch. Furthermore, the enhanced detachment rate is likely not due to the typical detachment mechanism following MgATP binding, but rather before MgADP release, and may involve reversal of the myosin power stroke.

Recurrent pericarditis (RP) occurs in 15% to 30% of patients following a first episode, despite standard treatment with nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids; many patients become dependent on corticosteroids. Rilonacept (KPL-914), an interleukin-1α and β inhibitor, is in development for the treatment of RP. RHAPSODY, a double-blind, placebo-controlled, randomized-withdrawal (RW) pivotal Phase 3 trial (NCT03737110), enrolls patients 12 years or older presenting with at least a third pericarditis episode, pericarditis pain score ≥4 (11-point numeric rating scale [NRS]), and C-reactive protein ≥1 mg/dL at screening. After a subcutaneous loading dose (adults, 320 mg; children, 4.4 mg/kg), all patients receive blinded weekly subcutaneous rilonacept (adults, 160 mg; children, 2.2 mg/kg) during the run-in period. Patients must taper and discontinue concomitant pericarditis medications during the blinded run-in period and achieve clinical response (C-reactive protein ≤0.5 mg/dL and weekly average NRS ≤2.0 during the 7 days prior to and including the day of randomization) by end of the run-in (while on rilonacept monotherapy) to be randomized to either continued rilonacept or placebo in the RW period. Primary efficacy end point was time to adjudicated pericarditis recurrence during the RW period; secondary efficacy end points were proportion of patients maintaining clinical response, percentage of days with NRS ≤2, and percentage of patients with no-to-minimal pericarditis symptoms at week 16 of the RW period. Safety evaluations include adverse event monitoring, physical examinations, and laboratory tests. The RHAPSODY trial will evaluate the efficacy and safety of rilonacept in the treatment of RP to improve outcomes and patient health-related quality of life.

The risk and benefit of mechanical interventions in valvular heart disease have been primarily described among patients with normal ejection fraction. The advent of nonsurgical mechanical interventions for aortic stenosis (transcatheter aortic valve replacement) may alter the risk-benefit ratio for patients who would otherwise be at increased risk for valve surgery. This review describes the epidemiology and pathophysiology of aortic stenosis with heart failure and reduced ejection fraction and summarizes the current registry and clinical trial data applicable to this frequently encountered high-risk group. It concludes with discussion of ongoing trials, new approaches, emerging indications, and a potential clinical algorithm incorporating optimal mechanical intervention for patients with aortic stenosis and concomitant reduced ejection fraction.

Epidemiological studies have demonstrated that high resting heart rates are associated with increased mortality. Clinical studies in patients with heart failure and reduced ejection fraction have shown that heart rate lowering with beta-blockers and ivabradine improves survival. It is therefore often assumed that heart rate lowering is beneficial in other patients as well. Here, we critically appraise the effects of pharmacological heart rate lowering in patients with both normal and reduced ejection fraction with an emphasis on the effects of pharmacological heart rate lowering in hypertension and heart failure. Emerging evidence from recent clinical trials and meta-analyses suggest that pharmacological heart rate lowering is not beneficial in patients with a normal or preserved ejection fraction. This has just begun to be reflected in some but not all guideline recommendations. The detrimental effects of pharmacological heart rate lowering are due to an increase in central blood pressures, higher left ventricular systolic and diastolic pressures, and increased ventricular wall stress. Therefore, we propose that heart rate lowering per se reproduces the hemodynamic effects of diastolic dysfunction and imposes an increased arterial load on the left ventricle, which combine to increase the risk of heart failure and atrial fibrillation. Pharmacologic heart rate lowering is clearly beneficial in patients with a dilated cardiomyopathy but not in patients with normal chamber dimensions and normal systolic function. These conflicting effects can be explained based on a model that considers the hemodynamic and ventricular structural effects of heart rate changes.

The normal pericardial sac contains up to 50 mL of fluid, which consists of a plasma ultrafiltrate. Anything greater constitutes a pathologic effusion. The curvilinear pressure-volume relationship of the pericardial sac dictates hemodynamic consequences of a pericardial effusion and is responsible for rapidly accumulating fluid that causes cardiac tamponade. A variety of diseases and complications cause pericardial effusion. The most common are idiopathic pericarditis, cancer, connective tissue disorders, and hemorrhage. Management of pericardial effusion is dictated by whether tamponade is present or threatened. If it is, urgent/emergent pericardiocentesis is indicated. If not, a systematic approach to diagnosis and management should be undertaken.

Background Recurrent pericarditis (RP) is managed with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids (CS), and colchicine; up to 15% of pericarditis patients experience multiple recurrences. Interleukin 1 (IL-1) is an important cytokine in the pathophysiology of RP. Rilonacept (KPL-914) is a recombinant fusion protein which binds IL-1α and IL-1β. An ongoing Phase 2 study of rilonacept demonstrated improvements in RP symptoms and inflammation. Purpose To evaluate the efficacy and safety of subcutaneous (SC) rilonacept in patients with RP in a Phase 3, randomized, placebo-controlled trial. Methods RHAPSODY is a double-blind, placebo-controlled, randomized-withdrawal trial; ∼50 patients will be enrolled (Figure). Patients (≥12 y) must present with at least a third pericarditis episode (all etiologies except infectious and malignant) characterized by a pain score ≥4 on the 11-point Numeric Rating Scale (NRS) and C-reactive protein (CRP) ≥1 mg/dL at screening. Patients may be receiving stable doses of analgesics, NSAIDs, colchicine, and/or CS. After a loading dose (320 mg SC in adults and 4.4 mg/kg SC in children), all patients will receive weekly rilonacept (160 mg SC in adults and 2.2 mg/kg SC in children) during the run-in period. Patients able to taper and discontinue concomitant pericarditis medications and achieve clinical response (mean daily NRS score ≤2.0 during the 7 days before randomization and CRP level ≤0.5 mg/dL) will be randomized 1:1 in a blinded fashion to continued rilonacept or matching placebo weekly SC injections. Investigators may choose different treatments for pericarditis recurrences based on patient clinical status, including bailout rilonacept, while maintaining the blind to prior treatment assignment. The primary efficacy endpoint is time to pericarditis recurrence (adjudicated by an independent committee) in the randomized-withdrawal portion of the study. Secondary efficacy endpoints are the proportion of patients maintaining a clinical response, percentage of days with NRS pain score ≤1, and percentage of patients with no-to-minimal pericarditis symptoms based on patient global assessment. Safety evaluations include adverse events monitoring, physical examinations, and laboratory tests. Figure 1 Conclusions RHAPSODY is a pivotal Phase 3 trial evaluating the efficacy and safety of rilonacept in patients with RP using a double-blind, placebo-controlled, randomized-withdrawal design. The results of this study may inform the management of RP. Acknowledgement/Funding This study is sponsored by Kiniksa Pharmaceuticals, Ltd.

Corticostroids (CSs) are often used long-term in patients (pts) with recurrent pericarditis (RP) who do not respond to first-line treatment with NSAIDs and colchicine. CSs are associated with substantial comorbidities. We report the CS-sparing effect of rilonacept (inhibitor of IL-1α/IL-1β, major

Importance There are few effective treatments for heart failure with preserved ejection fraction (HFpEF). Short-term administration of inorganic nitrite or nitrate preparations has been shown to enhance nitric oxide signaling, which may improve aerobic capacity in HFpEF. Objective To determine the effect of 4 weeks’ administration of inhaled, nebulized inorganic nitrite on exercise capacity in HFpEF. Design, Setting, and Participants Multicenter, double-blind, placebo-controlled, 2-treatment, crossover trial of 105 patients with HFpEF. Participants were enrolled from July 22, 2016, to September 12, 2017, at 17 US sites, with final date of follow-up of January 2, 2018. Interventions Inorganic nitrite or placebo administered via micronebulizer device. During each 6-week phase of the crossover study, participants received no study drug for 2 weeks (baseline/washout) followed by study drug (nitrite or placebo) at 46 mg 3 times a day for 1 week followed by 80 mg 3 times a day for 3 weeks. Main Outcomes and Measures The primary end point was peak oxygen consumption (mL/kg/min). Secondary end points included daily activity levels assessed by accelerometry, health status as assessed by the Kansas City Cardiomyopathy Questionnaire (score range, 0-100, with higher scores reflecting better quality of life), functional class, cardiac filling pressures assessed by echocardiography, N-terminal fragment of the prohormone brain natriuretic peptide levels, other exercise indices, adverse events, and tolerability. Outcomes were assessed after treatment for 4 weeks. Results Among 105 patients who were randomized (median age, 68 years; 56% women), 98 (93%) completed the trial. During the nitrite phase, there was no significant difference in mean peak oxygen consumption as compared with the placebo phase (13.5 vs 13.7 mL/kg/min; difference, −0.20 [95% CI, −0.56 to 0.16];P = .27). There were no significant between–treatment phase differences in daily activity levels (5497 vs 5503 accelerometry units; difference, −15 [95% CI, −264 to 234];P = .91), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (62.6 vs 61.9; difference, 1.1 [95% CI, −1.4 to 3.5];P = .39), functional class (2.5 vs 2.5; difference, 0.1 [95% CI, −0.1 to 0.2];P = .43), echocardiographic E/e′ ratio (16.4 vs 16.6; difference, 0.1 [95% CI, −1.2 to 1.3];P = .93), or N-terminal fragment of the prohormone brain natriuretic peptide levels (520 vs 533 pg/mL; difference, 11 [95% CI, −53 to 75];P = .74). Worsening heart failure occurred in 3 participants (2.9%) during the nitrite phase and 8 (7.6%) during the placebo phase. Conclusions and Relevance Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity. Trial Registration ClinicalTrials.gov Identifier:NCT02742129

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A 19-year-old woman with no significant medical history was admitted to the University of Vermont Medical Center with 3 weeks of abdominal pain, vomiting, and diarrhea, as well as 2 to 3 days of chest pain. Her only medication was oral contraceptives, which she had taken for the past 2 years. At presentation, her blood pressure was 97/78 mm Hg and heart rate 107 beats per minute and regular. Physical examination was remarkable for mild generalized pallor, diffuse abdominal tenderness, elevated jugular venous pressure, and a gallop rhythm. Laboratory results revealed a total white blood cell count count of 16.6 K/mm3 (Reference, 4.0-10.4 K/mm3), absolute eosinophil count of 8.52 (Reference, 0.03–0.61 K/mm3), troponin I of 9.99 (Reference

BACKGROUND: Exercise capacity is a powerful predictor of all‐cause mortality. The duration of exercise with treadmill stress testing is an important prognostic marker in both healthy subjects and patients with cardiovascular disease. Left ventricular (LV) structure is known to adapt to sustained changes in level of physical activity. HYPOTHESIS: Poor exercise capacity in patients with a preserved LV ejection fraction (LVEF) should be reflected in smaller LV dimensions, and a normal exercise capacity should be associated with larger LV dimensions, irrespective of comorbidities. METHODS: This hypothesis was first tested in a cross‐sectional analysis of 201 patients with normal chamber dimensions and preserved LVEF who underwent a clinically indicated treadmill stress echocardiogram using the Bruce protocol (derivation cohort). The best LV dimensional predictor of exercise capacity was then tested in 1285 patients who had a Bruce‐protocol treadmill exercise stress test and a separate transthoracic echocardiogram (validation cohort). RESULTS: In the derivation cohort, there was a strong positive relationship between exercise duration and LV end‐diastolic volume deciles (r (2) = 0.85; P

Background Underlying inflammation has been increasingly recognized in heart failure with a preserved ejection fraction ( HF p EF ). In this study we tested the hypothesis that pro‐inflammatory biomarkers are elevated in patients with acutely decompensated HF p EF ( AD ‐ HF p EF ) compared with patients with stable HF p EF (S‐ HF p EF ). Methods and Results Using a post hoc analysis the serum biomarkers tumor necrosis factor‐alpha, high‐sensitivity C‐reactive protein interleukin 6 and pentraxin 3 ( PTX 3) and clinical, demographic, echocardiographic‐Doppler and clinical outcomes data were analyzed in HF p EF patients enrolled in NHLBI Heart Failure Research Network clinical trials which enrolled patients with either AD ‐ HF p EF or S‐ HF p EF . Compared to S‐ HF p EF , AD ‐ HF p EF patients had higher levels of PTX 3 (3.08 ng/ mL versus 1.27 ng/ mL , P interleukin ‐6 (4.14 pg/ mL versus 1.71 pg/ mL , P tumor necrosis factor‐alpha (11.54 pg/ mL versus 8.62 pg/ mL , P =0.0015), and high‐sensitivity C‐reactive protein (11.90 mg/ dL versus 3.42 mg/ dL , P interleukin ‐6 and PTX 3 levels were significantly higher in AD ‐ HF p EF compared with S‐ HF p EF patients admitted for decompensated HF within the previous year. PTX 3 was positively correlated with left atrial volume index ( r =0.41, P =0.0017) and left ventricular mass ( r =0.26, P =0.0415), while tumor necrosis factor‐alpha was inversely correlated with E/A ratio ( r =−0.31, P =0.0395). Conclusions Levels of pro‐inflammatory biomarkers are strikingly higher in AD ‐ HF p EF compared with S‐ HF p EF patients. PTX 3 and tumor necrosis factor‐alpha are correlated with echocardiographic‐Doppler evidence of diastolic dysfunction. Taken together these data support the concept that a heightened pro‐inflammatory state has a pathophysiologic role in the development of AD ‐ HF p EF .

Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients.In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels.Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493.).

Background— Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. Methods and Results— We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ≤40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, –4.2 [–4.9, –3.5] mg/dL and –3.5 [–4.2, –2.7] mg/dL at 12 and 24 weeks, respectively, both P P =0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P =0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P =0.36). Conclusions— In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00987415.

Alterations of myofilament proteins have long been recognized in cardiomyopathic states. A variety of mutations play a prominent role in both hypertrophic and dilated cardiomyopathy (DCM).1 Thus, mutations in myosin heavy chain (MyHC) that cause enhanced mechanical performance often underlie hypertrophic cardiomyopathy, whereas those causing reduced performance lead to DCM.2 As summarized in Table 1, post-translational modifications, most prominently isoform variations and phosphorylation state, have received considerable attention in patients with DCM. In response to experimental acquired disease in rodents, MyHC undergoes a major shift from its normally predominant α-isoform to the β-isoform, resulting in lower myofibrillar ATPase activity and reduced mechanical performance.3,4 The same directional shift occurs in humans; because human myocardium normally consists of ≈90% β-MyHC, its magnitude is small and functional consequences seem modest.4,5 Ventricular expression of the atrial isoform of the myosin essential light chain is elevated in DCM and would be expected to improve contractile performance.6 Titin, the giant protein that accounts for cardiomyocyte passive stiffness, undergoes a shift to its more compliant N2BA isoform in human DCM. Protein kinase (PKA) and PKG phosphorylate identical sites on titin. Phosphorylation of these sites is reduced in DCM, which increases stiffness and offsets the isoform shift.7 The net result seems to be a decrease in cardiomyocyte stiffness. Reduced phosphorylation of troponin I (TnI) and myosin regulatory light chain have also been reported in human DCM and are thought to contribute to impaired thin filament activation and contractility.8,9 Pertinent to the papers in this issue of Circulation: Heart Failure that are the subject of this editorial,10,11 there are few reports of the phosphorylation state of cardiac myosin-binding protein C (MyBP-C) as a regulator of myofilament function at the whole heart level. …

Background— The purpose of this study was to determine whether patients with heart failure and a preserved ejection fraction (HFpEF) have an increase in passive myocardial stiffness and the extent to which discovered changes depend on changes in extracellular matrix fibrillar collagen and cardiomyocyte titin. Methods and Results— Seventy patients undergoing coronary artery bypass grafting underwent an echocardiogram, plasma biomarker determination, and intraoperative left ventricular epicardial anterior wall biopsy. Patients were divided into 3 groups: referent control (n=17, no hypertension or diabetes mellitus), hypertension (HTN) without (–) HFpEF (n=31), and HTN with (+) HFpEF (n=22). One or more of the following studies were performed on the biopsies: passive stiffness measurements to determine total, collagen-dependent and titin-dependent stiffness (differential extraction assay), collagen assays (biochemistry or histology), or titin isoform and phosphorylation assays. In comparison with controls, patients with HTN(–)HFpEF had no change in left ventricular end-diastolic pressure, myocardial passive stiffness, collagen, or titin phosphorylation but had an increase in biomarkers of inflammation (C-reactive protein, soluble ST2, tissue inhibitor of metalloproteinase 1). In comparison with both control and HTN(–)HFpEF, patients with HTN(+)HFpEF had increased left ventricular end-diastolic pressure, left atrial volume, N-terminal propeptide of brain natriuretic peptide, total, collagen-dependent, and titin-dependent stiffness, insoluble collagen, increased titin phosphorylation on PEVK S11878(S26), reduced phosphorylation on N2B S4185(S469), and increased biomarkers of inflammation. Conclusions— Hypertension in the absence of HFpEF did not alter passive myocardial stiffness. Patients with HTN(+)HFpEF had a significant increase in passive myocardial stiffness; collagen-dependent and titin-dependent stiffness were increased. These data suggest that the development of HFpEF depends on changes in both collagen and titin homeostasis.

Background Relaxation characteristics and Ca 2+ homeostasis have not been studied in isolated myocardium from patients with hypertensive heart disease (HHD) and heart failure with preserved ejection fraction (HFpEF). Prolonged myocardial relaxation is believed to play an important role in the pathophysiology of these conditions. In this study, we evaluated relaxation parameters, myocardial calcium (Ca 2+ ), and sodium (Na + ) handling, as well as ion transporter expression and tested the effect of Na + -influx inhibitors on relaxation in isolated myocardium from patients with HHD and HFpEF. Methods and Results Relaxation characteristics were studied in myocardial strip preparations under physiological conditions at stimulation rates of 60 and 180 per minute. Intracellular Ca 2+ and Na + were simultaneously assessed using Fura-2 and AsanteNATRIUMGreen-2, whereas elemental analysis was used to measure total myocardial concentrations of Ca, Na, and other elements. Quantitative polymerase chain reaction was used to measure expression levels of key ion transport proteins. The lusitropic effect of Na + -influx inhibitors ranolazine, furosemide, and amiloride was evaluated. Myocardial left ventricular biopsies were obtained from 36 control patients, 29 HHD and 19 HHD+HFpEF. When compared with control patients, half maximal relaxation time (RT 50 ) at 60 per minute was prolonged by 13% in HHD and by 18% in HHD+HFpEF (both P 2+ levels and a tachycardia-induced increase in diastolic Ca 2+ were associated with incomplete relaxation and an increase in diastolic tension in HHD and HHD+HFpEF. Na + levels were not increased, and expression levels of Ca 2+ - or Na + -handling proteins were not altered. Na + -influx inhibitors did not improve relaxation or prevent incomplete relaxation at high stimulation rates. Conclusions Contraction and relaxation are prolonged in isolated myocardium from patients with HHD and HHD+HFpEF. This leads to incomplete relaxation at higher rates. Elevated calcium levels in HFpEF are neither a result of an impaired Na + gradient nor expression changes in key ion transporters and regulatory proteins.

Background Diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF) are associated with myocardial fibrosis and concentric left ventricular hypertrophy (LVH). In a preclinical model of LVH, we demonstrated that a moderate increase in heart rate can reduce interstitial fibrosis and improve LV compliance. We therefore hypothesized that moderately elevated heart rates can be used to beneficially modify the myocardial substrate in patients with diastolic dysfunction and HFpEF. As a preliminary step to test this hypothesis, we evaluated if patients can tolerate this novel pacemaker-based treatment approach without adverse effects. Methods and Results A pacemaker-mediated increase in heart rate to 100 beats/min for 5 hours at night was tested over 4 weeks in 10 patients with diastolic dysfunction. The patients underwent a physical examination, biomarker collection, 6-minute walk test, heart failure questionnaire, and echocardiography before and after the pacing intervention. None of the patients reported any symptoms at night. No arrhythmias were induced. Eight patients completed the protocol. Three patients experienced unanticipated daytime pacing from an interfering pacemaker function. There were no detrimental changes in biomarkers or LV systolic function. Conclusions Nocturnal pacing at a rate of 100 beats/min appears to be safe and well tolerated in this small exploratory patient cohort.

Approximately half of patients with heart failure have preserved ejection fraction. There is no proven treatment that improves outcome. The pathophysiology of heart failure with preserved ejection fraction is complex and includes left ventricular systolic and diastolic dysfunction, pulmonary vascular disease, endothelial dysfunction, and peripheral abnormalities. Multiple lines of evidence point to impaired nitric oxide (NO)-cGMP bioavailability as playing a central role in each of these abnormalities. In contrast to traditional organic nitrate therapies, an alternative strategy to restore NO-cGMP signaling is via inorganic nitrite. Inorganic nitrite, previously considered to be an inert byproduct of NO metabolism, functions as an important in vivo reservoir for NO generation, particularly under hypoxic and acidosis conditions. As such, inorganic nitrite becomes most active at times of greater need for NO signaling, as during exercise when left ventricular filling pressures and pulmonary artery pressures increase. Herein, we present the rationale and design for the INDIE-HFpEF trial (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction), which is a multicenter, randomized, double-blind, placebo-controlled cross-over study assessing the effect of inhaled inorganic nitrite on peak exercise capacity, conducted in the National Heart, Lung, and Blood Institute–sponsored Heart Failure Clinical Research Network. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT02742129.

Heart failure with preserved ejection fraction (HFpEF) is a major public health problem and a therapeutic conundrum—various pharmacological treatment strategies have failed to achieve substantial improvement in outcomes.1–4 Thus, novel approaches to its treatment are badly needed. There are many alterations in cardiac function in HFpEF that constitute potential therapeutic targets, the details of which are beyond the scope of this editorial. However, reduced passive or end-diastolic chamber compliance seems to be the norm and is almost certainly an important component of its pathophysiology.5–7 The mechanisms of reduced chamber compliance include both increased myocardial stiffness because of changes in titin phosphorylation7–9 and increased content and cross-linking of extracellular matrix collagen,7,10 as well as an increase in mass to volume ratio in the many HFpEF patients with concentric left ventricular (LV) remodeling.11 However, there is no clinical evidence that reversing this abnormality leads to improvement in HFpEF outcomes; indeed, improvement in chamber compliance has never actually been documented in HFpEF patients subjected to various treatment strategies. Such an approach was shown to be efficacious in a mouse model of HFpEF in which genetic manipulation was used to produce a greater proportion of large, highly compliant titin isoforms with resultant improvement in chamber compliance and marked amelioration of the HFpEF phenotype.12 Clearly, TAC in mice is far removed from patients with HFpEF, but this result at least offers the promise that a strategy directly targeted at chamber compliance might have benefit. See Article by Borlaug et al The notion that pericardiectomy might be beneficial in HFpEF has been bandied about informally for some time and is based on the idea that relief of the restraining effect of the pericardium on cardiac volume would be expected to improve diastolic …

Guidelines recommend exercise-based cardiac rehabilitation (EBCR) for patients with heart failure (HF). However, established research has not investigated the longer-term outcomes including mortality and hospitalisation in light of the contemporary management of HF.This was a systematic review including a meta-analysis of EBCR on all-cause mortality, hospital admission, and standardised exercise capacity using four separate exercise tests in patients with heart failure over a minimum follow-up of six months from January 1999-January 2013. Electronic searches were performed in the databases: Medline, CENTRAL, EMBASE, CINAHL, and PsycINFO constrained to randomised controlled trials (RCTs).A total of 46 separate RCTs qualified for the meta-analysis, which employed conventional methods for binary and continuous data. The relative risk (RR) ratio for hospital admission (12 studies) was significantly reduced (RR ratio 0.65; 95% confidence interval (CI) 0.50-0.84; p = 0.001), but mortality (21 studies) was not (RR ratio 0.88; 95% CI 0.77-1.02; p = 0.08). The standardised exercise capacity (26 studies) showed a standardised mean difference (SMD) in favour of the exercise group as compared with the controls (SMD 0.98, 95% CI 0.59-1.37; p 0.001). Women and elderly people were less frequently enrolled in the RCTs independent of the outcomes. Heterogeneity was moderate to high in the analysis of hospital admission and the standardised exercise capacity demonstrated through skewedness in their funnel plots.EBCR in patients with HF is associated with significant improvements in exercise capacity and hospital admission over a minimum of six months follow-up, but not in all-cause mortality.