Recurrent Pericarditis: a Stubborn Opponent Meets New Treatments in 2022.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Health-related quality of life in patients with recurrent pericarditis: results from a phase 2 study of rilonacept.

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-1ß 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 .

Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.).

Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial.

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.

Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin.

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.

Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study.

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<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; 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.

Heart rate-induced modifications of concentric left ventricular hypertrophy: exploration of a novel therapeutic concept.

Lowering the heart rate is considered to be beneficial in heart failure (HF) with reduced ejection fraction (HFrEF). In a dilated left ventricle (LV), pharmacological heart rate lowering is associated with a reduction in LV chamber size. In patients with HFrEF, this structural change is associated with better survival. HF with preserved ejection fraction (HFpEF) is increasingly prevalent but, so far, without any evidence-based treatment. HFpEF is typically associated with LV concentric remodeling and hypertrophy. The effects of heart rate on this structural phenotype are not known. Analogous with the benefits of a low heart rate on a dilated heart, we hypothesized that increased heart rates could lead to potentially beneficial remodeling of a concentrically hypertrophied LV. This was explored in an established porcine model of concentric LV hypertrophy and fibrosis. Our results suggest that a moderate increase in heart rate can be used to reduce wall thickness, normalize LV chamber volumes, decrease myocardial fibrosis, and improve LV compliance. Our results also indicate that the effects of heart rate can be titrated, are reversible, and do not induce HF. These findings may provide the rationale for a novel therapeutic approach for HFpEF and its antecedent disease substrate.

Ultrafiltration in decompensated heart failure with cardiorenal syndrome.

BACKGROUND: Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. METHODS: We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. RESULTS: Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 µmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 µmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03). CONCLUSIONS: In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.).

Diuretic strategies in patients with acute decompensated heart failure.

BACKGROUND: Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. METHODS: In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. RESULTS: In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 µmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 µmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 µmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 µmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. CONCLUSIONS: Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).

Cardiac titin and heart disease.

The giant sarcomeric protein titin is a key determinant of myocardial passive stiffness and stress-sensitive signaling. Titin stiffness is modulated by isoform variation, phosphorylation by protein kinases, and, possibly, oxidative stress through disulfide bond formation. Titin has also emerged as an important human disease gene. Early studies in patients with dilated cardiomyopathy (DCM) revealed shifts toward more compliant isoforms, an adaptation that offsets increases in passive stiffness based on the extracellular matrix. Similar shifts are observed in heart failure with preserved ejection fraction. In contrast, hypophosphorylation of PKA/G sites contributes to a net increase in cardiomyocyte resting tension in heart failure with preserved ejection fraction. More recently, titin mutations have been recognized as the most common etiology of inherited DCM. In addition, some DCM-causing mutations affect RBM20, a titin splice factor. Titin mutations are a rare cause of hypertrophic cardiomyopathy and also underlie some cases of arrhythmogenic right ventricular dysplasia. Finally, mutations of genes encoding proteins that interact with and/or bind to titin are responsible for both DCM and hypertrophic cardiomyopathy. Targeting titin as a therapeutic strategy is in its infancy, but it could potentially involve manipulation of isoforms, posttranslational modifications, and upregulation of normal protein in patients with disease-causing mutations.

Sustained Pericarditis Recurrence Risk Reduction With Long-Term Rilonacept.

BACKGROUND: Rilonacept, a once-weekly interleukin-1 alpha and beta cytokine trap, reduced pericarditis recurrence in the phase 3 study, RHAPSODY (Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study). The RHAPSODY long-term extension further explored recurrent pericarditis natural history and treatment duration decision-making during 24 additional months of open-label rilonacept treatment. METHODS AND RESULTS: Seventy-four patients commenced the long-term extension, with a median (maximum) total rilonacept duration of 22 (35) months. Individually, 18 months after the most proximal pericarditis recurrence, investigators decided to continue rilonacept on study, suspend rilonacept for off-treatment observation (rescue allowed), or discontinue the study. The annualized incidence of pericarditis recurrence on rilonacept up to the 18-month decision milestone was 0.04 events/patient-year versus 4.4 events/patient-year prestudy while on oral therapies. At the 18-month decision milestone, 64% (33/52) continued rilonacept, 15% (8/52) suspended rilonacept for observation, and 21% (11/52) discontinued the study. Among the 33 patients (1/33; 3.0%) continuing rilonacept (median time to recurrence could not be estimated due to too few events), a single recurrence occurred 4 weeks after a treatment interruption. Among patients suspending rilonacept, 75% (6/8) experienced recurrence (median time to recurrence, 11.8 weeks [95% CI, 3.7 weeks to not estimable]). There was a 98% reduction in risk of pericarditis recurrence among patients continuing rilonacept treatment after the 18-month decision milestone versus those suspending treatment for observation (hazard ratio, 0.02; P<0.0001). CONCLUSIONS: In the RHAPSODY long-term extension, continued rilonacept treatment resulted in continued response; treatment suspension at the 18-month decision milestone was associated with pericarditis recurrence. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03737110.

Elevated rates of force development and MgATP binding in F764L and S532P myosin mutations causing dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a disease characterized by dilation of the ventricular chambers and reduced contractile function. We examined the contractile performance of chemically-skinned ventricular strips from two heterozygous murine models of DCM-causing missense mutations of myosin, F764L/+ and S532P/+, in an α-myosin heavy chain (MyHC) background. In Ca(2+)-activated skinned myocardial strips, the maximum developed tension in F764L/+ was only ~50% that of litter-mate controls (+/+). The F764L/+ also exhibited significantly reduced rigor stiffness, loaded shortening velocity and power output. Corresponding indices for S532P/+ strips were not different from controls. Manipulation of MgATP concentration in conjunction with measures of viscoelasticity, which provides estimates of myosin detachment rate 2πc, allowed us to probe the molecular basis of changes in crossbridge kinetics that occur with the myosin mutations. By examining the response of detachment rate to varying MgATP we found the rate of MgADP release was unaffected by the myosin mutations. However, MgATP binding rate was higher in the DCM groups compared to controls (422±109mM(-1)·s(-1) in F764L/+, 483±74mM(-1)·s(-1) in S532P/+ and 303±18mM(-1)·s(-1) in +/+). In addition, the rate constant of force development, 2πb, was significantly higher in DCM groups compared to controls (at 5mM MgATP: 36.9±4.9s(-1) in F764L/+, 32.9±4.5s(-1) in S532P/+ and 18.2±1.7s(-1) in +/+). These results suggest that elevated rates of force development and MgATP binding are features of cardiac myofilament function that underlie the development of DCM.

Cardiac myosin isoforms exhibit differential rates of MgADP release and MgATP binding detected by myocardial viscoelasticity.

We measured myosin crossbridge detachment rate and the rates of MgADP release and MgATP binding in mouse and rat myocardial strips bearing one of the two cardiac myosin heavy chain (MyHC) isoforms. Mice and rats were fed an iodine-deficient, propylthiouracil diet resulting in ~100% expression of ß-MyHC in the ventricles. Ventricles of control animals expressed ~100% α-MyHC. Chemically-skinned myocardial strips prepared from papillary muscle were subjected to sinusoidal length perturbation analysis at maximum calcium activation pCa 4.8 and 17°C. Frequency characteristics of myocardial viscoelasticity were used to calculate crossbridge detachment rate over 0.01 to 5mM [MgATP]. The rate of MgADP release, equivalent to the asymptotic value of crossbridge detachment rate at high MgATP, was highest in mouse α-MyHC (111.4±6.2s(-1)) followed by rat α-MyHC (65.0±7.3s(-1)), mouse ß-MyHC (24.3±1.8s(-1)) and rat ß-MyHC (15.5±0.8s(-1)). The rate of MgATP binding was highest in mouse α-MyHC (325±32 mM(-1) s(-1)) then mouse ß-MyHC (152±23 mM(-1) s(-1)), rat α-MyHC (108±10 mM(-1) s(-1)) and rat ß-MyHC (55±6 mM(-1) s(-1)). Because the events of MgADP release and MgATP binding occur in a post power-stroke state of the myosin crossbridge, we infer that MgATP release and MgATP binding must be regulated by isoform- and species-specific structural differences located outside the nucleotide binding pocket, which is identical in sequence for these four myosins. We postulate that differences in the stiffness profile of the entire myosin molecule, including the thick filament and the myosin-actin interface, are primarily responsible for determining the strain on the nucleotide binding pocket and the subsequent differences in the rates of nucleotide release and binding observed among the four myosins examined here.

High dose intracoronary N-acetylcysteine in a porcine model of ST-elevation myocardial infarction.

We sought to evaluate the safety and efficacy of N-acetylcysteine (NAC) on ischemia and reperfusion in a pig model focusing on cardio-renal protection. High doses of NAC may provide protection from contrast induced nephropathy (CIN). NAC has also been demonstrated to reduce myocardial infarction size and improve left ventricular function after ischemia in both humans and animals studies. In this study we tested the safety and cardiorenal protective efficacy of intracoronary NAC delivered in the radiographic contrast agent in a pig model that simulates the catheter based reperfusion therapy of ST elevation myocardial infarctions. 27 pigs underwent 45 min of ischemia after surgical ligation of distal left descending coronary artery. With coronary reperfusion the animals received at total of 200 mL of the contrast agent Iopamidol with and without NAC to mimic radiographic contrast use during invasive reperfusion therapy. At 24 h the following endpoints were compared: LV function (MRI, echocardiography), myocardial injury (infarct size, area-at-risk, troponin, creatinine kinase) and CIN (creatinine, BUN and renal histology). The effects of NAC on platelet reactivity were also evaluated. Intracoronary administration of NAC administered in the contrast agent is safe. NAC reduces platelet reactivity and there was a trend towards a better cardiac function at 24 h. There was no significant difference in the size of the myocardial infarction. In this model of ischemia-reperfusion high dose NAC did not protect from CIN. High dose intracoronary NAC administered with the radiographic contrast is safe but does not provide significant cardio-renal protection.

Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.

IMPORTANCE: Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). OBJECTIVE: To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. DESIGN: Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. INTERVENTIONS: Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. MAIN OUTCOME MEASURES: Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. RESULTS: Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). CONCLUSION AND RELEVANCE: Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00763867.

Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial.

IMPORTANCE: Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE: To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 µg/kg/min) or low-dose nesiritide (0.005 µg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS: Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES: Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS: Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE: In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01132846.

Effect of Personalized Accelerated Pacing on Quality of Life, Physical Activity, and Atrial Fibrillation in Patients With Preclinical and Overt Heart Failure With Preserved Ejection Fraction: The myPACE Randomized Clinical Trial.

Importance: Patients 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. Objective: To 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 Participants: This 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. Interventions: Participants 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 Measures: The 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. Results: Overall, 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 < .001) and worsened with usual care (median [IQR] baseline MLHFQ score, 19 [6-42]; at 1 month, 23 [5-39]; at 1 year, 27 [7-52]; 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 < .001), and device-detected atrial fibrillation (27% relative risk reduction compared with usual care; 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 Relevance: In 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 Registration: ClinicalTrials.gov Identifier: NCT04721314.

Erythropoietin induces positive inotropic and lusitropic effects in murine and human myocardium.

Initial clinical studies indicate a potential beneficial effect of erythropoietin (EPO) in patients with anemia and heart failure. Here, we investigate the direct contractile effects of erythropoietin on myocardial tissue. Treatment with EPO (50U/mL) using excitable murine and human left ventricular muscle preparations resulted in a 37% and 62% increase in twitch tension, respectively (P<0.05). Isolated murine cardiomyocytes exposed to EPO demonstrated a 41% increase in peak sarcomere shortening (P=0.012). Using compounds that specifically stimulate a non-erythropoietic EPO receptor yielded similar increases in contractile dynamics. Cardiomyocyte Ca(2+)dynamics showed an 18% increase in peak calcium in EPO treated cardiomyocytes over controls (P=0.03). Studies in muscle strips skinned after EPO treatment demonstrated a phosphorylation dependant increase in the viscous modulus as well as an increase in oscillatory work. The EPO mediated increase in peak sarcomere shortening was abrogated by PI3-K blockade via wortmannin and by non-isozyme specific PKC blockade by chelerythrine. Finally, EPO treatment resulted in an increase in PKCε in the particulate cellular fraction, indicating activation of this isoform. EPO exhibits direct positive inotropic and lusitropic effects in cardiomyocytes and ventricular muscle preparation. These effects are mediated through PI3-K and PKCε isoform signaling to directly affect both calcium release dynamics and myofilament function.

Resistance training alters skeletal muscle structure and function in human heart failure: effects at the tissue, cellular and molecular levels.

Reduced skeletal muscle function in heart failure (HF) patients may be partially explained by altered myofilament protein content and function. Resistance training increases muscle function, although whether these improvements are achieved by correction of myofilament deficits is not known. To address this question, we examined 10 HF patients and 14 controls prior to and following an 18 week high-intensity resistance training programme. Evaluations of whole muscle size and strength, single muscle fibre size, ultrastructure and tension and myosin-actin cross-bridge mechanics and kinetics were performed. Training improved whole muscle isometric torque in both groups, although there were no alterations in whole muscle size or single fibre cross-sectional area or isometric tension.Unexpectedly, training reduced the myofibril fractional area of muscle fibres in both groups. This structural change manifested functionally as a reduction in the number of strongly bound myosin-actin cross-bridges during Ca²âº activation. When post-training single fibre tension data were corrected for the loss of myofibril fractional area, we observed an increase in tension with resistance training. Additionally, training corrected alterations in cross-bridge kinetics (e.g. myosin attachment time) in HF patients back to levels observed in untrained controls. Collectively, our results indicate that improvements in myofilament function in sedentary elderly with and without HF may contribute to increased whole muscle function with resistance training. More broadly, these data highlight novel cellular and molecular adaptations in muscle structure and function that contribute to the resistance-trained phenotype.