Nayef Abouzaki

Heart failure with preserved ejection fraction: Refocusing on diastole

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of exercise intolerance and/or congestion, in the presence of a left ventricular (LV) ejection fraction within the normal limits (i.e. LVEF>50%). Determining the presence of impaired LV relaxation and/or filling (diastolic dysfunction) in HFpEF is needed to pragmatically to distinguish it from other cardiac and non-cardiac conditions where symptoms are not due to HF. There are multiple mechanisms for diastolic dysfunction ranging from structural abnormalities to functional derangements in HFpEF yet tailored therapies are lacking. Treatments proven effective in HF with systolic dysfunction have failed to show significant benefit in patients with HFpEF, which prognosis remains poor. This review will discuss the challenges inherent to the use of diagnostic criteria for HFpEF, differential diagnosis, prognostic evaluation, and treatment, highlighting the need for more research in this field.

Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies).

Two pilot studies of interleukin-1 (IL-1) blockade in ST-segment elevation myocardial infarction (STEMI) showed blunted acute inflammatory response and overall favorable outcomes at 3 months follow-up. We hereby present a patient-level pooled analysis with extended follow-up of 40 patients with clinically stable STEMI randomized to anakinra, a recombinant IL-1 receptor antagonist, 100 mg/day for 14 days or placebo in a double-blinded fashion. End points included death, cardiac death, recurrent acute myocardial infarction (AMI), stroke, unstable angina, and symptomatic heart failure. Median follow-up was 28 (interquartile range 3 to 38) months. Sixteen patients (40%) had a total of 22 adverse cardiovascular events: 1 cardiac death, 4 recurrent AMI, 5 episodes of unstable angina pectoris requiring hospitalization and/or urgent revascularization, and 11 new diagnoses of heart failure. Treatment with anakinra was associated with a hazard ratio of 1.08 (95% confidence interval 0.31 to 3.74, p = 0.90) for the combined end point of death, recurrent AMI, unstable angina pectoris, or stroke and a hazard ratio of 0.16 (95% confidence interval 0.03 to 0.76, p = 0.008) for death or heart failure. In conclusion, IL-1 blockade with anakinra for 2 weeks appears, therefore, to have a neutral effect on recurrent ischemic events, whereas it may prevent new-onset heart failure long term after STEMI.

Prognostic Indicators for Recurrent Thrombotic Events in HIV-infected Patients with Acute Coronary Syndromes: Use of Registry Data From 12 sites in Europe, South Africa and the United States

AIMS Limited data are available on prognostic indicators for HIV patients presenting with ACS. METHODS AND RESULTS Data on consecutive patients with HIV infection receiving standard highly active antiretroviral therapy (HAART) presenting with ACS between January 2001 and September 2012 were collected. Cardiac death and myocardial infarction (MI) were the primary end-points. 10,050 patients with ACS were screened, and among them a total of 201 patients (179 [89%] males and a median age of 53 [47-62] years) were included, 48% of them admitted for ST-elevation myocardial infarction and 14% having left ventricular systolic dysfunction (LVSD) at discharge. CD4+ counts less than 200 cells/mm(3) were reported in 18 patients (9%), and 136 patients (67%) were treated with nucleoside-reverse transcriptase inhibitors (NRTI). After a median of 24 months (10-41), 30 patients (15%) died, 12 (6%) for cardiac reasons, 20 (10%) suffered a MI, 29 (15%) a subsequent revascularization, and 7 (3%) a stent thrombosis. Other than LVSD (hazard ratio=6.4 [95% confidence interval [CI]: 1.6-26: p=0.009]), the only other independent predictor of cardiac death was not being treated with NRTI (hazard ratio=9.9 [95% CI: 2.1-46: p=0.03); a CD4 cell count <200 cells/mm(3) was the only predictor of MI (hazard ratio=5.9 [95% CI: 1.4-25: p=0.016]). CONCLUSIONS HIV patients presenting with ACS are at significantly increased risk for cardiac death if not treated with NRTI, and at significantly increased risk of MI if their CD4 cell count is <200 cells/mm(3), suggesting that the stage of HIV disease (and lack of NRTI treatment) may contribute to cardiovascular instability.

Interleukin-1 Blockade In Acute Decompensated Heart Failure: A Randomized, Double-Blinded, Placebo-Controlled Pilot Study.

Background: Heart failure is an inflammatory disease. Patients with acute decompensated heart failure (ADHF) exhibit significant inflammatory activity on admission. We hypothesized that Interleukin-1 blockade, with anakinra (Kineret, Swedish Orphan Biovitrum), would quench the acute inflammatory response in patients with ADHF. Methods: We randomized 30 patients with ADHF, reduced left ventricular ejection fraction (<40%), and elevated C reactive protein (CRP) levels (≥5 mg/L) to either anakinra 100 mg twice daily for 3 days followed by once daily for 11 days or matching placebo, in a 1:1 double blinded fashion. We measured daily CRP plasma levels using a high-sensitivity assay during hospitalization and then again at 14 days and evaluated the area-under-the-curve and interval changes (delta). Results: Treatment with anakinra was well tolerated. At 72 hours, anakinra reduced CRP by 61% versus baseline, compared with a 6% reduction among patients receiving placebo (P = 0.004 anakinra vs. placebo). Conclusions: Interleukin-1 blockade with anakinra reduces the systemic inflammatory response in patients with ADHF. Further studies are warranted to determine whether this anti-inflammatory effect translates into improved clinical outcomes.

Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2)

Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of confirmed HF cases in the United States. However, there are no highly effective evidence‐based treatments currently available for these patients. Inflammation correlates positively with adverse outcomes in HF patients. Interleukin (IL)‐1, a prototypical inflammatory cytokine, has been implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clinical trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D‐HART2) is a phase 2, 2:1 randomized, double‐blind, placebo‐controlled clinical trial that will test the hypothesis that IL‐1 blockade with anakinra (recombinant human IL‐1 receptor antagonist) improves (1) cardiorespiratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation in patients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co–primary endpoints will be placebo‐corrected interval changes in peak oxygen consumption and ventilatory efficiency at week 12. In addition, secondary and exploratory analyses will investigate the effects of IL‐1 blockade on cardiac structure and function, systemic inflammation, endothelial function, quality of life, body composition, nutritional status, and clinical outcomes. The D‐HART2 clinical trial will add to the growing body of evidence on the role of inflammation in cardiovascular disease, specifically focusing on patients with HFpEF.

Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial)

Background An enhanced inflammatory response predicts worse outcomes in heart failure (HF). We hypothesized that administration of IL-1 (interleukin-1) receptor antagonist (anakinra) could inhibit the inflammatory response and improve peak aerobic exercise capacity in patients with recently decompensated systolic HF. Methods and Results We randomly assigned 60 patients with reduced left ventricular ejection fraction (<50%) and elevated C-reactive protein levels (>2 mg/L), within 14 days of hospital discharge, to daily subcutaneous injections with anakinra 100 mg for 2 weeks, 12 weeks, or placebo. Patients underwent measurement of peak oxygen consumption (VO2 [mL/kg per minute]) and ventilatory efficiency (the VE/VCO2 slope). Treatment with anakinra did not affect peak VO2 or VE/VCO2 slope at 2 weeks. At 12 weeks, patients continued on anakinra showed an improvement in peak VO2 from 14.5 (10.5–16.6) mL/kg per minute to 16.1 (13.2–18.6) mL/kg per minute (P=0.009 for within-group changes), whereas no significant changes occurred within the anakinra 2-week or placebo groups. The between-groups differences, however, were not statistically significant. The incidence of death or rehospitalization for HF at 24 weeks was 6%, 31%, and 30%, in the anakinra 12-week, anakinra 2-week, and placebo groups, respectively (log-rank test P=0.10). Conclusions No change in peak VO2 occurred at 2 weeks in patients with recently decompensated systolic HF treated with anakinra, whereas an improvement was seen in those patients in whom anakinra was continued for 12 weeks. Additional larger studies are needed to validate the effects of prolonged anakinra on peak VO2 and rehospitalization for HF. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936909.

Leukocyte activity in patients with ST-segment elevation acute myocardial infarction treated with anakinra.

Anakinra, the recombinant form of the human interleukin (IL)-1 receptor antagonist, blunts the acute systemic inflammatory response in patients with ST-segment elevation myocardial infarction (STEMI), by determining a fall in peripheral blood leukocyte and plasma C-reactive protein levels. The aim of the present study was to determine the effects of anakinra on the activity of leukocytes measured ex vivo. Blood was collected 72 h after admission in 17 patients enrolled in the Virginia Commonwealth University — Anakirna Remodeling Trial (2) (VCU-ART2) and randomly treated with anakinra (N = 7) or placebo (N = 10). Whole blood was cultured at 37°C for 24 h to measure spontaneous production of IL-6 or stimulated with Escherichia coli lipopolysaccharide (LPS) for toll-like receptor (TLR)-4 or heat-killed Staphylococcus epidermidis (SE) for TLR-2 activation. The cultures of anakinra-treated patients produced significantly less IL-6 spontaneously (71 pg/mL (27–114)) compared with placebo-treated patients (290 pg/mL (211–617), p = 0.005). LPS- or SE-induced IL-6 production, on the other hand, was not statistically different between anakinra- versus placebo-treated patients (344 pg/mL (94–560) versus 370 pg/mL (306–991), p = 0.32 for LPS, and 484 pg/mL (77–612) versus 615 pg/mL (413–871), p = 0.31 for SE, respectively). IL-1 blockade with anakinra in STEMI patients results in reduced spontaneous leukocyte activity ex vivo without impairing the responsiveness to bacterial stimuli.

Clinical predictors of response to anakinra in patients with heart failure

Letter to the Editor Systemic inflammation is often present in patients with heart failure (HF)1. Interleukin-1 (IL-1) a key pro-inflammatory cytokine regulates cardiac function in acute and chronic inflammatory illnesses2. Recent data from two pilot studies showed that treatment with an interleukin-1 blocker, anakinra, improved cardiopulmonary exercise testing (CPX) performance in patients with heart failure - reduced ejection fraction (HFrEF)3 as well as in patients with heart failure - preserved ejection fraction (HFpEF)4. HFrEF and HFpEF share a similar burden of symptoms, such as exercise intolerance, but different mechanisms of disease5. The aim of this analysis was to pool data from the 2 pilot studies to explore whether baseline characteristics could serve as predictors of improved CPX performance with anakinra. The analysis included 19 patients, 7 with HFrEF 3 and 12 with HFpEF 4. Inclusion criteria included symptoms of HF (New York Heart Association [NYHA] class II-III) on stable medical therapy without any changes in medications in the prior 3 months, hospital admissions in the prior 12 months, and evidence of impaired left ventricular systolic function (left ventricular ejection fraction [LVEF] 2 mg/l. All patients underwent a baseline transthoracic Doppler echocardiographic study according to the American Society of Echocardiography recommendations 6: LVEF was measured using volumetric analysis for two perpendicular apical views, diastolic function was measured as ratio of transmitral early diastolic velocity (E) to the mitral annulus early diastolic velocity at tissue Doppler (E’) obtained from an average of the septal and lateral wall measurements, right ventricular function was measured as tricuspidal annulus plane systolic excursion (TAPSE). A CPX was completed according to the American Heart Association recommendations as previously described.7 Patients were then treated with anakinra (Kineret™, Swedish Orphan Biovitrum, Stockholm, Sweden); 100 mg subcutaneously daily for 14 days and repeated determination of CRP levels and CPX.3–4 Patients with HFrEF received open-label treatment, whereas patients with HFpEF had blinded treatment. 3–4 Peak VO2 and the minute ventilation/carbon dioxide production (VE/VCO2) slope were pre-specified primary end-points, reflecting 2 important and complementary prognostic indicators in HF.8–9 Additional endpoints included the oxygen uptake efficiency slope (OUES),10 the Duke activity status index (DASI)11, plasma CRP levels and B-type natriuretic peptide levels. Data are reported as median and interquartile range for continuous variables to account for potential deviation from a Gaussian distribution. Discrete variables are reported as a number (%). Paired changes in each variable were analyzed using the Wilcoxon test and correlations between variables were measured with the Spearman correlation test (SPSS 21, IBM, NY, USA). The characteristics of the 19 patients as a whole are reported in Table 1, whereas characteristics of the subgroups are available in the original publications3,4 Table 1 Clinical characteristics. Treatment with anakinra led to a significant improvement in peak VO2 (from 14.1 [11.4–16.7] to 15.9 [13.7–17.5] ml•kg−1•min−1, P=0.002), the VE/VCO2 slope (from 25.6 [22.8–31.1] to 24.9 [22.8–28.2], P=0.002), OUES (from 2.1 [1.7–2.4] to 2.2 [1.8–2.5], P=0.003), and the DASI (24 [15–31] to 27 [24–37], P=0.016). Anakinra also led to a significant reduction in CRP levels (6.6 [3.6–15.2] to 1.3 [0.5–3.1] mg/l, P<0.001), and no significant change in B-type natriuretic peptide (25 [15–112] to 37 [10–57] pg/ml, P=0.48). Anakinra had no significant effects on blood pressure, heart rate or body weight (data not shown). Baseline LVEF was linearly correlated with peak VO2 (R=+0.52, P=0.024) but not with the VE/VCO2 slope or OUES (both P>0.2). Reduced LVEF predicted greater improvement peak VO2 with treatment (R=-0.47, P=0.044), but not in the VE/VCO2 slope or OUES. Values of E/E’ ratio or TAPSE did not correlate with baseline CPX variables or changes following anakinra treatment. On the other hand, the greater baseline impairment in peak VO2 (i.e. lower value), the VE/VCO2 slope (i.e. higher value), and OUES (i.e. lower value), the greater the improvement seen with anakinra treatment in each of these variables (Figure 1). Baseline CRP or BNP levels failed to predict changes in peak VO2, the VE/VCO2 slope or OUES. Figure 1 Baseline cardiopulmonary exercise test (CPX) variables such as peak oxygen consumption (peak VO2) and ventilatory efficiency (VE/VCO2 slope and OUES) predict improvement with anakinra. In summary, the data pooled from two pilot studies confirm the improvement in CPX performance with anakinra across the spectrum of HFrEF and HFpEF, with improvements in peak VO2, (+1.8 ml•kg−1•min−1), the VE/VCO2 slope (−0.7) and the OUES (+0.1) that are considered clinically relevant,8–10 and an associated improvement in perceived functional capacity (DASI questionnaire +3).11 Inflammatory biomarkers, such as CRP, predict cardiac dysfunction and risk.12–14 The current study shows a significant reduction in CRP levels with anakinra. In this pooled analysis, we explored whether baseline characteristics, such as CRP, could serve as predictors of improved performance. We set forth 4 hypotheses. First, we proposed that inflammation (CRP levels) would predict improvement. However, in this analysis of all patients with CRP>2.0 mg/l, this was not the case. Second, we hypothesized that the degree of LV systolic or diastolic dysfunction or RV systolic dysfunction would identify a group of subjects with greater improvement with treatment. While this was in part true for LVEF, the strength of the relationship and statistical significance were marginal and limited to peak VO2. Third, we analyzed whether the effects of anakinra were most evident in those subjects with more severe baseline impairment.15 In our data, peak VO2, the VE/VCO2 slope and OUES prior to treatment strongly predicted the improvement in each of the 3 variables, with greater improvement seen with anakinra in patients with worse baseline CPX performance. The superior prognostic value of exercise parameters should not come as a surprise considering that majority of symptoms in HF are provoked by exertion and are absent at rest, and these parameters are equally valuable in HFrEF and HFpEF.16 Fourth, we explored whether baseline BNP levels, used to stratify patients with HF,17 would predict improvement, but found no association between BNP levels and changes in CPX variables.

Rationale and design of the Virginia Commonwealth University–Anakinra Remodeling Trial-3 (VCU-ART3): A randomized, placebo-controlled, double-blinded, multicenter study

There is clear association between the intensity of the acute inflammatory response during acute myocardial infarction (AMI) and adverse prognosis after AMI. Interleukin‐1 (IL‐1) is a pro‐inflammatory cytokine released during AMI and involved in adverse remodeling and heart failure (HF). We describe a study to evaluate the safety and efficacy of IL‐1 blockade using an IL‐1 receptor antagonist (anakinra) during the acute phase of ST‐segment elevation myocardial infarction (STEMI). The Virginia Commonwealth University–Anakinra Remodeling Trial‐3 (VCU‐ART3; http://www.ClinicalTrials.gov NCT01950299) is a phase 2, multicenter, double‐blinded, randomized, placebo‐controlled clinical trial comparing anakinra 100 mg once or twice daily vs matching placebo (1:1:1) for 14 days in 99 patients with STEMI. Patients who present to the hospital with STEMI within 12 hours of symptom onset will be eligible for enrollment. Patients will be excluded for a history of HF (functional class III–IV), severe valvular disease, severe kidney disease (stage 4–5), active infection, recent use of immunosuppressive drugs, active malignancy, or chronic autoimmune/auto‐inflammatory diseases. We will measure the difference in the area under the curve for C‐reactive protein between admission and day 14, separately comparing each of the anakinra groups with the placebo group. The P value will be considered significant if <0.025 to adjust for multiple comparisons. Patients will also be followed for up to 12 months from enrollment to evaluate cardiac remodeling (echocardiography), cardiac function (echocardiography), and major adverse cardiovascular outcomes (cardiovascular death, MI, revascularization, and new onset of HF).

Usefulness of Canakinumab to Improve Exercise Capacity in Patients With Long-Term Systolic Heart Failure and Elevated C-Reactive Protein

Interleukin-1β (IL-1β) is a cytokine involved in atherothrombosis and is known to depress cardiac function. We hypothesized that blocking IL-1β in patients with symptomatic systolic heart failure (HF) would improve their cardiorespiratory fitness. The purpose of the study was to measure changes in peak oxygen consumption (VO2) in 30 patients with prior myocardial infarction, high-sensitivity C-reactive protein ≥ 2 mg/l and HF with left ventricular ejection fraction (LVEF) < 50% enrolled in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) in an independent single center substudy. We measured peak VO2 before and after 3 and 12 months of treatment with Canakinumab every 3 months (50, 150, or 300mg subcutaneously) or placebo, and measured LVEF before and after 12 months. In December 2013, the CANTOS study announced early termination of enrollment, halting enrollment for this substudy after only 15 patients, of which 3 were assigned to placebo and 12 to Canakinumab (50mg [1; 7%], 150mg [5; 33%], 300mg [6; 40%]). Patients treated with Canakinumab had a significant improvement in peak VO2, from 19.2 to 22.8 ml/kg/min at 3 months (p = 0.023 within-group changes, p = 0.026 for time_x_group interaction versus placebo [primary end point]), and an improvement in LVEF 38% (33-43) to 44% (38-52) at 12 months (p = 0.012 for within-group changes). No significant changes were seen in the placebo group. In conclusion, the findings of this small prespecified secondary analysis of the CANTOS trial support the positive results of the overall study, and confirm IL-1 as a potential therapeutic target in HF. https://clinicaltrials.gov/ct2/show/NCT01900600.