beta(1)-Adrenoreceptor Autoantibodies in Heart Failure Physiology and Therapeutic Implications

Antibodies that activate the β1-AR (β1-adrenoreceptor) can induce heart failure in animal models. These antibodies are often found in patients with heart failure secondary to varying etiologies. Their binding to the β1 receptor leads to prolonged receptor activation with subsequent induction of cellular dysfunction, apoptosis, and arrhythmias. β-blocker therapy while highly effective for heart failure, may not be sufficient treatment for patients who have β1 receptor autoantibodies. Removal of these autoantibodies by immunoadsorption has been shown to improve heart failure in small studies. However, immunoadsorption is costly, time consuming, and carries potential risks. An alternative to immunoadsorption is neutralization of autoantibodies through the intravenous application of small soluble molecules, such as peptides or aptamers, which specifically target and neutralize β1-AR autoantibodies. Peptides may induce immunogenicity. Animal as well as early phase human studies with aptamers have not shown safety concerns to date and have demonstrated effectiveness in reducing autoantibody levels. Novel aptamers have the potential advantage of having a wide spectrum of action, neutralizing a variety of known circulating G-protein coupled receptor autoantibodies. These aptamers, therefore, have the potential to be novel therapeutic option for patients with heart failure who have positive for β1-AR autoantibodies. However, clinical outcomes trials are needed to assess the clinical utility of this novel approach to treat heart failure

Heart failure therapy in diabetic patients-comparison with the recent ESC/EASD guideline

<p>Abstract</p> <p>Background</p> <p>To assess heart failure therapies in diabetic patients with preserved as compared to impaired systolic ventricular function.</p> <p>Methods</p> <p>3304 patients with heart failure from 9 different studies were included (mean age 63 ± 14 years); out of these, 711 subjects had preserved left ventricular ejection fraction (≥ 50%) and 994 patients in the whole cohort suffered from diabetes.</p> <p>Results</p> <p>The majority (>90%) of heart failure patients with reduced ejection fraction (SHF) and diabetes were treated with an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) or with beta-blockers. By contrast, patients with diabetes and preserved ejection fraction (HFNEF) were less likely to receive these substance classes (p < 0.001) and had a worse blood pressure control (p < 0.001). In comparison to patients without diabetes, the probability to receive these therapies was increased in diabetic HFNEF patients (p < 0.001), but not in diabetic SHF patients. Aldosterone receptor blockers were given more often to diabetic patients with reduced ejection fraction (p < 0.001), and the presence and severity of diabetes decreased the probability to receive this substance class, irrespective of renal function.</p> <p>Conclusions</p> <p>Diabetic patients with HFNEF received less heart failure medication and showed a poorer control of blood pressure as compared to diabetic patients with SHF. SHF patients with diabetes were less likely to receive aldosterone receptor blocker therapy, irrespective of renal function.</p

Baseline characteristics of patients with heart failure and preserved ejection fraction in the PARAGON-HF trial

Background: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. Methods and Results: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), β-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464–1610), and structural heart disease. Conclusions: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure

Heart failure (HF) represents a global public health and economic problem associated with unacceptable rates of death, hospitalization, and healthcare expenditure. Despite available therapy, HF carries a prognosis comparable to many forms of cancer with a 5-year survival rate of similar to 50 %. The current treatment paradigm for HF with reduced ejection fraction (EF) centers on blocking maladaptive neurohormonal activation and decreasing cardiac workload with therapies that concurrently lower blood pressure and heart rate. Continued development of hemodynamically active medications for stepwise addition to existing therapies carries the risk of limited tolerability and safety. Moreover, this treatment paradigm has thus far failed for HF with preserved EF. Accordingly, development of hemodynamically neutral HF therapies targeting primary cardiac pathologies must be considered. In this context, a partial adenosine A1 receptor (A1R) agonist holds promise as a potentially hemodynamically neutral therapy for HF that could simultaneous improve cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term clinical outcomes when added to background therapies. In this review, we describe the physiology and pathophysiology of HF as it relates to adenosine agonism, examine the existing body of evidence and biologic rationale for modulation of adenosine A1R activity, and review the current state of drug development of a partial A1R agonist for the treatment of HF

Effects of beta-blocker therapy on hs-CRP levels in elderly patients with ischemic and non-ischemic heart failure: results from the CIBIS-ELD trail

Congress of the European-Society-of-Cardiology (ESC), Aug 29-Sep 02, 2015, London, Englan