Pathophysiology and Treatment Opportunities of Iron Deficiency in Heart Failure: Is There a Need for Further Trials?

PURPOSE OF REVIEW: Iron deficiency (ID) complicates heart failure (HF) at different stages of the natural history of the disease; however, this frequent comorbidity is still not comprehensively understood and investigated in terms of pathophysiology. Intravenous iron therapy with ferric carboxymaltose (FCM) should be considered to improve the quality of life, exercise capacity, and symptoms in stable HF with ID, as well as to reduce HF hospitalizations in iron-deficient patients stabilized after an episode of acute HF. The therapy with intravenous iron, however, continues to generate important clinical questions for cardiologists. RECENT FINDINGS: In the current paper, we discuss the class effect concept for intravenous iron formulations beyond FCM, based on the experiences of nephrologists who administer different intravenous iron formulations in advanced chronic kidney disease complicated with ID and anemia. Furthermore, we discuss the neutral effects of oral iron therapy in patients with HF, because there are still some reasons to further explore this route of supplementation. The different definitions of ID applied in HF studies and new doubts regarding possible interactions of intravenous iron with sodium-glucose co-transporter type 2 inhibitors are also emphasized. The experiences of other medical specializations may provide new information on how to optimally replenish iron in patients with HF and ID.

Baroreflex activation therapy with the Barostim™ device in patients with heart failure with reduced ejection fraction: a patient level meta-analysis of randomized controlled trials.

AIMS: Heart failure with reduced ejection fraction (HFrEF) remains associated with high morbidity and mortality, poor quality of life (QoL) and significant exercise limitation. Sympatho-vagal imbalance has been shown to predict adverse prognosis and symptoms in HFrEF, yet it has not been specifically targeted by any guideline-recommended device therapy to date. Barostim™, which directly addresses this imbalance, is the first Food and Drug Administration approved neuromodulation technology for HFrEF. We aimed to analyse all randomized trial evidence to evaluate the effect of baroreflex activation therapy (BAT) on heart failure symptoms, QoL and N-terminal pro-brain natriuretic peptide (NT-proBNP) in HFrEF. METHODS AND RESULTS: An individual patient data (IPD) meta-analysis was performed on all eligible trials that randomized HFrEF patients to BAT + guideline-directed medical therapy (GDMT) or GDMT alone (open label). Endpoints included 6-month changes in 6-min hall walk (6MHW) distance, Minnesota Living With Heart Failure (MLWHF) QoL score, NT-proBNP, and New York Heart Association (NYHA) class in all patients and three subgroups. A total of 554 randomized patients were included. In all patients, BAT provided significant improvement in 6MHW distance of 49 m (95% confidence interval [CI] 33, 64), MLWHF QoL of -13 points (95% CI -17, -10), and 3.4 higher odds of improving at least one NYHA class (95% CI 2.3, 4.9) when comparing from baseline to 6 months. These improvements were similar, or better, in patients who had baseline NT-proBNP <1600 pg/ml, regardless of the cardiac resynchronization therapy indication status. CONCLUSION: An IPD meta-analysis suggests that BAT improves exercise capacity, NYHA class, and QoL in HFrEF patients receiving GDMT. These clinically meaningful improvements were consistent across the range of patients studies. BAT was also associated with an improvement in NT-proBNP in subjects with a lower baseline NT-proBNP.

Dietary interventions and nutritional supplements for heart failure: a systematic appraisal and evidence map.

AIMS: To appraise meta-analytically determined effect of dietary interventions and nutritional supplements on heart failure (HF)-related outcomes, and create an evidence map to visualize the findings and certainty of evidence. METHODS AND RESULTS: Online databases were systematically searched for meta-analyses of randomized controlled trials (RCTs) evaluating the effect of dietary interventions and nutritional supplements on HF outcomes and incidence. These were then updated if new RCTs were available. Estimates were pooled using a random-effects model and reported as risk ratios (RRs) or mean differences with 95% confidence intervals. We identified 14 relevant meta-analyses, to which 21 new RCTs were added. The total evidence base reviewed included 122 RCTs (n = 176 097 participants) assessing 14 interventions. We found that coenzyme Q10 was associated with lower all-cause mortality [RR 0.69 (0.50-0.96); I2  = 0%; low certainty of evidence] in HF patients. Incident HF risk was reduced with Mediterranean diet [RR 0.45 (0.26-0.79); I2  = 0%; low certainty of evidence]. Vitamin E supplementation was associated with a small but significant increase in the risk of HF hospitalization [RR 1.21 (1.04-1.40); I2 = 0%; moderate certainty of evidence]. There was moderate certainty of evidence that thiamine, vitamin D, iron, and L-carnitine supplementation had a beneficial effect on left ventricular ejection fraction. CONCLUSION: Coenzyme Q10 may reduce all-cause mortality in HF patients, while a Mediterranean diet may reduce the risk of incident HF; however, the low certainty of evidence warrants the need for further RCTs to confirm a definite clinical role. RCT data were lacking for several common interventions including intermittent fasting, caffeine, DASH diet, and ketogenic diet. More research is needed to fill the knowledge gap.

Increasing Blood Pressure by Greater Splanchnic Nerve Stimulation: a Feasibility Study.

The splanchnic vascular compartment is the major reservoir for intravascular blood volume, and dysregulation of the compartment was implicated in a series of cardiovascular conditions. We explored feasibility and effectiveness of an implantable cuff system on the greater splanchnic nerve (GSN) in healthy canines for short- and long-term neuromodulation to affect the circulation. Five mongrel hounds underwent minimally invasive right-sided unilateral GSN cuff placement. All animals underwent same day GSN stimulation and repeat stimulation at 9-30 days. Stimulation parameter optimization was conducted both acutely and chronically. Parameters ranged from 1-250 Hz, 0.25 mA-35 mA, 0.1-0.5 ms, and 30-s pulse duration. Two animals were survived for 9 days and 3 animals for 30 days. Stimulation of the right GSN increased mean arterial blood pressure by 36.9 mmHg ± 13.4 (p < 0.0001), central venous pressure by 6.9 mmHg ± 1.7 (p < 0.0001), and mean pulmonary arterial pressure by 6.3 mmHg ± 2.0 (p < 0.0001). Peak effects were observed within 30 s, and magnitude of effects was comparable between stimulation cycles (p = 0.4). Stimulation-induced changes in hemodynamics were independent of afferent nerve fibers (pain response) or the adrenal gland. Necropsy showed no evidence of nerve damage on histologic studies up to 30 days after implantation. GSN stimulation via an implanted nerve cuff provided a reproducible and rapid method to increase arterial, central venous, and pulmonary arterial pressures. The neuromodulation cuff was well tolerated and elicited a response up to 30 days after implantation. The clinical application of GSN stimulation as a tool to change central and peripheral cardiovascular hemodynamics needs to be explored.

Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnea: A Pooled Cohort Analysis.

STUDY OBJECTIVES: Early evidence with transvenous phrenic nerve stimulation (PNS) demonstrates improved disease severity and quality of life (QOL) in patients with central sleep apnea (CSA). The goal of this analysis is to evaluate the complete prospective experience with PNS in order to better characterize its efficacy and safety, including in patients with concomitant heart failure (HF). METHODS: Using pooled individual data from the pilot (n = 57) and pivotal (n = 151) studies of the remede System in patients with predominant moderate to severe CSA, we evaluated 12-month safety and 6- and 12-month effectiveness based on polysomnography data, QOL, and cardiac function. RESULTS: Among 208 combined patients (June 2010 to May 2015), a remede device implant was successful in 197 patients (95%), 50/57 pilot study patients (88%) and 147/151 pivotal trial patients (97%). The pooled cohort included patients with CSA of various etiologies, and 141 (68%) had concomitant HF. PNS reduced apnea-hypopnea index (AHI) at 6 months by a median of -22.6 episodes/h (25th and 75th percentile; -38.6 and -8.4, respectively) (median 58% reduction from baseline, P < .001). Improvement in sleep variables was maintained through 12 months of follow-up. In patients with HF and ejection fraction ≤ 45%, PNS was associated with improvement in systolic function from 27.0% (23.3, 36.0) to 31.1% (24.0, 41.5) at 12 months (P = .003). In the entire cohort, improvement in QOL was concordant with amelioration of sleep measures. CONCLUSIONS: Transvenous PNS significantly improves CSA severity, sleep quality, ventricular function, and QOL regardless of HF status. Improvements, which are independent of patient compliance, are sustained at 1 year and are associated with acceptable safety.

Spironolactone in Acute Heart Failure Patients With Renal Dysfunction and Risk Factors for Diuretic Resistance: From the ATHENA-HF Trial.

BACKGROUND: Acute heart failure (HF) patients with renal insufficiency and risk factors for diuretic resistance may be most likely to derive incremental improvement in congestion with the addition of spironolactone. METHODS: The Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF) trial randomized 360 acute HF patients with reduced or preserved ejection fraction to spironolactone 100 mg daily or usual care for 96 hours. The current analysis assessed the effects of study therapy within tertiles of baseline estimated glomerular filtration rate (eGFR) and subgroups at heightened risk for diuretic resistance. RESULTS: Across eGFR tertiles, there was no incremental benefit of high-dose spironolactone on any efficacy endpoint, including changes in log N-terminal pro-B-type natriuretic peptide and signs and symptoms of congestion (all P for interaction ≥ 0.06). High-dose spironolactone had no significant effect on N-terminal pro-B-type natriuretic peptide reduction regardless of blood pressure, diabetes mellitus status, and loop diuretic dose (all P for interaction ≥ 0.38). In-hospital changes in serum potassium and creatinine were similar between treatment groups for all GFR tertiles (all P for interaction ≥ 0.18). Rates of inpatient worsening HF, 30-day worsening HF, and 60-day all-cause mortality were numerically higher among patients with lower baseline eGFR, but relative effects of study treatment did not differ with renal function (all P for interaction ≥ 0.27). CONCLUSIONS: High-dose spironolactone did not improve congestion over usual care among patients with acute HF, irrespective of renal function and risk factors for diuretic resistance. In-hospital initiation or continuation of spironolactone was safe during the inpatient stay, even when administered at high doses to patients with moderate renal dysfunction.

Identifying responders to oral iron supplementation in heart failure with a reduced ejection fraction: a post-hoc analysis of the IRONOUT-HF trial.

BACKGROUND: The IRONOUT-HF trial previously demonstrated that oral iron supplementation minimally increased iron stores and did not improve exercise capacity in patients with heart failure with a reduced ejection fraction (HFrEF) and iron deficiency. METHODS: The IRONOUT-HF trial was a double-blind, placebo-controlled, randomized clinical trial designed to test the efficacy and safety of oral iron polysaccharide compared to matching placebo among patients with HFrEF and iron deficiency. Study participants received oral iron polysaccharide 150 mg twice daily or matching placebo for 16 weeks. Response to oral iron was defined as a ferritin level >300 ng/mL or a ferritin level 100-300 ng/mL with a transferrin saturation >20% at the end of the study. RESULTS: The final analytical cohort included 98 patients with HFrEF and iron deficiency at baseline. Study participants had a median (25, 75) age of 63 years (54 years, 71 years), included 40% women (N = 39). After 16 weeks of therapy, 24 patients (24%) responded to oral iron supplementation while 74 patients (76%) remained iron deficient despite treatment. There was no association between response to oral iron supplementation and improvement in functional status (i.e. peak VO2 or anaerobic threshold), myocardial stress (i.e. NT-proBNP levels), or HRQOL (i.e. Kansas City Cardiomyopathy Questionnaire) at week 16. CONCLUSION: This study failed to identify a subset of responders more likely to derive a clinical benefit from oral iron therapy and does not support its routine use in patients with symptomatic HFrEF and iron deficiency.