The effect of a standardized capsule of Aloe vera gel on the quality of life in patients with systolic heart failure: A randomized double-blind placebo-controlled clinical trial.

This trial was designed to evaluate the effect of a standardized capsule of Aloe vera gel (AVG) on the quality of life (QOL) in patients with systolic heart failure (HF). Forty-two patients were randomly divided into two groups to receive either AVG 150 mg or harmonized placebo capsules twice a day for 8 weeks. The patients were evaluated before and after the intervention using the Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association (NYHA) functional class, six-minute walk test (6MWT), Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI) and STOP-BANG questionnaires. Post-intervention, AVG group indicated a significant reduction in the total score of MLHFQ (p < 0.001). The changes in MLHFQ and NYHA class were statistically significant after taking medication (p < 0.001 and p = 0.004, respectively). The change of 6MWT in the AVG group was more advanced; however, it was not statistically significant (p = 0.353). Moreover, in the AVG group, the severity of insomnia and obstructive sleep apnea decreased (p < 0.001, p = 0.01 respectively) and the sleep quality improved as well (p < 0.001). There were significantly fewer adverse events reported in the AVG group (p = 0.047). Therefore, AVG combined with standard medical therapy could provide more clinical benefits for patients with systolic HF.

Oral N-acetylcysteine as an adjunct to standard medical therapy improved heart function in cases with stable class II and III systolic heart failure.

BACKGROUND: This research attempted to assess whether N-acetylcysteine (NAC) as adjunctive therapy can be useful in the treatment of patients with heart failure (HF). METHODS: Fifty-five cases with diagnosed systolic HF and stable symptomatic New York Heart Association (NYHA) functional class II and III and on optimal medical treatment of HF for at least 3 months were assigned for receiving oral NAC (600 mg twice daily) or placebo for 12 weeks. The outcomes were changes in the echocardiographic hemodynamic indices as well as the patients' functional capacity assessed by NYHA classification over a 12-week treatment. RESULTS: Compared to placebo, NAC more significantly improved the systolic left ventricular (LV) function expressed as the ejection fraction and Tei index. These changes are accompanied by more improvement in other LV echocardiographic indices including LV end-diastolic volume index and LV global longitudinal strain in the patients receiving NAC in comparison with those receiving placebo. In parallel with the improvement of LV function, right ventricular (RV) function expressed as RV fractional area change and RV Tei-index also got more improvement in those receiving NAC than those receiving placebo. However, the change in RV global longitudinal strain did not show a significant difference between study groups. Additionally, at week 12, the distribution of the NYHA functional class also shifted toward a better outcome in the NAC group in comparison with the placebo group; however, it was not significant. CONCLUSIONS: These preliminary data support experimental findings showing that NAC supplementation is able to improve heart function. TRIAL REGISTRATION: The registration of the trial was done at the Iranian Registry of Clinical Trials ( www.irct.ir ). Identifier code: IRCT20120215009014N333. Registration date: 2020-01-11.

Efficacy of Blended Collaborative Care for Patients With Heart Failure and Comorbid Depression: A Randomized Clinical Trial.

Importance: Depression is often comorbid in patients with heart failure (HF) and is associated with worse clinical outcomes. However, depression generally goes unrecognized and untreated in this population. Objective: To determine whether a blended collaborative care program for treating both HF and depression can improve clinical outcomes more than collaborative care for HF only and physicians' usual care (UC). Design, Setting, and Participants: This 3-arm, single-blind, randomized effectiveness trial recruited 756 participants with HF with reduced left ventricular ejection fraction (<45%) from 8 university-based and community hospitals in southwestern Pennsylvania between March 2014 and October 2017 and observed them until November 2018. Participants included 629 who screened positive for depression during hospitalization and 2 weeks postdischarge and 127 randomly sampled participants without depression to facilitate further comparisons. Key analyses were performed November 2018 to March 2019. Interventions: Separate physician-supervised nurse teams provided either 12 months of collaborative care for HF and depression ("blended" care) or collaborative care for HF only (enhanced UC [eUC]). Main Outcomes and Measures: The primary outcome was mental health-related quality of life (mHRQOL) as measured by the Mental Component Summary of the 12-item Short Form Health Survey (MCS-12). Secondary outcomes included mood, physical function, HF pharmacotherapy use, rehospitalizations, and mortality. Results: Of the 756 participants (mean [SD] age, 64.0 [13.0] years; 425 [56%] male), those with depression reported worse mHRQOL, mood, and physical function but were otherwise similar to those without depression (eg, mean left ventricular ejection fraction, 28%). At 12 months, blended care participants reported a 4.47-point improvement on the MCS-12 vs UC (95% CI, 1.65 to 7.28; P = .002), but similar scores as the eUC arm (1.12; 95% CI, -1.15 to 3.40; P = .33). Blended care participants also reported better mood than UC participants (Patient-Reported Outcomes Measurement Information System-Depression effect size, 0.47; 95% CI, 0.28 to 0.67) and eUC participants (0.24; 95% CI, 0.07 to 0.41), but physical function, HF pharmacotherapy use, rehospitalizations, and mortality were similar by both baseline depression and randomization status. Conclusions and Relevance: In this randomized clinical trial of patients with HF and depression, telephone-delivered blended collaborative care produced modest improvements in mHRQOL, the primary outcome, on the MCS-12 vs UC but not eUC. Although blended care did not differentially affect rehospitalization and mortality, it improved mood better than eUC and UC and thus may enable organized health care systems to provide effective first-line depression care to medically complex patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02044211.

Response by Sex in Patient-Centered Outcomes With Baroreflex Activation Therapy in Systolic Heart Failure.

OBJECTIVES: The aim of this study was to assess sex differences in the efficacy and safety of baroreflex activation therapy (BAT) in the BeAT-HF (Baroreflex Activation Therapy for Heart Failure) trial. BACKGROUND: Patients were randomized 1:1 to receive guideline-directed medical therapy (GDMT) alone (control group) or BAT plus GDMT. METHODS: Pre-specified subgroup analyses including change from baseline to 6 months in 6-min walk distance (6MWD), quality of life (QoL) assessed using the Minnesota Living With Heart Failure Questionnaire (MLWHQ), New York Heart Association (NYHA) functional class, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were conducted in men versus women. RESULTS: Fifty-three women and 211 men were evaluated. Women had similar baseline NT-proBNP levels, 6MWDs, and percentage of subjects with NYHA functional class III symptoms but poorer MLWHQ scores (mean 62 ± 22 vs. 50 ± 24; p = 0.01) compared with men. Women experienced significant improvement from baseline to 6 months with BAT plus GDMT relative to GDMT alone in MLWHQ score (-34 ± 27 vs. -9 ± 23, respectively; p < 0.01), 6MWD (44 ± 45 m vs. -32 ± 118 m; p < 0.01), and improvement in NYHA functional class (70% vs. 27%; p < 0.01), similar to the responses seen in men, with no significant difference in safety. Women receiving BAT plus GDMT had a significant decrease in NT-proBNP (-43% vs. 7% with GDMT alone; difference -48%; p < 0.01), while in men this decrease was -15% versus 2%, respectively (difference -17%; p = 0.08), with an interaction p value of 0.05. CONCLUSIONS: Women in BeAT-HF had poorer baseline QoL than men but demonstrated similar improvements with BAT in 6MWD, QoL, and NYHA functional class. Women had a significant improvement in NT-proBNP, whereas men did not. (Baroreflex Activation Therapy for Heart Failure [BeAT-HF]; NCT02627196).

Outcomes of Cardiac Contractility Modulation: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Cardiac contractility modulation (CCM) is a device therapy for systolic heart failure (HF) in patients with narrow QRS. We aimed to perform an updated meta-analysis of the randomized clinical trials (RCTs) to assess the efficacy and safety of CCM therapy. METHODS: We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) between January 2001 and June 2018. Outcomes of interest were peak oxygen consumption (peak VO2), 6-Minute Walk Distance (6MWD), Minnesota Living with Heart Failure Questionnaire (MLHFQ), HF hospitalizations, cardiac arrhythmias, pacemaker/ICD malfunctioning, all-cause hospitalizations, and mortality. Data were expressed as standardized mean difference (SMD) or odds ratio (OR). RESULTS: Four RCTs including 801 patients (CCM n = 394) were available for analysis. The mean age was 59.63 ± 0.84 years, mean ejection fraction was 29.14 ± 1.22%, and mean QRS duration was 106.23 ± 1.65 msec. Mean follow-up duration was six months. CCM was associated with improved MLWHFQ (SMD -0.69, p = 0.0008). There were no differences in HF hospitalizations (OR 0.76, p = 0.12), 6MWD (SMD 0.67, p = 0.10), arrhythmias (OR 1.40, p = 0.14), pacemaker/ICD malfunction/sensing defect (OR 2.23, p = 0.06), all-cause hospitalizations (OR 0.73, p = 0.33), or all-cause mortality (OR 1.04, p = 0.92) between the CCM and non-CCM groups. CONCLUSIONS: Short-term treatment with CCM may improve MLFHQ without significant difference in 6MWD, arrhythmic events, HF hospitalizations, all-cause hospitalizations, and all-cause mortality. There is a trend towards increased pacemaker/ICD device malfunction. Larger RCTs might be needed to determine if the CCM therapy will be beneficial with longer follow-up.

The effect of posture, exercise, and atrial pacing on atrioventricular conduction in systolic heart failure.

BACKGROUND: Optimization of atrioventricular (AV) intervals for cardiac resynchronization therapy (CRT) programming is typically performed in supine patients at rest, which may not reflect AV timing in other conditions. OBJECTIVE: To evaluate the effects of posture, exercise, and atrial pacing on intrinsic AV intervals in patients with CRT devices. METHODS: Rate-dependent A-V delay by exercise was a multicenter, prospective trial of patients in sinus rhythm following CRT implantation. Intracardiac electrograms were recorded to analyze atrial to right ventricular (ARV), atrial to left ventricular (ALV), and RV to LV (VV) time intervals. Heart rate was increased with incremental atrial pacing in different postures, followed by an exercise treadmill test. RESULTS: This study included 36 patients. At rest, AV intervals changed minimally with posture. With atrial pacing, AV interval immediately increased compared with sinus rhythm, with ARV slopes being 8.1 ± 7.7, 8.8 ± 13.4, and 6.8 ± 6.5 milliseconds per beat per minute (ms/bpm) and ALV slopes being 8.2 ± 7.7, 9.1 ± 12.8, and 7.0 ± 6.5 ms/bpm for supine, standing and sitting positions, respectively. As the paced heart rate increased, ARV and ALV intervals increased more gradually with similar trends. Interventricular conduction times changed less than 0.2 ms/bpm with atrial pacing. During exercise, the direction of change of intrinsic ARV intervals, as heart rate increased, was variable between patients with relatively small overall group changes (0.1 ± 1.4 and 0.2 ± 1.2 ms/bpm for ARV and ALV, respectively). CONCLUSION: Posture and exercise have a smaller effect on AV timing compared with atrial pacing. However, individualized optimization and dynamic rate related changes may be needed to maintain optimal fusion with left ventricular (LV) stimulation.

Tai Chi exercise and functional electrical stimulation of lower limb muscles for rehabilitation in older adults with chronic systolic heart failure: a non-randomized clinical trial.

Exercise-based training decreases hospitalizations in heart failure patients but such patients have exercise intolerance. The objectives of the study were to evaluate the effect of 12 weeks of Tai Chi exercise and lower limb muscles' functional electrical stimulation in older chronic heart failure adults. A total of 1,084 older adults with chronic systolic heart failure were included in a non-randomized clinical trial (n=271 per group). The control group did not receive any kind of intervention, one group received functional electrical stimulation of lower limb muscles (FES group), another group practiced Tai Chi exercise (TCE group), and another received functional electrical stimulation of lower limb muscles and practiced Tai Chi exercise (FES & TCE group). Quality of life and cardiorespiratory functions of all patients were evaluated. Compared to the control group, only FES group had increased Kansas City Cardiomyopathy Questionnaire (KCCQ) score (P<0.0001, q=9.06), only the TCE group had decreased heart rate (P<0.0001, q=5.72), and decreased peak oxygen consumption was reported in the TCE group (P<0.0001, q=9.15) and FES & TCE group (P<0.0001, q=10.69). FES of lower limb muscles and Tai Chi exercise can recover the quality of life and cardiorespiratory functions of older chronic heart failure adults (trial registration: Research Registry 4474, January 1, 2015).

Anti-HMGCR myopathy presenting with acute systolic heart failure.

Necrotising autoimmune myopathy (NAM) is an immune-mediated myopathy that may be associated with statin use, malignancy or an autoimmune connective tissue disease, but it can also be idiopathic. Anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) myopathy is an extremely rare side effect of statin use, occurring in approximately 2-3 out of every 100 000 patients who use statins. Patients typically present with subacute proximal muscle weakness and creatine kinase levels >10 times the upper limit of normal. The diagnosis is suggested by muscle biopsy showing necrotic fibres with minimal inflammation along with positive anti-HMGCR antibodies. Treatment nearly always requires multiple immunosuppressive agents, the earlier use of which is associated with improved outcomes. Reports of statin-induced NAM leading to heart failure are limited. We present the case of a 69-year-old woman with statin-induced NAM who presented with acute systolic heart failure. Early initiation of high-dose corticosteroids and IVIG resulted in significant improvement in her symptoms.

Spironolactone to increase natriuresis in congestive heart failure with cardiorenal syndrome.

BACKGROUND: Signs and symptoms of volume overload are the most frequent reason for hospital admission in acute heart failure (AHF). Diuretics are mainstay treatment, but their optimal type and dose regimen remain unclear, especially in patients with cardiorenal syndrome. METHODS: This prospective study aimed to include 80 AHF patients with volume overload and cardiorenal syndrome. Through a 2 × 2 factorial design, patients were randomised towards (1) combinational treatment with acetazolamide and low-dose loop diuretics versus high-dose loop diuretics; and (2) open-label oral spironolactone 25 mg OD given upfront versus at discharge. Here reported are the results of the spironolactone treatment arm after complete follow-up of 34/80 patients (since the study was stopped because of slow recruitment). The primary study end-point was incident hypokalaemia (<3.5 mmol/L) or hyperkalaemia (>5.5 mmol/L). RESULTS: Serum potassium derangements were numerically less frequent in the upfront versus discharge spironolactone group, yet this result was underpowered due to incomplete study recruitment (hyperkalaemia: 6% vs. 11%; hypokalaemia: 13% vs. 28%, respectively; p-value = .270). Natriuresis after 24 h was higher in the upfront vs. discharge spironolactone group (314 ± 142 vs. 200 ± 91 mmol/L, respectively; p-value = .010). Relative change in plasma NT-proBNP level after 72 h was similar among both groups (-16 ± 29% vs. -5 ± 45%, respectively; p value = .393), with no difference in all-cause mortality (p-value = .682) or the combination of all-cause mortality and heart failure readmission (p-value = .799). DISCUSSION: Spironolactone use upfront in AHF patients at high risk for cardiorenal syndrome is safe and increases natriuresis.

Tai Chi exercise and functional electrical stimulation of lower limb muscles for rehabilitation in older adults with chronic systolic heart failure: a non-randomized clinical trial

Exercise-based training decreases hospitalizations in heart failure patients but such patients have exercise intolerance. The objectives of the study were to evaluate the effect of 12 weeks of Tai Chi exercise and lower limb muscles' functional electrical stimulation in older chronic heart failure adults. A total of 1,084 older adults with chronic systolic heart failure were included in a non-randomized clinical trial (n=271 per group). The control group did not receive any kind of intervention, one group received functional electrical stimulation of lower limb muscles (FES group), another group practiced Tai Chi exercise (TCE group), and another received functional electrical stimulation of lower limb muscles and practiced Tai Chi exercise (FES & TCE group). Quality of life and cardiorespiratory functions of all patients were evaluated. Compared to the control group, only FES group had increased Kansas City Cardiomyopathy Questionnaire (KCCQ) score (P<0.0001, q=9.06), only the TCE group had decreased heart rate (P<0.0001, q=5.72), and decreased peak oxygen consumption was reported in the TCE group (P<0.0001, q=9.15) and FES & TCE group (P<0.0001, q=10.69). FES of lower limb muscles and Tai Chi exercise can recover the quality of life and cardiorespiratory functions of older chronic heart failure adults (trial registration: Research Registry 4474, January 1, 2015).

Absolute iron deficiency without anaemia in patients with chronic systolic heart failure is associated with poorer functional capacity.

BACKGROUND: Functional status is one of the main concerns in the management of heart failure (HF). Recently, the FAIR-HF and CONFIRM-HF trials showed that correcting anaemia using intravenous iron supplementation improved functional variables in patients with absolute or relative iron deficiency. Relative iron deficiency is supposed to be a marker of HF severity, as ferritin concentration increases with advanced stages of HF, but little is known about the impact of absolute iron deficiency (AID). AIMS: To study the impact of AID on functional variables and survival in patients with chronic systolic HF. METHODS: One hundred and thirty-eight non-anaemic patients with chronic systolic HF were included retrospectively. Patients were divided into two groups according to iron status: the AID group, defined by a ferritin concentration<100µg/L and the non-AID group, defined by a ferritin concentration≥100µg/L. Functional, morphological and biological variables were collected, and survival was assessed. RESULTS: Patients in the AID group had a poorer 6-minute walking test (342 vs. 387m; P=0.03) and poorer peak exercise oxygen consumption (13.8 vs. 16.0mL/min/kg; P=0.01). By multivariable analysis, ferritin<100µg/L was associated with impaired capacity of effort, assessed by peak exercise oxygen consumption. By multivariable analysis, there was no difference in total mortality between groups, with a mean follow-up of 5.1±1.1 years. CONCLUSIONS: The poorer functional evaluations in iron-deficient patients previously reported are not caused by the merging of two different populations (i.e. patients with absolute or relative iron deficiency). Our study has confirmed that non-anaemic HF patients with AID have poorer peak oxygen consumption. However, AID has no impact on the survival of these patients.

Furosemide Prescription During the Dry State Is a Predictor of Long-Term Survival of Stable, Optimally Medicated Patients With Systolic Heart Failure.

BACKGROUND: Furosemide is associated with poor prognosis in patients with heart failure and reduced ejection fraction (HFrEF). AIM: To evaluate the association between daily furosemide dose prescribed during the dry state and long-term survival in stable, optimally medicated outpatients with HFrEF. POPULATION AND METHODS: Two hundred sixty-six consecutive outpatients with left ventricular ejection fraction <40%, clinically stable in the dry state and on optimal heart failure therapy, were followed up for 3 years in a heart failure unit. The end point was all-cause death. There were no changes in New York Heart Association class and therapeutics, including diuretics, and no decompensation or hospitalization during 6 months. Furosemide doses were categorized as low or none (0-40 mg/d), intermediate (41-80 mg/d), and high (>80 mg). Cox regression was adjusted for significant confounders. RESULTS: The 3-year mortality rate was 33.8%. Mean dose of furosemide was 57.3 ± 21.4 mg/d. A total of 47.6% of patients received the low dose, 42.1% the intermediate dose, and 2.3% the high dose. Receiver operating characteristics for death associated with furosemide dose showed an area under the curve of 0.74 (95% confidence interval [CI]: 0.68-0.79; P < .001), and the best cutoff was >40 mg/d. An increasing daily dose of furosemide was associated with worse prognosis. Those receiving the intermediate dose (hazard ratio [HR] = 4.1; 95% CI: 2.57-6.64; P < .001) or high dose (HR = 19.8; 95% CI: 7.9-49.6; P < .001) had a higher risk of mortality compared to those receiving a low dose. Patients receiving >40 mg/d, in a propensity score-matched cohort, had a greater risk of mortality than those receiving a low dose (HR = 4.02; 95% CI: 1.8-8.8; P = .001) and those not receiving furosemide (HR = 3.9; 95% CI: 0.07-14.2; P = .039). CONCLUSION: Furosemide administration during the dry state in stable, optimally medicated outpatients with HFrEF is unfavorably associated with long-term survival. The threshold dose was 40 mg/d.

Failing Left Ventricles Have an Enhanced Post-Stimulation Potentiation Despite Their Impaired Force Frequency Relationship.

The left ventricular contractile force (LV dP/dtmax) of patients with left ventricular systolic dysfunction does not increase effectively with an increase in heart rate. In other words, their force-frequency relationship (FFR) is impaired. However, it is unknown whether a longer coupling interval subsequent to tachycardia causes a stronger contraction (poststimulation potentiation, PSP) in a rate-dependent manner.In 16 patients with idiopathic dilated cardiomyopathy (DCM) (48 ± 2 years old, LVEF 30 ± 10%) and 6 control patients (58 ± 4 years old, LVEF 70 ± 7%), FFR was assessed by right atrial pacing using a micro-manometer-tipped catheter. At each pacing rate, the increase of LV dP/dtmax over basal LV dP/dt (ΔFFR) and the increase of LV dP/dtmax of the first beat after pacing cessation over LV dP/dtmax during pacing (ΔPSP) were evaluated.Patients with DCM had smaller LV dP/dtmax at baseline (872 ± 251 versus 1370 ± 123 mmHg/second, P = 0.0002) and developed smaller ΔFFR (eg, at 120/minute, 77 ± 143 versus 331 ± 131 mmHg/second, P = 0.0011). In contrast, they showed a rate-dependent increase of LV dP/dtmax of PSP and had greater ΔPSP (eg, at 120/minute, 294 ± 173 versus -152 ± 131 mmHg/second, P < 0.0001).Failing left ventricles develop little contractile force during tachycardia despite their rate-dependent enhancement in post-stimulation potentiation, suggesting that refractoriness of contractile force underlies impaired FFR.

Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID(2) ): an evidence-based mnemonic for the treatment of systolic heart failure.

Heart failure causes significant morbidity and mortality, with recognised underutilisation rates of guideline-based therapies. Our aim was to review current evidence for heart failure treatments and derive a mnemonic summarising best practice, which might assist physicians in patient care. Treatments were identified for review from multinational society guidelines and recent randomised trials, with a primary aim of examining their effects in systolic heart failure patients on mortality, hospitalisation rates and symptoms. Secondary aims were to consider other clinical benefits. MEDLINE and EMBASE were searched using a structured keyword strategy and the retrieved articles were evaluated methodically to produce an optimised reference list for each treatment. We devised the mnemonic BANDAID (2) , standing for beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine (or potentially neprilysin inhibitor), diuretics, aldosterone antagonist, ivabradine, devices (automatic implantable cardioverter defibrillator, cardiac resynchronisation therapy or both) and digoxin as a representation of treatments with strong evidence for their use in systolic heart failure. Treatment with omega-3 fatty acids, statins or anti-thrombotic therapies has limited benefits in a general heart failure population. Adoption of this mnemonic for current evidence-based treatments for heart failure may help improve prescribing rates and patient outcomes in this debilitating, high mortality condition.

Determining the Role of Thiamine Deficiency in Systolic Heart Failure: A Meta-Analysis and Systematic Review.

BACKGROUND: Approximately 5.7 million Americans carry the diagnosis of systolic heart failure (HF), a major health care burden. HF is a known manifestation of thiamine deficiency (TD). HF patients are at unique risk for developing TD, which may contribute to further altered cardiac function and symptoms. METHODS AND RESULTS: We performed a systematic review of the literature and a meta-analysis to evaluate the prevalence of TD in HF patients, risk factors for and mechanisms of development of TD in HF population, and outcomes of thiamine supplementation in HF patients. We found 54 studies that met our selection criteria, 9 of which were suitable for meta-analysis. TD is more common in HF patients than control subjects (odds ratio 2.53, 95% confidence interval 1.65-3.87). Diuretic use, changes in dietary habits, and altered thiamine absorption and metabolism were identified as possible mechanisms of TD in HF patients. Small observational studies and randomized control trials suggest that thiamine supplementation in HF population may improve ejection fraction and reduce symptoms. CONCLUSIONS: Thiamine deficiency is more prevalent in the HF population, and its supplementation may be beneficial. The therapeutic role of thiamine in HF warrants further study.

Repletion of Iron Stores With the Use of Oral Iron Supplementation in Patients With Systolic Heart Failure.

BACKGROUND: Iron deficiency is associated with reduced functional capacity and increased mortality in patients with heart failure with reduced ejection fraction (HFrEF). Correction of iron deficiency in HFrEF patients with the use of intravenous iron improves symptoms, quality of life, and exercise performance. Whether oral iron improves iron stores in HFrEF patients is unknown. We conducted a retrospective study to assess the efficacy of oral iron supplementation in iron-deficient HFrEF patients. METHODS AND RESULTS: Iron-deficient HFrEF patients with a record of oral iron supplementation and iron studies before and ∼180 days after supplementation were identified. Iron deficiency was defined as ferritin <100 ng/mL or as ferritin 100-300 ng/mL with transferrin saturation (Tsat) <20%. Spearman correlation was performed to assess for treatment responsiveness. In 105 patients, ferritin (from median 39 ng/mL to 75 ng/mL), Tsat (from 10% to 21%), iron (from 34 µg/dL to 69 µg/dL), and hemoglobin (from 10.4 g/dL to 11.6 g/dL) values increased (P < .0001), whereas total iron-binding capacity decreased (from 343 to 313 µg/dL; P = .0007) at 164 days after initiation of oral iron supplementation. CONCLUSIONS: In this retrospective study, oral iron supplementation improved iron stores similarly to previously reported results with the use of intravenous iron repletion in HFrEF patients, suggesting that oral iron merits prospective evaluation as an intervention strategy in HFrEF.

Pharmacologic Options for the Management of Systolic Heart Failure: Examining Underlying Mechanisms.

The optimal management of systolic heart failure includes combination therapy to influence myocardial remodelling favourably by affecting neurohormonal activation and underlying maladaptive pathophysiological pathways. These medications include modulators of the renin-angiotensin-aldosterone system (eg, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists) and ß-adrenergic receptor blockers. In addition, an agent with a distinct and complementary mechanism of bradycardic action, the selective pacemaker-current (If) inhibitor ivabradine, provides further reduction of heart rate. Also, a new drug that incorporates neprilysin inhibition combined with angiotensin receptor blockade shows incremental effectiveness. The primary goal of this review is to provide a mechanistic explanation of the complementary role of therapeutic interventions in modulating pathways leading to progressive systolic heart failure. A secondary goal is to summarize the key findings of the pivotal clinical trials that have demonstrated the efficacy of these agents in this population.

Association of serum androgen concentrations with cardiovascular risk factors in elderly male patients with chronic systolic heart failure in China.

OBJECTIVE: To survey the serum androgen concentrations and investigate the relationship between androgen levels and cardiovascular risk factors in elderly male patients with chronic systolic heart failure (HF) in China. METHODS: 106 consecutive male patients hospitalized for chronic systolic HF aged from 60 to 87 were enrolled. About 400 healthy age-matched men were compared as a control group. Total testosterone (TT), free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were measured. Differences of androgen levels between HF patients and healthy men were determined by t-test and associations of androgen with cardiovascular risk factors were evaluated by partial correlations analyses. RESULTS: Compared with healthy men, TT, FT and DHEAS levels in patients with HF decreased, whereas SHBG level increased significantly (both p < 0.01). TT was negatively correlated with TC, TG and DBP (p < 0.05), FT was negatively correlated with TC, LDL-C and DBP (p < 0.05). SHBG correlated with BMI and smoking history positively (p < 0.05). CONCLUSIONS: Level of bio-available testosterone decreased with advancing age, especially in men with HF. Men with low levels of bio-available testosterone had worse profiles of cardiovascular risk factors. Treatment of HF is still challenging and testosterone supplementation therapy may be an effective therapeutic option.

Unfolded protein response regulates cardiac sodium current in systolic human heart failure.

BACKGROUND: Human heart failure (HF) increases alternative mRNA splicing of the type V, voltage-gated cardiac Na+ channel α-subunit (SCN5A), generating variants encoding truncated, nonfunctional channels that are trapped in the endoplasmic reticulum. In this work, we tested whether truncated Na+ channels activate the unfolded protein response (UPR), contributing to SCN5A electric remodeling in HF. METHODS AND RESULTS: UPR and SCN5A were analyzed in human ventricular systolic HF tissue samples and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Cells were exposed to angiotensin II (AngII) and hypoxia, known activators of abnormal SCN5A mRNA splicing, or were induced to overexpress SCN5A variants. UPR effectors, protein kinase R-like ER kinase (PERK), calreticulin, and CHOP, were increased in human HF tissues. Induction of SCN5A variants with AngII or hypoxia or the expression of exogenous variants induced the UPR with concomitant downregulation of Na+ current. PERK activation destabilized SCN5A and, surprisingly, Kv4.3 channel mRNAs but not transient receptor potential cation channel M7 (TRPM7) channel mRNA. PERK inhibition prevented the loss of full-length SCN5A and Kv4.3 mRNA levels resulting from expressing Na+ channel mRNA splice variants. CONCLUSIONS: UPR can be initiated by Na+ channel mRNA splice variants and is involved in the reduction of cardiac Na+ current during human HF. Because the effect is not entirely specific to the SCN5A transcript, the UPR may play an important role in downregulation of multiple cardiac genes in HF.