Potential proarrhythmic side effect of high dose and prolonged infusion of sodium nitroprusside through calcium ion reduction: a case report.

Background: Sodium nitroprusside (SNP) is an excellent drug in acute decompensated heart failure (HF) patients with high vascular peripheral resistance. Its prolonged administration may cause thiocyanate accumulation and toxicity. A proarrhythmic side effect has never been reported. Case summary: Herein, we report a case of an adult male affected by advanced HF due to a valvular cardiomyopathy admitted to our intensive cardiology unit with severe decompensation and waiting for a heart transplant. He was treated for several weeks with high-dose SNP, due to severe pulmonary hypertension and an extremely labile haemodynamic profile. He progressively developed high thiocyanate levels and, concomitantly, free calcium ion depletion, despite normal total calcium levels, with iterative ventricular arrhythmias. Calcium ion depletion was not responsive to calcium supplementation. We suspected a causative role of thiocyanate since the negatively charged sulfur atom of the thiocyanate molecules could bind the positively charged free calcium ions, leading to a free calcium ion depletion. Thus, we cautiously reduced SNP dosage, according to the patient's haemodynamic profile, with concomitant progressive free calcium ion normalization, thus reducing the arrhythmic burden of the patient, being able to finally perform heart transplantation. Conclusion: We describe for the first time a proarrhythmic side effect of prolonged SNP administration, namely, calcium ion depletion, likely related to thiocyanate toxicity. Despite aggressive calcium supplementation, the only way to reduce the arrhythmic burden was SNP down titration.

Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial.

AIMS: To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13-43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: -0.10 mmol/l (95% confidence interval, CI -0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. CONCLUSION: Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights From a Combined PARAGON-HF and PARADIGM-HF Analysis.

BACKGROUND: The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction. METHODS: We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality. RESULTS: Higher scores of the cardiac domain were observed in PARADIGM-HF (10 [7-13] versus 5 [3-6], P<0.001) and higher scores of the demographic domain in PARAGON-HF (10 [8-13] versus 5 [2-9], P<0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain (P<0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes (P<0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction P<0.05 for both outcomes). CONCLUSIONS: Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.

Autologous blood reinfusion during iatrogenic acute hemorrhagic cardiac tamponade: Safety and feasibility in a cohort of 30 patients.

BACKGROUND: Iatrogenic hemorrhagic pericardial tamponade (IHPT) represents a life-threating condition requiring emergency pericardiocentesis. In this clinical context, reinfusion of pericardial blood can stabilize the patient and sustain hemodynamic conditions. AIMS AND METHODS: We reviewed all cases of IHPT occurred at our hospital over a 10 years span. In all patient autologous blood reinfusion through a femoral vein was performed. RESULTS: In our clinical experience of 30 consecutive patients with hemorrhagic cardiac tamponade, this technique was successful to limit blood transfusions, to prevent further clinical worsening and bridge patients with intractable bleeding, to cardiac surgery. No major adverse reactions were directly related to blood autotransfusion. CONCLUSION: In the complex clinical scenario of acute tamponade occurring during catheter-based cardiac procedures, autotransfusion of pericardial blood through a femoral vein is safe and effective. It can be a useful trick up the sleeve of the interventional cardiologist.

Safety and Tolerability of the Chymase Inhibitor Fulacimstat in Patients With Left Ventricular Dysfunction After Myocardial Infarction-Results of the CHIARA MIA 1 Trial.

The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose. Patients were treated for 2 weeks with either placebo (n = 12) or 4 different doses of fulacimstat (5 mg twice daily, n = 9; 10 mg twice daily, n = 9; 25 mg twice daily, n = 10; 50 mg once daily, n = 9). Fulacimstat was safe and well tolerated at all examined doses. There were no clinically relevant effects on vital signs or potassium levels compared with placebo treatment. Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI.

Baroreflex activation therapy for the treatment of heart failure with reduced ejection fraction in patients with and without coronary artery disease.

BACKGROUND: In a randomized trial, baroreflex activation therapy (BAT) improved exercise capacity, quality of life and NT-proBNP in patients with heart failure with reduced ejection fraction (HFrEF). In view of different mechanisms underlying HFrEF, we performed a post-hoc subgroup analysis of efficacy and safety of BAT in patients with and without coronary artery disease (CAD). METHODS AND RESULTS: Patients with left ventricular ejection fraction <35% and NYHA Class III were randomized 1:1 to guideline-directed medical and device therapy alone or plus BAT. Patients with a history of CAD, prior myocardial infarction or coronary artery bypass graft were assigned to the CAD group with all others assigned to the no-CAD group. Of 71 BAT treated patients, 52 had CAD and 19 had no CAD. In the control group, 49 of 69 patients had CAD and 20 had no CAD. The system- or procedure-related major adverse neurological or cardiovascular event rate was 3.8% in the CAD group vs. 0% in the no-CAD group (p = 1.0). In the whole cohort, NYHA Class, Minnesota Living with Heart Failure score, 6-minute hall walk distance and NTproBNP were improved in BAT treated patients compared with controls. Statistical analyses revealed no interaction between the presence of CAD and effect of BAT (all p > 0.05). CONCLUSION: No major differences were found in BAT efficacy or safety between patients with and without CAD, indicating that BAT improves exercise capacity, quality of life and NTproBNP in patients with ischemic and non-ischemic cardiomyopathy. CLINICALTRIALS. GOV IDENTIFIER: NCT01471860 and NCT01720160.

Temporal Relation Between Myocardial Fibrosis and Heart Failure With Preserved Ejection Fraction: Association With Baseline Disease Severity and Subsequent Outcome.

Importance: Among myriad changes occurring during the evolution of heart failure with preserved ejection fraction (HFpEF), cardiomyocyte-extracellular matrix interactions from excess collagen may affect microvascular, mechanical, and electrical function. Objective: To investigate whether myocardial fibrosis (MF) is similarly prevalent both in those with HFpEF and those at risk for HFpEF, similarly associating with disease severity and outcomes. Design, Setting, and Participants: Observational cohort study from June 1, 2010, to September 17, 2015, with follow-up until December 14, 2015, at a cardiovascular magnetic resonance (CMR) center serving an integrated health system. Consecutive patients with preserved systolic function referred for CMR were eligible. Cardiovascular magnetic resonance was used to exclude patients with cardiac amyloidosis (n = 19). Exposures: Myocardial fibrosis quantified by extracellular volume (ECV) CMR measures. Main Outcome and Measures: Baseline BNP; subsequent hospitalization for heart failure or death. Results: Of 1174 patients identified (537 [46%] female; median [interquartile range {IQR}] age, 56 [44-66] years), 250 were "at risk" for HFpEF given elevated brain-type natriuretic peptide (BNP) level; 160 had HFpEF by documented clinical diagnosis, and 745 did not have HFpEF. Patients either at risk for HFpEF or with HFpEF demonstrated similarly higher prevalence/extent of MF and worse prognosis compared with patients with no HFpEF. Among those at risk for HFpEF or with HFpEF, the actual diagnosis of HFpEF was not associated with significant differences in MF (median ECV, 28.2%; IQR, 26.2%-30.7% vs 28.3%; IQR, 25.5%-31.4%; P = .60) or prognosis (log-rank 0.8; P = .38). Over a median of 1.9 years, 61 patients at risk for HFpEF or with HFpEF experienced adverse events (19 hospitalization for heart failure, 48 deaths, 6 with both). In those with HFpEF, ECV was associated with baseline log BNP (disease severity surrogate) in multivariable linear regression models, and was associated with outcomes in multivariable Cox regression models (eg, hazard ratio 1.75 per 5% increase in ECV, 95% CI, 1.25-2.45; P = .001 in stepwise model) whether grouped with patients at risk for HFpEF or not. Conclusions and Relevance: Among myriad changes occurring during the apparent evolution of HFpEF where elevated BNP is prevalent, MF was similarly prevalent in those with or at risk for HFpEF. Conceivably, MF might precede clinical HFpEF diagnosis. Regardless, MF was associated with disease severity (ie, BNP) and outcomes. Whether cells and secretomes mediating MF represent therapeutic targets in HFpEF warrants further evaluation.

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

AIMS: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). METHODS AND RESULTS: A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure <95 mmHg, serum potassium >5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. CONCLUSIONS: Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.

Surgical Experience and Long-term Results of Baroreflex Activation Therapy for Heart Failure With Reduced Ejection Fraction.

The purpose of this publication is to describe the intraoperative experience along with long-term safety and efficacy of the second-generation baroreflex activation therapy (BAT) system in patients with heart failure (HF) and reduced ejection fraction HF (HFrEF). In a randomized trial of New York Heart Association Class III HFrEF, 140 patients were assigned 1:1 to receive BAT plus medical therapy or medical therapy alone. Procedural information along with safety and efficacy data were collected and analyzed over 12 months. Within the cohort of 71 patients randomized to BAT, implant procedure time decreased with experience, from 106 ± 37 minutes on the first case to 83 ± 32 minutes on the third case. The rate of freedom from system- and procedure-related complications was 86% through 12 months, with the percentage of days alive without a complication related to system, procedure, or underlying cardiovascular condition identical to the control group. The complications that did occur were generally mild and short-lived. Overall, 12 months therapeutic benefit from BAT was consistent with previously reported efficacy through 6 months: there was a significant and sustained beneficial treatment effect on New York Heart Association functional Class, quality of life, 6-minute hall walk distance, plasma N-terminal pro-brain natriuretic peptide, and systolic blood pressure. This was true for the full trial cohort and a predefined subset not receiving cardiac resynchronization therapy. There is a rapid learning curve for the specialized procedures entailed in a BAT system implant. BAT system implantation is safe with the therapeutic benefits of BAT in patients with HFrEF being substantial and maintained for at least 1 year.

Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy.

AIMS: Increased sympathetic and decreased parasympathetic activity contribute to heart failure (HF) symptoms and disease progression. Carotid baroreceptor stimulation (baroreflex activation therapy, BAT) results in centrally mediated reduction of sympathetic and increase in parasympathetic activity. Because patients treated with cardiac resynchronization therapy (CRT) may have less sympathetic/parasympathetic imbalance, we hypothesized that there would be differences in the response to BAT in patients with CRT vs. those without CRT. METHODS AND RESULTS: New York Heart Association (NYHA) Class III patients with an ejection fraction (EF) ≤35% were randomized (1 : 1) to ongoing guideline-directed medical and device therapy (GDMT, control) or ongoing GDMT plus BAT. Safety endpoint was system-/procedure-related major adverse neurological and cardiovascular events (MANCE). Efficacy endpoints were Minnesota Living with Heart Failure Quality of Life (QoL), 6-min hall walk distance (6MHWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and HF hospitalization rate. In this sample, 146 patients were randomized (70 control; 76 BAT) and were 140 activated (45 with CRT and 95 without CRT). MANCE-free rate at 6 months was 100% in CRT and 96% in no-CRT group. At 6 months, in the no-CRT group, QoL score, 6MHWD, LVEF, NT-proBNP and HF hospitalizations were significantly improved in BAT patients compared with controls. Changes in efficacy endpoints in the CRT group favoured BAT; however, the improvements were less than in the no-CRT group and were not statistically different from control. CONCLUSIONS: BAT is safe and significantly improved QoL, exercise capacity, NTpro-BNP, EF, and rate of HF hospitalizations in GDMT-treated NYHA Class III HF patients. These effects were most pronounced in patients not treated with CRT.

Baroreflex Activation Therapy for the Treatment of Heart Failure With a Reduced Ejection Fraction.

OBJECTIVES: The objective of this clinical trial was to assess the safety and efficacy of carotid BAT in advanced HF. BACKGROUND: Increased sympathetic and decreased parasympathetic activity contribute to heart failure (HF) symptoms and disease progression. Baroreflex activation therapy (BAT) results in centrally mediated reduction of sympathetic outflow and increased parasympathetic activity. METHODS: Patients with New York Heart Association (NYHA) functional class III HF and ejection fractions ≤35% on chronic stable guideline-directed medical therapy (GDMT) were enrolled at 45 centers in the United States, Canada, and Europe. They were randomly assigned to receive ongoing GDMT alone (control group) or ongoing GDMT plus BAT (treatment group) for 6 months. The primary safety end point was system- and procedure-related major adverse neurological and cardiovascular events. The primary efficacy end points were changes in NYHA functional class, quality-of-life score, and 6-minute hall walk distance. RESULTS: One hundred forty-six patients were randomized, 70 to control and 76 to treatment. The major adverse neurological and cardiovascular event-free rate was 97.2% (lower 95% confidence bound 91.4%). Patients assigned to BAT, compared with control group patients, experienced improvements in the distance walked in 6 min (59.6 ± 14 m vs. 1.5 ± 13.2 m; p = 0.004), quality-of-life score (-17.4 ± 2.8 points vs. 2.1 ± 3.1 points; p < 0.001), and NYHA functional class ranking (p = 0.002 for change in distribution). BAT significantly reduced N-terminal pro-brain natriuretic peptide (p = 0.02) and was associated with a trend toward fewer days hospitalized for HF (p = 0.08). CONCLUSIONS: BAT is safe and improves functional status, quality of life, exercise capacity, N-terminal pro-brain natriuretic peptide, and possibly the burden of heart failure hospitalizations in patients with GDMT-treated NYHA functional class III HF. (Barostim Neo System in the Treatment of Heart Failure; NCT01471860; Barostim HOPE4HF [Hope for Heart Failure] Study; NCT01720160).

[Present and future options for the surgical treatment of patients with advanced heart failure]. / Che novità possiamo attenderci dalla terapia chirurgica dello scompenso cardiaco avanzato.

Despite considerable improvement in the medical treatment of heart failure, cardiac transplantation remains the gold standard for the treatment of end-stage patients. However, organ shortage forces to look for alternative therapies. A number of innovative approaches are being investigated in terms of improved survival and quality of life in patients refractory to medical therapy. The main cause of heart failure is represented by ischemic cardiomyopathy, responsible for up to 65% of its prevalence in the population. Long-term survival of patients affected by advanced heart failure due to ischemic cardiomyopathy is still unsatisfactory, in spite of improved medical therapy. Besides heart transplantation and the implantation of ventricular assist devices, a surgical option is represented by conventional heart surgery, consisting of myocardial revascularization associated with surgical ventricular restoration, correction of mitral valve regurgitation, and cardiac resynchronization therapy. The STICH trial (Surgical Treatment for Ischemic Heart Failure), an international multicenter trial sponsored by the US National Heart Lung and Blood Institute, will provide important information regarding the effectiveness of such surgical treatment. A new therapeutic option could be represented in the next future by the clinical use of intracardiac elastic devices, currently under investigation, which can be implanted at the mitral annulus and at the level of the left ventricular equator.

[Inotrope therapy in acute heart failure: a critical review of clinical and scientific evidence for levosimendan in the context of traditional treatment]. / Terapia con inotropi nello scompenso cardiaco acuto: rivisitazione critica delle evidenze scientifiche e cliniche per levosimendan nel contesto del trattamento tradizionale.

The clinical heterogeneity of acute heart failure and the low number of controlled trials, to date, are the main causes of the lack of agreement on therapeutic objectives, uncertainty on the most appropriate management, and difficulties to obtain robust evidence for the treatment of this syndrome. The inappropriate use of inotropic agents is one the most common pitfalls shown by registries. Two to 10% of patients admitted for acute heart failure present with a low output syndrome, a clinical profile associated with high mortality, where inotropes may be a rational therapeutic choice. Crucial points for an effective use of inotropes are an accurate evaluation and selection of patients, tailoring of therapeutic schemes and strict patient monitoring. Beta-adrenergic agonists and phosphodiesterase inhibitors increase myocardial oxygen demand, favor arrhythmias and may cause peripheral vasodilation with a secondary decrease in coronary perfusion pressure. These effects may translate in myocardial ischemia, loss of cardiomyocytes and accelerated ventricular remodeling with worse prognosis. Levosimendan, a novel inotropic agent studied according to the principles of evidence-based medicine, augments myocardial contractility without changes in intracellular calcium concentrations, and with minimal impact on myocardial oxygen consumption. This paper, based on an expert consensus, aims to suggest criteria for the appropriate use of inotropic agents in acute heart failure, based on a critical appraisal of the existing evidence and clinical experience.