Sodium loading in ambulatory patients with heart failure with reduced ejection fraction: Mechanistic insights into sodium handling.

AIMS: Sodium restriction was not associated with improved outcomes in heart failure patients in recent trials. The skin might act as a sodium buffer, potentially explaining tolerance to fluctuations in sodium intake without volume overload, but this is insufficiently understood. Therefore, we studied the handling of an increased sodium load in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Twenty-one ambulatory, stable HFrEF patients and 10 healthy controls underwent a 2-week run-in phase, followed by a 4-week period of daily 1.2 g (51 mmol) sodium intake increment. Clinical, echocardiographic, 24-h urine collection, and bioelectrical impedance data were collected every 2 weeks. Blood volume, skin sodium content, and skin glycosaminoglycan content were assessed before and after sodium loading. Sodium loading did not significantly affect weight, blood pressure, congestion score, N-terminal pro-brain natriuretic peptide, echocardiographic indices of congestion, or total body water in HFrEF (all p > 0.09). There was no change in total blood volume (4748 ml vs. 4885 ml; p = 0.327). Natriuresis increased from 150 mmol/24 h to 173 mmol/24 h (p = 0.024), while plasma renin decreased from 286 to 88 µU/L (p = 0.002). There were no significant changes in skin sodium content, total glycosaminoglycan content, or sulfated glycosaminoglycan content (all p > 0.265). Healthy controls had no change in volume status, but a higher increase in natriuresis without any change in renin. CONCLUSIONS: Selected HFrEF patients can tolerate sodium loading, with increased renal sodium excretion and decreased neurohormonal activation.

Protocolized Natriuresis-Guided Decongestion Improves Diuretic Response: The Multicenter ENACT-HF Study.

BACKGROUND: The use of urinary sodium to guide diuretics in acute heart failure is recommended by experts and the most recent European Society of Cardiology guidelines. However, there are limited data to support this recommendation. The ENACT-HF study (Efficacy of a Standardized Diuretic Protocol in Acute Heart Failure) investigated the feasibility and efficacy of a standardized natriuresis-guided diuretic protocol in patients with acute heart failure and signs of volume overload. METHODS: ENACT-HF was an international, multicenter, open-label, pragmatic, 2-phase study, comparing the current standard of care of each center with a standardized diuretic protocol, including urinary sodium to guide therapy. The primary end point was natriuresis after 1 day. Secondary end points included cumulative natriuresis and diuresis after 2 days of treatment, length of stay, and in-hospital mortality. All end points were adjusted for baseline differences between both treatment arms. RESULTS: Four hundred one patients from 29 centers in 18 countries worldwide were included in the study. The natriuresis after 1 day was significantly higher in the protocol arm compared with the standard of care arm (282 versus 174 mmol; adjusted mean ratio, 1.64; P<0.001). After 2 days, the natriuresis remained higher in the protocol arm (538 versus 365 mmol; adjusted mean ratio, 1.52; P<0.001), with a significantly higher diuresis (5776 versus 4381 mL; adjusted mean ratio, 1.33; P<0.001). The protocol arm had a shorter length of stay (5.8 versus 7.0 days; adjusted mean ratio, 0.87; P=0.036). In-hospital mortality was low and did not significantly differ between the 2 arms (1.4% versus 2.0%; P=0.852). CONCLUSIONS: A standardized natriuresis-guided diuretic protocol to guide decongestion in acute heart failure was feasible, safe, and resulted in higher natriuresis and diuresis, as well as a shorter length of stay.

Exercise pulmonary hypertension by the mPAP/CO slope in primary mitral regurgitation.

AIMS: Exercise-induced pulmonary hypertension (PH), defined by a mean pulmonary arterial pressure over cardiac output (mPAP/CO) slope >3 mmHg/L/min, has important diagnostic and prognostic implications. The aim of this study is to investigate the value of the mPAP/CO slope in patients with more than moderate primary mitral regurgitation (MR) with preserved ejection fraction and no or discordant symptoms. METHODS AND RESULTS: A total of 128 consecutive patients were evaluated with exercise echocardiography and cardiopulmonary testing. Clinical outcome was defined as the composite of mitral valve intervention, new-onset atrial fibrillation, cardiovascular hospitalization, and all-cause mortality. The mean age was 63 years, 61% were male, and the mean LVEF was 66 ± 6%. The mPAP/CO slope correlated with peak VO2 (r = -0.52, P < 0.001), while the peak systolic pulmonary artery pressure (sPAP) did not (r = -0.06, P = 0.584). Forty-six per cent (n = 59) had peak exercise sPAP ≥60 mmHg, and 37% (n = 47) had mPAP/CO slope >3 mmHg/L/min. Event-free survival was 55% at 1 year and 46% at 2 years, with reduced survival in patients with mPAP/CO slope >3 mmHg/L/min (hazard ratio, 4.9; 95% confidence interval, 2.9-8.2; P < 0.001). In 53 cases (41%), mPAP/CO slope and peak sPAP were discordant: patients with slope >3 mmHg/L/mmHg and sPAP <60 mmHg (n = 21) had worse outcome vs. peak sPAP ≥60 mmHg and normal slope (n = 32, log-rank P = 0.003). The mPAP/CO slope improved predictive models for outcome, incremental to resting and exercise sPAP, and peak VO2. CONCLUSION: Exercise PH defined by the mPAP/CO slope >3 mmHg/L/min is associated with decreased exercise capacity and a higher risk of adverse events in significant primary MR and no or discordant symptoms. The slope provides a greater prognostic value than single sPAP measures and peak VO2.

Renal function and decongestion with acetazolamide in acute decompensated heart failure: the ADVOR trial.

BACKGROUND AND AIMS: In the ADVOR trial, acetazolamide improved decongestion in acute decompensated heart failure (ADHF). Whether the beneficial effects of acetazolamide are consistent across the entire range of renal function remains unclear. METHODS: This is a pre-specified analysis of the ADVOR trial that randomized 519 patients with ADHF to intravenous acetazolamide or matching placebo on top of intravenous loop diuretics. The main endpoints of decongestion, diuresis, natriuresis, and clinical outcomes are assessed according to baseline renal function. Changes in renal function are evaluated between treatment arms. RESULTS: On admission, median estimated glomerular filtration rate (eGFR) was 40 (30-52) mL/min/1.73 m². Acetazolamide consistently increased the likelihood of decongestion across the entire spectrum of eGFR (P-interaction = .977). Overall, natriuresis and diuresis were higher with acetazolamide, with a higher treatment effect for patients with low eGFR (both P-interaction < .007). Acetazolamide was associated with a higher incidence of worsening renal function (WRF; rise in creatinine ≥ 0.3 mg/dL) during the treatment period (40.5% vs. 18.9%; P < .001), but there was no difference in creatinine after 3 months (P = .565). This was not associated with a higher incidence of heart failure hospitalizations and mortality (P-interaction = .467). However, decongestion at discharge was associated with a lower incidence of adverse clinical outcomes irrespective of the onset of WRF (P-interaction = .805). CONCLUSIONS: Acetazolamide is associated with a higher rate of successful decongestion across the entire range of renal function with more pronounced effects regarding natriuresis and diuresis in patients with a lower eGFR. While WRF occurred more frequently with acetazolamide, this was not associated with adverse clinical outcomes. CLINICALTRIALS.GOV IDENTIFIER: NCT03505788.

Natriuretic Response to Acetazolamide in Patients With Acute Heart Failure and Volume Overload.

BACKGROUND: Acetazolamide facilitates decongestion in acute decompensated heart failure (ADHF). OBJECTIVES: This study sought to investigate the effect of acetazolamide on natriuresis in ADHF and its relationship with outcomes. METHODS: Patients from the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial with complete data on urine output and urine sodium concentration (UNa) were analyzed. Predictors of natriuresis and its relationship with the main trial endpoints were evaluated. RESULTS: This analysis included 462 of 519 patients (89%) from the ADVOR trial. During 2 days after randomization, UNa was 92 ± 25 mmol/L on average, and total natriuresis was 425 ± 234 mmol. Allocation to acetazolamide strongly and independently predicted natriuresis with a 16 mmol/L (19%) increase in UNa and 115 mmol (32%) greater total natriuresis. Higher systolic blood pressure, better renal function, higher serum sodium levels, and male sex also independently predicted both a higher UNa and greater total natriuresis. A stronger natriuretic response was associated with faster and more complete relief of signs of volume overload, and this effect was already significant on the first morning of assessment (P = 0.022). A significant interaction was observed between the effect of allocation to acetazolamide and UNa on decongestion (P = 0.007). Stronger natriuresis with better decongestion translated into a shorter hospital stay (P < 0.001). After multivariable adjustments, every 10 mmol/L UNa increase was independently associated with a lower risk of all-cause death or heart failure readmission (HR: 0.92; 95% CI: 0.85-0.99). CONCLUSIONS: Increased natriuresis is strongly related to successful decongestion with acetazolamide in ADHF. UNa may be an attractive measure of effective decongestion for future trials. (Acetazolamide in Decompensated Heart Failure with Volume Overload [ADVOR]; NCT03505788).

Pre-treatment bicarbonate levels and decongestion by acetazolamide: the ADVOR trial.

AIMS: Acetazolamide inhibits proximal tubular sodium and bicarbonate re-absorption and improved decongestive response in acute heart failure in the ADVOR trial. It is unknown whether bicarbonate levels alter the decongestive response to acetazolamide. METHODS AND RESULTS: This is a sub-analysis of the randomized, double-blind, placebo-controlled ADVOR trial that randomized 519 patients with acute heart failure and volume overload in a 1:1 ratio to intravenous acetazolamide (500 mg/day) or matching placebo on top of standardized intravenous loop diuretics (dose equivalent of twice oral maintenance dose). The primary endpoint was complete decongestion after 3 days of treatment (morning of day 4). Impact of baseline HCO3 levels on the treatment effect of acetazolamide was assessed. : Of the 519 enrolled patients, 516 (99.4%) had a baseline HCO3 measurement. Continuous HCO3 modelling illustrated a higher proportional treatment effect for acetazolamide if baseline HCO3 ≥ 27 mmol/l. A total of 234 (45%) had a baseline HCO3 ≥ 27 mmol/l. Randomization towards acetazolamide improved decongestive response over the entire range of baseline HCO3- levels (P = 0.004); however, patients with elevated baseline HCO3 exhibited a significant higher response to acetazolamide [primary endpoint: no vs. elevated HCO3; OR 1.37 (0.79-2.37) vs. OR 2.39 (1.35-4.22), P-interaction = 0.065), with higher proportional diuretic and natriuretic response (both P-interaction < 0.001), greater reduction in congestion score on consecutive days (treatment × time by HCO3-interaction <0.001) and length of stay (P-interaction = 0.019). The larger proportional treatment effect was mainly explained by the development of diminished decongestive response in the placebo arm (loop diuretics only), both with regard to reaching the primary endpoint of decongestion as well as reduction in congestion score. Development of elevated HCO3 further worsened decongestive response in the placebo arm (P-interaction = 0.041). A loop diuretic only strategy was associated with an increase in the HCO3 during the treatment phase which was prevented by acetazolamide (day 3: placebo 74.8% vs. acetazolamide 41.3%, P < 0.001). CONCLUSION: Acetazolamide improves decongestive response over the entire range of HCO3- levels; however, the treatment response is magnified in patients with baseline or loop diuretic-induced elevated HCO3 (marker of proximal nephron NaHCO3 retention) by specifically counteracting this component of diuretic resistance.

Sodium and potassium changes during decongestion with acetazolamide - A pre-specified analysis from the ADVOR trial.

AIMS: Acetazolamide, an inhibitor of proximal tubular sodium reabsorption, leads to more effective decongestion in acute heart failure (AHF). It is unknown whether acetazolamide alters serum sodium and potassium levels on top of loop diuretics and if baseline values modify the treatment effect of acetazolamide. METHODS AND RESULTS: This is a pre-specified sub-analysis of the ADVOR trial that randomized 519 patients with AHF and volume overload in a 1:1 ratio to intravenous acetazolamide or matching placebo on top of standardized intravenous loop diuretics. Mean potassium and sodium levels at randomization were 4.2 ± 0.6 and 139 ± 4 mmol/L in the acetazolamide arm versus 4.2 ± 0.6 and 140 ± 4 mmol/L in the placebo arm. Hypokalaemia (<3.5 mmol/L) on admission was present in 44 (9%) patients and hyponatraemia (≤135 mmol/L) in 82 (16%) patients. After 3 days of treatment, 44 (17%) patients in the acetazolamide arm and 35 (14%) patients in the placebo arm developed hyponatraemia (p = 0.255). Patients randomized to acetazolamide demonstrated a slight decrease in mean potassium levels during decongestion, which was non-significant over time (p = 0.053) and had no significant impact on hypokalaemia incidence (p = 0.061). Severe hypokalaemia (<3.0 mmol/L) occurred in only 7 (1%) patients, similarly distributed between the two treatment arms (p = 0.676). Randomization towards acetazolamide improved decongestive response irrespective of baseline serum sodium and potassium levels. CONCLUSIONS: Acetazolamide on top of standardized loop diuretic therapy does not lead to clinically important hypokalaemia or hyponatraemia and improves decongestion over the entire range of baseline serum potassium and sodium levels.

Decongestion With Acetazolamide in Acute Decompensated Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction: A Prespecified Analysis From the ADVOR Trial.

BACKGROUND: Acetazolamide inhibits proximal tubular sodium reabsorption and improved decongestion in the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial. It remains unclear whether the decongestive effects of acetazolamide differ across the spectrum of left ventricular ejection fraction (LVEF). METHODS: This is a prespecified analysis of the randomized, double-blind, placebo-controlled ADVOR trial that enrolled 519 patients with acute heart failure (HF), clinical signs of volume overload (eg, edema, pleural effusion, or ascites), NTproBNP (N-terminal pro-B-type natriuretic peptide) >1000 ng/L, or BNP (B-type natriuretic peptide) >250 ng/mL to receive intravenous acetazolamide (500 mg once daily) or placebo in addition to standardized intravenous loop diuretics (twice that of the oral home maintenance dose). Randomization was stratified according to LVEF (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload within 3 days from randomization without the need for mandatory escalation of decongestive therapy because of poor urine output. RESULTS: Median LVEF was 45% (25th to 75th percentile; 30% to 55%), and 43% had an LVEF ≤40%. Patients with lower LVEF were younger and more likely to be male with a higher prevalence of ischemic heart disease, higher NTproBNP, less atrial fibrillation, and lower estimated glomerular filtration rate. No interaction on the overall beneficial treatment effect of acetazolamide to the primary end point of successful decongestion (OR, 1.77 [95% CI, 1.18-2.63]; P=0.005; all P values for interaction >0.401) was found when LVEF was assessed per randomization stratum (≤40% or >40%), or as HF with reduced ejection fraction, HF with mildly reduced ejection fraction, and HF with preserved ejection fraction, or on a continuous scale. Acetazolamide resulted in improved diuretic response measured by higher cumulative diuresis and natriuresis and shortened length of stay without treatment effect modification by baseline LVEF (all P values for interaction >0.160). CONCLUSIONS: When added to treatment with loop diuretics in patients with acute decompensated HF, acetazolamide improves the incidence of successful decongestion and diuretic response, and shortens length of stay without treatment effect modification by baseline LVEF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03505788.

Acetazolamide in Acute Decompensated Heart Failure with Volume Overload.

BACKGROUND: Whether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear. METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed. RESULTS: A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P<0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups. CONCLUSIONS: The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.).

Ambulatory haemodynamic-guided management reduces heart failure hospitalizations in a multicentre European heart failure cohort.

AIMS: To investigate the outcomes and associated costs of haemodynamic-guided heart failure (HF) management with a pulmonary artery pressure (PAP) sensor in a multicentre European cohort. METHODS AND RESULTS: Data from all consecutive patients receiving a PAP sensor in Ziekenhuis Oost-Limburg, University Hospital Zurich and Sheffield Teaching Hospitals NHS Foundation Trust before January 2021 were collected. Medication changes, total number of HF hospitalizations and HF related health care costs (composed of HF hospitalizations, outpatient cardiology visits and monitoring costs) were compared between the pre-implantation and post-implantation period at 3, 6, and 12 months. PAP evolution post-implantation were grouped according to baseline mPAP ≥25 mmHg versus <25 mmHg and changes from baseline were analyzed via an area under the curve (AUC) analysis. A total of 48 patients received a PAP sensor (29 CardioMEMS and 19 Cordella devices) with a median follow-up of 19 (13-30) months. Mean age was 71 ± 10 years, 25.0% were female, 68.8% had a left ventricular ejection fraction < 50%, median NT-proBNP was 1801 (827-4503) pg/mL, and 89.6% were in NYHA class III. The number of diuretic therapy changes were non-significantly increased after 3 months (49 vs. 82; P = 0.284) and 6 months (82 vs. 127; P = 0.093) with a significant increase noted after 12 months (118 vs. 195; P = 0.005). The mPAP AUC decreased by -1418 mmHg-days for patients with a baseline mean PAP ≥ 25 mmHg. The number of HF hospitalizations was reduced for all patients after 6 (34 vs. 17; P = 0.014) and 12 months (48 vs. 29; P = 0.032). HF related health care costs were reduced from € 6286 to € 3761 at 6 months (P = 0.012) and from € 8960 to € 6167 at 12 months (P = 0.032). CONCLUSION: Haemodynamic-guided HF management reduces HF hospitalizations and HF related health care costs in selected HF patients amongst different European health care systems.

Acetazolamide in Decompensated Heart Failure with Volume Overload trial (ADVOR): baseline characteristics.

AIMS: To describe the baseline characteristics of participants in the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial and compare these with other contemporary diuretic trials in acute heart failure (AHF). METHODS AND RESULTS: ADVOR recruited 519 patients with AHF, clinically evident volume overload, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) and maintenance loop diuretic therapy prior to admission. All participants received standardized loop diuretics and were randomized towards once daily intravenous acetazolamide (500 mg) versus placebo, stratified according to study centre and left ventricular ejection fraction (LVEF) (≤40% vs. >40%). The primary endpoint was successful decongestion assessed by a dedicated score indicating no more than trace oedema and no other signs of congestion after three consecutive days of treatment without need for escalating treatment. Mean age was 78 years, 63% were men, mean LVEF was 43%, and median NT-proBNP 6173 pg/ml. The median clinical congestion score was 4 with an EuroQol-5 dimensions health utility index of 0.6. Patients with LVEF ≤40% were more often male, had more ischaemic heart disease, higher levels of NT-proBNP and less atrial fibrillation. Compared with diuretic trials in AHF, patients enrolled in ADVOR were considerably older with higher NT-proBNP levels, reflecting the real-world clinical situation. CONCLUSION: ADVOR is the largest randomized diuretic trial in AHF, investigating acetazolamide to improve decongestion on top of standardized loop diuretics. The elderly enrolled population with poor quality of life provides a good representation of the real-world AHF population. The pragmatic design will provide novel insights in the diuretic treatment of patients with AHF.

The MADIT-ICD benefit score helps to select implantable cardioverter-defibrillator candidates in cardiac resynchronization therapy.

AIMS: The aim of this study is to evaluate whether the MADIT-ICD benefit score can predict who benefits most from the addition of implantable cardioverter-defibrillator (ICD) to cardiac resynchronization therapy (CRT) in real-world patients with heart failure with reduced ejection fraction (HFrEF) and to compare this with selection according to a multidisciplinary expert centre approach. METHODS AND RESULTS: Consecutive HFrEF patients who received a CRT for a guideline indication at a tertiary care hospital (Ziekenhuis Oost-Limburg, Genk, Belgium) between October 2008 and September 2016, were retrospectively evaluated. The MADIT-ICD benefit groups (low, intermediate, and high) were compared with the current multidisciplinary expert centre approach. Endpoints were (i) sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) and (ii) non-arrhythmic mortality. Of the 475 included patients, 165 (34.7%) were in the lowest, 220 (46.3%) in the intermediate, and 90 (19.0%) in the highest benefit group. After a median follow-up of 34 months, VT/VF occurred in 3 (1.8%) patients in the lowest, 9 (4.1%) in the intermediate, and 13 (14.4%) in the highest benefit group (P < 0.001). Vice versa, non-arrhythmic death occurred in 32 (19.4%) in the lowest, 32 (14.6%) in the intermediate, and 3 (3.3%) in the highest benefit group (P = 0.002). The predictive power for ICD benefit was comparable between expert multidisciplinary judgement and the MADIT-ICD benefit score: Uno's C-statistic 0.69 vs. 0.69 (P = 0.936) for VT/VF and 0.62 vs. 0.60 (P = 0.790) for non-arrhythmic mortality. CONCLUSION: The MADIT-ICD benefit score can identify who benefits most from CRT-D and is comparable with multidisciplinary judgement in a CRT expert centre.

The effect of intravenous ferric carboxymaltose on right ventricular function - insights from the IRON-CRT trial.

AIMS: Ferric carboxymaltose (FCM) improves left ventricular function in heart failure with reduced ejection fraction (HFrEF). Yet, the effect of FCM on right ventricular (RV) function remains insufficiently elucidated. METHODS AND RESULTS: This is a pre-defined analysis of the IRON-CRT trial in which symptomatic HFrEF patients with iron deficiency and reduced left ventricular ejection fraction (LVEF) despite optimal medical therapy and cardiac resynchronization therapy (CRT) underwent 1:1 randomization to FCM or placebo in a double-blind fashion. RV function was measured as the change from baseline to 3-month follow-up in RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE) and pulsed Doppler peak velocity at the RV lateral annulus (RV S'), systolic pulmonary artery pressure (SPAP) and its coupling to the right ventricle (TAPSE/SPAP ratio). The RV contractile reserve was measured as the change in TAPSE during incremental pacing at 70, 90 and 110 bpm. A total of 75 patients underwent randomization and received FCM (n = 37) or placebo (n = 38). At baseline 72.5% had RV dysfunction and 70% had RV dilatation. At 3-month follow-up, patients receiving FCM had a significant improvement in RV FAC (+4.1% [+1.4% - +6.9%] vs. -2.2% [-4.9% - +0.6%] in the placebo group, p = 0.002) and TAPSE (+0.98 mm [+0.28 mm - +1.62 mm] vs. -0.19 mm [-0.85 mm - +0.48 mm] in the placebo group, p = 0.020), but not RV S'. Patients receiving FCM had a numerically lower SPAP (p = 0.073) and significant improvement in TAPSE/SPAP ratio (+0.097 [+0.048 - +0.146] vs. +0.002 [-0.046 - +0.051] in the placebo group, p = 0.008). At baseline both groups had diminished RV contractile reserve during incremental pacing, which was attenuated at 3-month follow-up in the FCM group (p = 0.004). Patients manifesting more RV function improvement were more likely to exhibit higher degrees of LVEF improvement (p < 0.05 for all). CONCLUSIONS: Treatment with FCM in HFrEF patients results in an improvement in RV function and structure and improves the RV contractile reserve.

Cardiac device troubleshooting in the intensive care unit: an educational review.

Numerous patients with a cardiac implantable electronic device are admitted to the cardiac intensive care unit (ICU). When taking care of these patients, it is essential to have basic knowledge of potential device problems and how they could be tackled. This review summarizes common issues with pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization devices and provides a framework for troubleshooting in the ICU. In addition, specific aspects of intensive care that might interfere with cardiac devices are discussed.

The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy-the IRON-CRT trial.

AIMS: Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF) and negatively affects cardiac function and structure. The study the effect of ferric carboxymaltose (FCM) on cardiac reverse remodelling and contractile status in HFrEF. METHODS AND RESULTS: Symptomatic HFrEF patients with iron deficiency and a persistently reduced left ventricular ejection fraction (LVEF <45%) at least 6 months after cardiac resynchronization therapy (CRT) implant were prospectively randomized to FCM or standard of care (SOC) in a double-blind manner. The primary endpoint was the change in LVEF from baseline to 3-month follow-up assessed by three-dimensional echocardiography. Secondary endpoints included the change in left ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) from baseline to 3-month follow-up. Cardiac performance was evaluated by the force-frequency relationship as assessed by the slope change of the cardiac contractility index (CCI = systolic blood pressure/LVESV index) at 70, 90, and 110 beats of biventricular pacing. A total of 75 patients were randomized to FCM (n = 37) or SOC (n = 38). At baseline, both treatment groups were well matched including baseline LVEF (34 ± 7 vs. 33 ± 8, P = 0.411). After 3 months, the change in LVEF was significantly higher in the FMC group [+4.22%, 95% confidence interval (CI) +3.05%; +5.38%] than in the SOC group (-0.23%, 95% CI -1.44%; +0.97%; P < 0.001). Similarly, LVESV (-9.72 mL, 95% CI -13.5 mL; -5.93 mL vs. -1.83 mL, 95% CI -5.7 mL; 2.1 mL; P = 0.001), but not LVEDV (P = 0.748), improved in the FCM vs. the SOC group. At baseline, both treatment groups demonstrated a negative force-frequency relationship, as defined by a decrease in CCI at higher heart rates (negative slope). FCM resulted in an improvement in the CCI slope during incremental biventricular pacing, with a positive force-frequency relationship at 3 months. Functional status and exercise capacity, as measured by the Kansas City Cardiomyopathy Questionnaire and peak oxygen consumption, were improved by FCM. CONCLUSIONS: Treatment with FCM in HFrEF patients with iron deficiency and persistently reduced LVEF after CRT results in an improvement of cardiac function measured by LVEF, LVESV, and cardiac force-frequency relationship.

Left ventricular function recovery after ST-elevation myocardial infarction: correlates and outcomes.

BACKGROUND: Contemporary data on left ventricular function (LVF) recovery in patients with left ventricular dysfunction after ST-elevation myocardial infarction (STEMI) are scarce and to date, no comparison has been made with patients with a baseline normal LVF. This study examined predictors of LVF recovery and its relation to outcomes in STEMI. METHODS: Patients presenting with STEMI between January 2010 and December 2016 were categorized in three groups after 3 months according to left ventricular ejection fraction (EF): (i) baseline normal LVF (EF ≥ 50% at baseline); (ii) recovered LVF (EF < 50% at baseline and ≥ 50% after 3 months); and (iii) reduced LVF (EF < 50% at baseline and after 3 months). Heart failure hospitalization, all-cause mortality and cardiovascular mortality were compared between the three groups. RESULTS: Of 577 patients, 341 (59%) patients had a baseline normal LVF, 112 (19%) had a recovered LVF and 124 (22%) had a reduced LVF. Independent correlates of LVF recovery were higher baseline EF, lower peak troponin and cardiac arrest. After median 5.8 years, there was no difference in outcomes between patients with LVF recovery and baseline normal LVF. In contrast, even after multivariate adjustment, patients with persistently reduced LVF had a higher risk for heart failure hospitalization (HR 5.00; 95% CI 2.17-11.46) and all-cause mortality (HR 1.87; 95% CI 1.11-3.16). CONCLUSION: In contemporary treated STEMI patients, prognosis is significantly worse in those with a persistently reduced LVF after 3 months, compared with patients with a baseline normal LVF and those with LVF recovery.

Recent advances in the diagnosis and management of amyloid cardiomyopathy.

Amyloidosis is a disorder characterized by misfolded precursor proteins that form depositions of fibrillar aggregates with an abnormal cross-beta-sheet conformation, known as amyloid, in the extracellular space of several tissues. Although there are more than 30 known amyloidogenic proteins, both hereditary and non-hereditary, cardiac amyloidosis (CA) typically arises from either misfolded transthyretin (ATTR amyloidosis) or immunoglobulin light-chain aggregation (AL amyloidosis). Its prevalence is more common than previously thought, especially among patients with heart failure and preserved ejection fraction (HFpEF) and aortic stenosis. If there is a clinical suspicion of CA, focused echocardiography, laboratory screening for the presence of a monoclonal protein (serum and urinary electrophoresis with immunofixation and serum free light-chain ratio), and cardiac scintigraphy with 99mtechnetium-labeled bone-tracers are sensitive and specific initial diagnostic tests. In some cases, more advanced/invasive techniques are necessary and, in the last several years, treatment options for both AL CA and ATTR CA have rapidly expanded. It is important to note that the aims of therapy are different. Systemic AL amyloidosis requires treatment targeted against the abnormal plasma cell clone, whereas therapy for ATTR CA must be targeted to the production and stabilization of the TTR molecule. It is likely that a multistep treatment approach will be optimal for both AL CA and ATTR CA. Additionally, treatment of CA includes the management of restrictive cardiomyopathy with preserved or reduced ejection fraction in addition to treating the amyloid deposition. Future studies are necessary to define optimal management strategies for AL CA and ATTR CA and confirm cardiac response to therapy.

Diuretic response and effects of diuretic omission in ambulatory heart failure patients on chronic low-dose loop diuretic therapy.

AIMS: To study loop diuretic response and effect of loop diuretic omission in ambulatory heart failure (HF) patients on chronic low-dose loop diuretics. METHODS AND RESULTS: Urine collections were performed on two consecutive days in 40 ambulatory HF patients with 40-80 mg furosemide (day 1 with loop diuretic; day 2 without loop diuretic). Three phases were collected each day: (i) first 6 h; (ii) rest of the day; and (iii) night. On the day of loop diuretic intake, the total natriuresis was 125.9 (86.9-155.0) mmol/24 h and urine output was 1650 (1380-2025) mL/24 h. There was a clear loop diuretic response with a natriuresis of 9.4 (6.7-15.9) mmol/h and a urine output of 117 (83-167) mL/h during the first 6 h, followed by a significant drop in natriuresis and urine output during the rest of the day [2.6 (1.8-4.8) mmol/h and 55 (33-71) mL/h] and night [2.2 (1.6-3.5) mmol/h and 44 (34-73) mL/h]. On day 2, after loop diuretic omission, the natriuresis and urine output remained similarly low the entire day, resulting in a 50% reduction in natriuresis [55.1 (33.5-77.7) mmol/24 h; P < 0.001] and a 31% reduction in urine output [1035 (875-1425) mL/24 h; P < 0.001] compared with the day of loop diuretic intake. CONCLUSION: Patients with HF on chronic loop diuretic treatment still have a clear diuretic response phase, while loop diuretic omission leads to a significant drop in natriuresis and urine output, arguing against routine cessation of low-dose loop diuretics.