Carbohydrate antigen 125: a useful marker of congestion, fibrosis, and prognosis in heart failure with preserved ejection fraction.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) is a disease associated with high morbidity and mortality, for which it is difficult to identify patients with the poorest prognosis in routine clinical practice. Carbohydrate antigen 125 (CA 125) has been shown to be a potential marker of congestion and prognosis in HF. We sought to better characterize HFpEF patients with high CA 125 levels by using a multimodal approach. METHODS AND RESULTS: We prospectively enrolled 139 HFpEF patients (78 ± 8 years; 60% females) and 25 controls matched for age and sex (77 ± 5 years; 60% females). They underwent two-dimensional echocardiography, cardiac magnetic resonance with late gadolinium enhancement [including extracellular volume (ECV) measurement], and serum measurements of CA 125 level. The primary endpoint of the study was a composite of all-cause mortality or first HF hospitalization. The prognostic impact of CA 125 was determined using Cox proportional hazard models. Median CA 125 levels were significantly higher in HFpEF patients compared with controls [CA 125: 23.5 (14.5-44.7) vs. 14.6 (10.3-21.0) U/mL, P = 0.004]. CA 125 levels were positively correlated with a congestion marker [N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, Pearson's r = 0.37, P < 0.001] and markers of cardiac fibrosis estimated by both ECV (Pearson's r = 0.26, P = 0.003) and fibroblast growth factor 23 levels (Pearson's r = 0.50, P < 0.001). Over a median follow-up of 49 (22-64) months, 97 HFpEF patients reached the composite endpoint. Even after adjustment for the Meta-Analysis Global Group in Chronic risk score, a CA 125 level ≥35 U/mL was still a significant predictor of the composite endpoint [hazard ratio (HR): 1.58 (1.04-2.41), P = 0.032] and more particularly of HF hospitalization [HR: 1.81 (1.13-2.92), P = 0.014]. In contrast, NT-proBNP levels were not an independent predictor. CONCLUSIONS: CA 125 levels were significantly higher in HFpEF patients compared with controls matched for age and sex and were associated with markers of congestion and cardiac fibrosis. CA 125 levels were a strong and independent predictor of HF hospitalization in HFpEF patients. These data suggest a potential value of CA 125 as a biomarker for staging and risk prediction in HFpEF.

Cardiac structure, function, and coronary anatomy 10 years after isolated contemporary adjuvant radiotherapy in breast cancer patients with low cardiovascular baseline risk.

AIMS: The effects of isolated contemporary low-dose breast cancer (BC) radiotherapy (RT) on the heart remain poorly understood. This study aims to assess the long-term impacts of BC-RT on cardiac structure and function. METHODS AND RESULTS: Seventy-six women (62 ± 7 years) without history of prior heart disease, who had undergone RT for either first left (n = 36) or right (n = 40) BC, without additional medical oncology therapy apart from hormonal treatment 11 ± 1 years earlier, underwent transthoracic echocardiography, cardiac magnetic resonance imaging (CMR), computed tomography coronary angiography (CTCA), NT-proBNP, and a 6-min walk test (6MWT). They were compared with 54 age-matched healthy female controls. By CTCA, 68% of BC patients exhibited no or very mild coronary disease, while only 11% had moderate stenosis (50-69%) and 3% had significant stenosis (>70%). Despite slightly reduced regional echocardiographic midventricular strains, BC patients exhibited similar global left and right ventricular volumes, ejection fractions, and global strains by echocardiography and CMR as controls. Mitral E/e' ratios were slightly higher, and mitral deceleration times were slightly lower, but NT-proBNP was similar to controls. Also, 6MWT was normal. None had late gadolinium enhancement, and extracellular volume fraction was similar in BC (28 ± 3 vs. 29 ± 3, P = 0.15) and controls. No differences were observed relative to dose or side of RT. CONCLUSION: Aside from minor alterations of regional strains and diastolic parameters, women who received isolated RT for BC had low prevalence of coronary disease, normal global systolic function, NT-proBNP, and exercise capacity and showed no structural changes by CMR, refuting significant long-term cardiotoxicity in such low-risk patients.

Repurposing the ß3-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial.

Importance: Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The ß3-adrenergic receptors (ß3ARs) may represent a new target, as their activation attenuates LV remodeling. Objective: To determine whether activation of ß3ARs by repurposing a ß3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF. Design, Setting, and Participants: The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of ≥95 g/m2 for women or ≥115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022. Intervention: Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months. Main Outcomes and Measures: The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication. Results: Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial. Conclusions: In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT02599480.

Dual antiplatelet therapy is associated with high α-tubulin acetylation in circulating platelets from coronary artery disease patients.

Platelet inhibition is the main treatment strategy to prevent atherothrombotic complications after acute coronary syndrome or percutaneous coronary intervention. Despite dual antiplatelet therapy (DAPT) combining aspirin and a P2Y12 receptor inhibitor, high on-treatment platelet reactivity (HPR) persists in some patients due to poor response to treatment and is associated with ischemic risk. Tubulin acetylation has been pointed out as a hallmark of stable microtubules responsible for the discoid shape of resting platelets. However, the impact of antiplatelet treatments on this post-translational modification has never been studied. This study investigated whether tubulin acetylation differs according to antiplatelet therapy and on-treatment platelet reactivity. Platelets were isolated from arterial blood samples of 240 patients admitted for coronary angiography, and levels of α-tubulin acetylation on lysine 40 (α-tubulin K40 acetylation) were assessed by western blot. We show that platelet α-tubulin K40 acetylation was significantly increased in DAPT-treated patients. In addition, the proportion of patients with high levels of α-tubulin K40 acetylation was drastically reduced among DAPT-treated patients with HPR. Multivariate logistic regression confirmed that DAPT resulting in adequate platelet inhibition was strongly associated with elevated α-tubulin K40 acetylation. In conclusion, our study highlights the role of elevated platelet α-tubulin K40 acetylation as a marker of platelet inhibition in response to DAPT.Clinical trial registration: https://clinicaltrials.gov - NCT03034148.

What is the context? High on-treatment platelet reactivity due to dual antiplatelet therapy poor response is associated with thrombotic risk.Acetylation of α-tubulin K40 plays a crucial role in regulating platelet shape.High α-tubulin K40 acetylation is a hallmark of stable microtubules.What is new? α-tubulin K40 acetylation is increased in platelets from dual antiplatelet therapy-treated patients.High platelet α-tubulin K40 acetylation is mainly observed in clopidogrel-responsive patients.What is the impact? Elevated acetylated K40 α-tubulin could be used as a readout of adequate platelet inhibition in response to dual antiplatelet therapy.High α-tubulin K40 acetylation could contribute to maintaining the resting morphology of circulating platelets and therefore modify their capacity to be involved in thrombotic events.

Age, Sex, and Outcomes in Heart Failure With Reduced EF: Insights From the VICTORIA Trial.

BACKGROUND: Age and sex influence treatment and outcomes in patients with heart failure (HF). OBJECTIVES: The authors examined the associations of age and sex with clinical characteristics, background therapies, outcomes, and response to vericiguat in this post hoc analysis of 5,050 VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) patients with HF and reduced ejection fraction; 1,568 (31%) were ≥75 years of age, of whom 445 (24%) were women. METHODS: Clinical characteristics were compared across age (<65, 65 to <75, and ≥75 years) and sex. The treatment effect of vericiguat was estimated by age and sex on the primary composite outcome (time to first HF hospitalization or cardiovascular death) using Cox proportional hazards regression. RESULTS: Compared with younger patients, those ≥75 years of age had more class III and IV symptoms, higher N-terminal pro-B-type natriuretic peptide levels, and worse kidney function but had the lowest use of triple therapy. No sex differences in triple therapy existed by age, but achieving target doses of triple therapy was less likely in older patients. Men ≥75 years of age were more than twice as likely to receive defibrillators and 65% more likely to undergo cardiac resynchronization than women. The primary composite outcome was nominally lower in women than men across all age groups. Vericiguat dosing did not differ between sexes in each age group, and its beneficial effect on the primary endpoint was not modified by age (continuous age, Pinteraction = 0.169; categorical age, Pinteraction = 0.189); and sex (3-way interaction; P = 0.847). CONCLUSIONS: Although elderly women received less intense background HF therapy than men, their prognosis was nominally better. The benefit of vericiguat was independent of age and sex. (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).

Impact of early versus class I-triggered surgery on postoperative survival in severe aortic regurgitation: An observational study from the Aortic Valve Insufficiency and Ascending Aorta Aneurysm International Registry.

OBJECTIVES: Class I triggers for severe and chronic aortic regurgitation surgery mainly rely on symptoms or systolic dysfunction, resulting in a negative outcome despite surgical correction. Therefore, US and European guidelines now advocate for earlier surgery. We sought to determine whether earlier surgery leads to improved postoperative survival. METHODS: We evaluated the postoperative survival of patients who underwent surgery for severe aortic regurgitation in the international multicenter registry for aortic valve surgery, Aortic Valve Insufficiency and Ascending Aorta Aneurysm International Registry, over a median follow-up of 37 months. RESULTS: Among 1899 patients (aged 49 ± 15 years, 85% were male), 83% and 84% had class I indication according to the American Heart Association and European Society of Cardiology, respectively, and most were offered repair surgery (92%). Twelve patients (0.6%) died after surgery, and 68 patients died within 10 years after the procedure. Heart failure symptoms (hazard ratio, 2.60 [1.20-5.66], P = .016) and either left ventricular end-systolic diameter greater than 50 mm or left ventricular end-systolic diameter index greater than 25 mm/m2 (hazard ratio, 1.64 [1.05-2.55], P = .030) predicted survival independently over and above age, gender, and bicuspid phenotype. Therefore, patients who underwent surgery based on any class I trigger had worse adjusted survival. However, patients who underwent surgery while meeting early imaging triggers (left ventricular end-systolic diameter index 20-25 mm/m2 or left ventricular ejection fraction 50% to 55%) had no significant outcome penalty. CONCLUSIONS: In this international registry of severe aortic regurgitation, surgery when meeting class I triggers led to postoperative outcome penalty compared with earlier triggers (left ventricular end-systolic diameter index 20-25 mm/m2 or ventricular ejection fraction 50%-55%). This observation, which applies to expert centers where aortic valve repair is feasible, should encourage the global use of repair techniques and the conduction of randomized trials.

CA125, Galectin-3 and FGF-23 are interrelated in heart failure with reduced ejection fraction.

Background: Carbohydrate Antigen 125 (CA125) is the most widely used biomarker in ovarian cancer screening. In patients with heart failure (HF), increased levels of CA125 have been observed and related to disease severity. Our objective was to determine the association of CA125 levels with two biomarkers of adverse remodeling in HF patients with reduced ejection fraction (HFrEF). Methods: CA125 circulating levels were determined with an electrochemiluminscent immunoassay. Concentrations of B-type natriuretic peptide (BNP), N-terminal proBNP (Nt-proBNP), Galectin-3 and Fibroblast Growth Factor 23 (FGF23) were also measured by immunoassays. Results: CA125 levels were increased in HFrEF, were associated to disease severity according NYHA classes. Median CA125 concentration was also significantly related to cardiovascular mortality. CA125 concentrations were positively and significantly associated to Galectin-3 and FGF23. Conclusions: Concentrations of CA125 are increased in patients with HFrEF, associated to disease severity and adverse cardiovascular outcomes. CA125 levels are also correlated to Galectin-3 and FGF-23, two biomarkers related to fibrosis and cardiovascular remodeling.

Mean platelet volume: a prognostic marker in heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with high burden of comorbidities known to increase the mean platelet volume (MPV). This parameter has been associated with morbidity and mortality in HF. However, the role of platelets and the prognostic relevance of MPV in HFpEF remain largely unexplored. We aimed to evaluate the clinical usefulness of MPV as a prognostic marker in HFpEF. We prospectively enrolled 228 patients with HFpEF (79 ± 9 years; 66% females) and 38 controls of similar age and gender (78 ± 5 years; 63% females). All subjects underwent two-dimensional echocardiography and MPV measurements. Patients were followed-up for a primary end point of all-cause mortality or first HF hospitalization. The prognostic impact of MPV was determined using Cox proportional hazard models. Mean MPV was significantly higher in HFpEF patients compared with controls (MPV: 10.7 ± 1.1fL vs. 10.1 ± 1.1fL, p = .005). HFpEF patients (n = 56) with MPV >75th percentile (11.3 fL) displayed more commonly a history of ischemic cardiomyopathy. Over a median follow-up of 26 months, 136 HFpEF patients reached the composite endpoint. MPV >75th percentile was a significant predictor of the primary endpoint (HR: 1.70 [1.08; 2.67], p = .023) adjusted for NYHA class, chronic obstructive pulmonary disease, loop diuretics, renal function, and hemoglobin. We demonstrated that MPV was significantly higher in HFpEF patients compared with controls of similar age and gender. Elevated MPV was a strong and independent predictor of poor outcome in HFpEF patients and may be relevant for clinical use.

What is the context? Heart failure with preserved ejection fraction (HFpEF) is associated with several comorbidities known to increase the mean platelet volume (MPV).MPV is a measure of platelet size and a potential marker of platelet reactivity. An increased MPV results from an increased platelet turnover.MPV has been associated with morbidity and mortality from heart failure.No study has previously compared MPV between HFpEF and controls and investigated the prognostic relevance of MPV in HFpEF disease.What is new? In this study, we compared the MPV between HFpEF patients and controls of similar age and gender, prospectively enrolled between 2015 and 2021. We evaluated the prognostic role of elevated MPV in HFpEF patients.Our main results:The MPV was higher in HFpEF patients compared to controls of similar age and gender.HFpEF patients with elevated MPV displayed more commonly a history of ischemic cardiomyopathy.Elevated MPV was a strong and independent predictor of poor outcome in HFpEF patients.What is the impact? MPV may be relevant for clinical use to predict clinical outcome in HFpEF patients.Elevated MPV reflecting platelet activity supports the potential role of platelets in HFpEF's pathophysiology.

Sex-related differences in left ventricular assist device utilization and outcomes: results from the PCHF-VAD registry.

AIMS: Data on sex and left ventricular assist device (LVAD) utilization and outcomes have been conflicting and mostly confined to US studies incorporating older devices. This study aimed to investigate sex-related differences in LVAD utilization and outcomes in a contemporary European LVAD cohort. METHODS AND RESULTS: This analysis is part of the multicentre PCHF-VAD registry studying continuous-flow LVAD patients. The primary outcome was all-cause mortality. Secondary outcomes included ventricular arrhythmias, right ventricular failure, bleeding, thromboembolism, and the haemocompatibility score. Multivariable Cox regression models were used to assess associations between sex and outcomes. Overall, 457 men (81%) and 105 women (19%) were analysed. At LVAD implant, women were more often in Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 or 2 (55% vs. 41%, P = 0.009) and more often required temporary mechanical circulatory support (39% vs. 23%, P = 0.001). Mean age was comparable (52.1 vs. 53.4 years, P = 0.33), and median follow-up duration was 344 [range 147-823] days for women and 435 [range 190-816] days for men (P = 0.40). No significant sex-related differences were found in all-cause mortality (hazard ratio [HR] 0.79 for female vs. male sex, 95% confidence interval [CI] [0.50-1.27]). Female LVAD patients had a lower risk of ventricular arrhythmias (HR 0.56, 95% CI [0.33-0.95]) but more often experienced right ventricular failure. No significant sex-related differences were found in other outcomes. CONCLUSIONS: In this contemporary European cohort of LVAD patients, far fewer women than men underwent LVAD implantation despite similar clinical outcomes. This is important as the proportion of female LVAD patients (19%) was lower than the proportion of females with advanced HF as reported in previous studies, suggesting underutilization. Also, female patients were remarkably more often in INTERMACS profile 1 or 2, suggesting later referral for LVAD therapy. Additional research in female patients is warranted.

Sex Differences in Characteristics, Outcomes, and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in Patients With Heart Failure: Insights From DAPA-HF and DELIVER.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of sodium-glucose cotransporter-2 inhibitors remains unclear. Our analyses aim to assess the effect of sex on the efficacy and safety of dapagliflozin. METHODS: In a prespecified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), clinical outcomes were compared by sex (including the composite of cardiovascular death or worsening HF events, cardiovascular death, all-cause death, total events [first and recurrent HF hospitalization and cardiovascular death], and Kansas City Cardiomyopathy Questionnaire scores) across the spectrum of left ventricular ejection fraction. RESULTS: Of a total of 11 007 randomized patients, 3856 (35%) were women. Women with HF were older and had higher body mass index but were less likely to have a history of diabetes and myocardial infarction or stroke and more likely to have hypertension and atrial fibrillation compared with men. At baseline, women had higher ejection fraction but worse Kansas City Cardiomyopathy Questionnaire scores than men did. After adjustment for baseline differences, women were less likely than men to experience cardiovascular death (adjusted hazard ratio, 0.69 [95% CI, 0.60-0.79]), all-cause death (adjusted hazard ratio, 0.69 [95% CI, 0.62-0.78]), HF hospitalizations (adjusted hazard ratio, 0.82 [95% CI, 0.72-0.94]), and total events (adjusted rate ratio, 0.77 [95% CI, 0.71-0.84]). Dapagliflozin reduced the primary end point in both men and women similarly (Pinteraction=0.77) with no sex-related differences in secondary outcomes (all Pinteraction>0.35) or safety events. The benefit of dapagliflozin was observed across the entire ejection fraction spectrum and was not modified by sex (Pinteraction>0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation attributable to adverse events. CONCLUSIONS: In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.

How does age affect outcomes after left ventricular assist device implantation: results from the PCHF-VAD registry.

AIMS: Use of left ventricular assist devices (LVADs) in older patients has increased, and assessing outcomes in older LVAD recipients is important. Therefore, this study aimed to investigate associations between age and outcomes after continuous-flow LVAD (cf-LVAD) implantation. METHODS AND RESULTS: Cf-LVAD patients from the multicentre European PCHF-VAD registry were included and categorized into those <50, 50-64, and ≥65 years old. The primary endpoint was all-cause mortality. Among secondary outcomes were heart failure (HF) hospitalizations, right ventricular (RV) failure, haemocompatibility score, bleeding events, non-fatal thromboembolic events, and device-related infections. Of 562 patients, 184 (32.7%) were <50, 305 (54.3%) were aged 50-64, whereas 73 (13.0%) were ≥65 years old. Median follow-up was 1.1 years. Patients in the oldest age group were significantly more often designated as destination therapy (DT) candidates (61%). A 10 year increase in age was associated with a significantly higher risk of mortality (hazard ratio [HR] 1.34, 95% confidence interval [CI] [1.15-1.57]), intracranial bleeding (HR 1.49, 95% CI [1.10-2.02]), and non-intracranial bleeding (HR 1.30, 95% CI [1.09-1.56]), which was confirmed by a higher mean haemocompatibility score (1.37 vs. 0.77, oldest vs. youngest groups, respectively, P = 0.033). Older patients suffered from less device-related infections requiring systemic antibiotics. No age-related differences were observed in HF-related hospitalizations, ventricular arrhythmias, pump thrombosis, non-fatal thromboembolic events, or RV failure. CONCLUSIONS: In the PCHF-VAD registry, higher age was associated with increased risk of mortality, and especially with increased risk of major bleeding, which is particularly relevant for the DT population. The risks of HF hospitalizations, pump thrombosis, ventricular arrhythmia, or RV failure were comparable. Strikingly, older patients had less device-related infections.

Impact of progressive aortic regurgitation on outcomes after left ventricular assist device implantation.

Aortic regurgitation (AR) following continuous flow left ventricular assist device implantation (cf-LVAD) may adversely impact outcomes. We aimed to assess the incidence and impact of progressive AR after cf-LVAD on prognosis, biomarkers, functional capacity and echocardiographic findings. In an analysis of the PCHF-VAD database encompassing 12 European heart failure centers, patients were dichotomized according to the progression of AR following LVAD implantation. Patients with de-novo AR or AR progression (AR_1) were compared to patients without worsening AR (AR_0). Among 396 patients (mean age 53 ± 12 years, 82% male), 153 (39%) experienced progression of AR over a median of 1.4 years on LVAD support. Before LVAD implantation, AR_1 patients were less frequently diabetic, had lower body mass indices and higher baseline NT-proBNP values. Progressive AR did not adversely impact mortality (26% in both groups, HR 0.91 [95% CI 0.61-1.36]; P = 0.65). No intergroup variability was observed in NT-proBNP values and 6-minute walk test results at index hospitalization discharge and at 6-month follow-up. However, AR_1 patients were more likely to remain in NYHA class III and had worse right ventricular function at 6-month follow-up. Lack of aortic valve opening was related to de-novo or worsening AR (P < 0.001), irrespective of systolic blood pressure (P = 0.67). Patients commonly experience de-novo or worsening AR when exposed to continuous flow of contemporary LVADs. While reducing effective forward flow, worsening AR did not influence survival. However, less complete functional recovery and worse RV performance among AR_1 patients were observed. Lack of aortic valve opening was associated with progressive AR.

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.

Improved survival of left ventricular assist device carriers in Europe according to implantation eras: results from the PCHF-VAD registry.

AIMS: Temporal changes in patient selection and major technological developments have occurred in the field of left ventricular assist devices (LVADs), yet analyses depicting this trend are lacking for Europe. We describe the advances of European LVAD programmes from the PCHF-VAD registry across device implantation eras. METHODS AND RESULTS: Of 583 patients from 13 European centres in the registry, 556 patients (mean age 53 ± 12 years, 82% male) were eligible for this analysis. Patients were divided into eras (E) by date of LVAD implantation: E1 from December 2006 to December 2012 (6 years), E2 from January 2013 to January 2020 (7 years). Patients implanted more recently were older with more comorbidities, but less acutely ill. Receiving an LVAD in E2 was associated with improved 1-year survival in adjusted analysis (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.35-0.98; p = 0.043). LVAD implantation in E2 was associated with a significantly lower chance of heart transplantation (adjusted HR 0.40, 95% CI 0.23-0.67; p = 0.001), and lower risk of LVAD-related infections (adjusted HR 0.64, 95% CI 0.43-0.95; p = 0.027), both in unadjusted and adjusted analyses. The adjusted risk of haemocompatibility-related events decreased (HR 0.60, 95% CI 0.39-0.91; p = 0.016), while heart failure-related events increased in E2 (HR 1.67, 95% CI 1.02-2.75; p = 0.043). CONCLUSION: In an analysis depicting the evolving landscape of continuous-flow LVAD carriers in Europe over 13 years, a trend towards better survival was seen in recent years, despite older recipients with more comorbidities, potentially attributable to increasing expertise of LVAD centres, improved patient selection and pump technology. However, a smaller chance of undergoing heart transplantation was noted in the second era, underscoring the relevance of improved outcomes on LVAD support.

Treatment with sodium-glucose cotransporter-2 inhibitors in heart failure patients: The potential benefits of monitoring FGF-23 levels?

Inhibitors of sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown effective glucose-lowering effects associated with improved clinical outcomes in diabetic patients and heart failure patients. As SGLT2 inhibitors can increase phosphate levels, they can also modulate FGF-23 production, a hormone directly involved in regulation of bone and mineral metabolism, but also a strong predictor of adverse cardiovascular events. We therefore discuss the relevance of FGF-23 as a companion testing of SGLT2 treatment, in addition to standard clinical biology tests.

Clinical and Hemodynamic Effects of Percutaneous Edge-to-Edge Mitral Valve Repair in Atrial Versus Ventricular Functional Mitral Regurgitation.

The present study aims to assess the clinical and hemodynamic impact of percutaneous edge-to-edge mitral valve repair with MitraClip in patients with atrial functional mitral regurgitation (A-FMR) compared with ventricular functional mitral regurgitation (V-FMR). Mitral regurgitation (MR) grade, functional status (New York Heart Association class), and major adverse cardiac events (MACE; all-cause mortality or hospitalization for heart failure) were evaluated in 52 patients with A-FMR and in 307 patients with V-FMR. In 56 patients, hemodynamic assessment during exercise echocardiography was performed before and 6 months after intervention. MR reduction after MitraClip implantation was noninferior in A-FMR compared with V-FMR (MR grade ≤2 at 6 months in 94% vs 82%, respectively, p <0.001 for noninferiority) and was associated with improvement of functional status (New York Heart Association class ≤2 at 6 months in 90% vs 80%, respectively, p = 0.2). Hemodynamic assessment revealed that cardiac output at 6 months was higher in A-FMR at rest (5.1 ± 1.5 L/min vs 3.8 ± 1.5 L/min, p = 0.002) and during peak exercise (7.9 ± 2.4 L/min vs 6.1 ± 2.1 L/min, p = 0.02). In addition, the reduction in systolic pulmonary artery pressure at rest was more pronounced in A-FMR: Δ SPAP -13.1 ± 15.1 mm Hg versus -2.2 ± 13.3 mm Hg (p = 0.03). MACE rate at follow-up was significantly lower in A-FMR versus V-FMR, with an adjusted odds ratio of 0.46 (95% confidence interval 0.24 to 0.88), which was caused by a reduction in hospitalization for heart failure. In conclusion, percutaneous edge-to-edge mitral valve repair with MitraClip is at least as effective in A-FMR as in V-FMR in reducing MR. However, the hemodynamic improvement and reduction of MACE were significantly better in A-FMR.

Heart failure in COVID-19: the multicentre, multinational PCHF-COVICAV registry.

AIMS: We assessed the outcome of hospitalized coronavirus disease 2019 (COVID-19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations. METHODS AND RESULTS: International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID-19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF-COVICAV). The primary endpoint was in-hospital mortality. Of 1974 patients hospitalized with COVID-19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62-81] years, 58% male), with HF being present in 256 [20%] patients. Overall in-hospital mortality was 25% (n = 323/1282 deaths). In-hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non-HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44-2.59], P < 0.001). After adjusting, HF remained associated with in-hospital mortality (OR 1.45 [95% confidence interval: 1.01-2.06], P = 0.041). Importantly, 186 of 1282 [15%] patients had an acute HF event during hospitalization (76 [40%] with de novo HF), which was associated with higher in-hospital mortality (89 [48%] vs. 220 [23%]) than in patients without HF event (OR 3.10 [2.24-4.29], P < 0.001). CONCLUSIONS: Hospitalized COVID-19 patients with HF are at increased risk for in-hospital death. In-hospital worsening of HF or acute HF de novo are common and associated with a further increase in in-hospital mortality.

A colossal, enigmatic, and long-lasting high-sensitivity cardiac troponin T elevation.

This case describes the incidental finding of a massive and persistent elevation of troponin T in a patient with end-stage renal disease. This high troponin T value was not consistent with the patient's clinical condition and the laboratory was called in to investigate this discrepancy. After exclusion of analytical interference and discovery of a discordance between troponin T and troponin I, a clinical investigation including cardiac and whole-body magnetic resonance imaging was performed. Magnetic resonance imaging results allowed us to exclude a cardiac origin of troponin elevation but revealed a skeletal muscle pathology. This case constitutes the first description of high-sensitivity cardiac troponin T elevation due to musculoskeletal pathology without cardiac involvement in a patient with end-stage renal disease.

Diagnostic and Prognostic Accuracy of Aortic Valve Calcium Scoring in Patients With Moderate-to-Severe Aortic Stenosis.

Background: Assessing the true severity of aortic stenosis (AS) remains a challenge, particularly when echocardiography yields discordant results. Recent European and American guidelines recommend measuring aortic valve calcium (AVC) by multidetector row computed tomography (MDCT) to improve this assessment. Aim: To define, using a standardized MDCT scanning protocol, the optimal AVC load criteria for truly severe AS in patients with concordant echocardiographic findings, to establish the ability of these criteria to predict clinical outcomes, and to investigate their ability to delineate truly severe AS in patients with discordant echocardiographic AS grading. Methods and Results: Two hundred and sixty-six patients with moderate-to-severe AS and normal LVEF prospectively underwent MDCT and Doppler-echocardiography to assess AS severity. In patients with concordant AS grading, ROC analysis identified optimal cut-off values for diagnosing severe AS using different AVC load criteria. In these patients, 4-year event-free survival was better with low AVC load (60-63%) by these criteria than with high AVC load (23-26%, log rank p < 0.001). Patients with discordant AS grading had higher AVC load than those with moderate AS but lower AVC load than those with severe high-gradient AS. Between 36 and 55% of patients with severe LG-AS met AVC load criteria for severe AS. Although AVC load predicted outcome in these patients as well, its prognostic impact was less than in patients with concordant AS grading. Conclusions: Assessment of AVC load accurately identifies truly severe AS and provides powerful prognostic information. Our data further indicate that patients with discordant AS grading consist in a heterogenous group, as evidenced by their large range of AVC load. MDCT allows to differentiate between truly severe and pseudo-severe AS in this population as well, although the prognostic implications thereof are less pronounced than in patients with concordant AS grading.