Search

José Ramón González-Juanatey,1 Josep Comín-Colet,2 Domingo Pascual Figal,3 Antoni Bayes-Genis,4 Jose Maria Cepeda,5 José M García-Pinilla,6,7 Antonio García-Quintana,8 Luis Manzano,9 Jose Luis Zamorano10 1Cardiology Department, Hospital Clínico Universitario Santiago de Compostela, Centro de investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Santiago de Compostela, Spain; 2Cardiology Department, Hospital Universitario de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain; 3Cardiology Department, Hospital Virgen de la Arrixaca, University of Murcia, Murcia, Spain; 4Cardiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 5Department of Internal Medicine, Hospital Vega Baja, Orihuela, Alicante, Spain; 6Cardiology Department, Hospital Universitario Virgen de la Victoria, IBIMA, Málaga, Spain; 7Department of Medicine and Dermatology, Universidad de Málaga, Málaga, Spain; 8Cardiology Department, Hospital Universitario de Gran Canaria Doctor Negrín, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; 9Department of Internal Medicine, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Universidad de Alcalá, Madrid, Spain; 10Cardiology Department, Hospital Universitario Ramón y Cajal, Madrid, SpainCorrespondence: José Ramón González-Juanatey, Email Jose.Ramon.Gonzalez.Juanatey@sergas.esAbstract: Heart failure (HF) is a progressive condition with periods of apparent stability and repeated worsening HF events. Over time, unless optimization of HF treatment, worsening HF events become more frequent and patients enter into a cycle of recurrent events with high morbidity and mortality. In patients with HF there is an activation of deleterious neurohormonal pathways, such as the renin angiotensin aldosterone system and the sympathetic system, and an inhibition of protective pathways, including natriuretic peptides and guanylate cyclase. Therefore, HF burden can be reduced only through a holistic approach that targets all neurohormonal systems. In this context, vericiguat may play a key role, as it is the only HF drug that activates the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate system. On the other hand, it has been described relevant disparities in the management of HF population. Consequently, it is necessary to homogenize the management of these patients, through an integrated patient-care pathway that should be adapted at the local level. In this context, the development of new technologies (ie, video call, specific platforms, remote control devices, etc.) may be very helpful. In this manuscript, a multidisciplinary group of experts analyzed the current evidence and shared their own experience to provide some recommendations about the therapeutic optimization of patients with recent worsening HF, with a particular focus on vericiguat, and also about how the integrated patient-care pathway should be performed.Keywords: heart failure, worsening heart failure, patient-care pathway, vericiguat

Purpose of Review: Differences in HF biomarker levels by sex may be due to hormonal, genetic, and fat distribution differences. Knowledge of these differences is scarce, and it is not well established whether they may affect their usefulness in the management of HF., Recent Findings: The different biomarker profiles in women and men have been confirmed in recent studies: in women, markers of cardiac stretch and fibrosis (NP and galectin-3) are higher, whereas in men, higher levels of markers of cardiac injury and inflammation (cTn and sST2) are found. The use of new biomarkers, together with growing evidence that a multimarker approach can provide better risk stratification, raises the question of building models that incorporate sex-specific diagnostic criteria. More and more research are being devoted to understanding sex-related differences in HF. The aim of this review is to review the dynamics of HF biomarkers according to sex and in different situations, to learn whether these sex differences may affect their use in the diagnosis and follow-up of HF patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Heart failure (HF) guidelines recommend treating all patients with HF and reduced ejection fraction (HFrEF) with quadruple therapy, although they do not establish how to start it. This study aimed to evaluate the implementation of these recommendations, analyzing the efficacy and safety of the different therapeutic schedules., Methods and Results: Prospective, observational, and multicenter registry that evaluated the treatment initiated in patients with newly diagnosed HFrEF and its evolution at 3 months. Clinical and analytical data were collected, as well as adverse reactions and events during follow-up. Five hundred and thirty-three patients were included, selecting four hundred and ninety-seven, aged 65.5 ± 12.9 years (72% male). The most frequent etiologies were ischemic (25.5%) and idiopathic (21.1%), with a left ventricular ejection fraction of 28.7 ± 7.4%. Quadruple therapy was started in 314 (63.2%) patients, triple in 120 (24.1%), and double in 63 (12.7%). Follow-up was 112 days [IQI 91; 154], with 10 (2%) patients dying. At 3 months, 78.5% had quadruple therapy (p < 0.001). There were no differences in achieving maximum doses or reducing or withdrawing drugs (< 6%) depending on the starting scheme. Twenty-seven (5.7%) patients had any emergency room visits or admission for HF, less frequent in those with quadruple therapy (p = 0.02)., Conclusion: It is possible to achieve quadruple therapy in patients with newly diagnosed HFrEF early. This strategy makes it possible to reduce admissions and visits to the emergency room for HF without associating a more significant reduction or withdrawal of drugs or significant difficulty in achieving the target doses., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction and Objectives: Transthyretin cardiac amyloidosis (ATTR-CA) is a frequent cause of heart failure with preserved ejection fraction (HFpEF). This study sought to determine the prevalence of ATTR-CA among HFpEF patients in a multicenter nationwide study., Methods: Consecutive ambulatory or hospitalized patients aged ≥ 50 years with HFpEF and left ventricle hypertrophy ≥ 12mm were studied at 20 Spanish hospitals. Screening for cardiac amyloidosis was initiated according to the usual clinical practice of each center. Positive scintigraphs were centrally analyzed., Results: 422 patients were included, of whom 387 underwent further screening for cardiac amyloidosis. A total of 65 patients (16.8%) were diagnosed with ATTR-CA, none below 75 years. There was an increase of prevalence with age. Of them, 60% were male, with a mean age of 85.3±5.2 years, mean left ventricle ejection fraction of 60.3±7.6% and a mean maximum left ventricle wall thickness of 17.2 [12-25] mm. Most of the patients were New York Heart Association class II (48.4%) or III (46.8%). Besides being older than non-ATTR-CA patients, ATTR-CA patients had higher median NT-proBNP levels (3801 [2266-7132] vs 2391 [1141-4796] pg/mL; P=.003). There was no statistical difference in the prevalence of ATTR-CA by sex (19.7% for men and 13.8% for women, P=.085). A ∼7% (4/56) of the patients exhibited a genetic variant (ATTRv)., Conclusions: This multicenter nationwide study found a prevalence of 16.8%, confirming that ATTR-CA is a significant contributor to HFpEF in male and female patients with left ventricle hypertrophy and more than 75 years., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Aims: Combination of hypertonic saline solution (HSS) with intravenous loop diuretics has been suggested to improve diuretic response in patients hospitalized for heart failure (HF). The efficacy and safety of this approach in the ambulatory setting remain unexplored., Methods and Results: In this multicentre, double-blind, randomized study, we allocated ambulatory patients with worsening heart failure (WHF) to a 1-h infusion of intravenous furosemide ( iv Furosemide)-HSS versus iv Furosemide. The primary endpoint was the volume of diuresis at 3 h. Secondary endpoints included 3-h natriuresis and weight variation, 7-day congestion data, kidney function and electrolytes, and 30-day clinical events. Overall, 167 participants (median age: 81 years, 30.5% female) were randomized across 13 sites between December 2020 and March 2023. There were no differences in 3-h diuresis between treatments ( iv Furosemide-HSS: 1099 ml vs. iv Furosemide: 1103 ml, p = 0.963), 3-h natriuresis (∆ +2.642 mEq/L, p = 0.559), or 3-h weight (∆ +0.012 kg, p = 0.920). Patients in the iv Furosemide-HSS arm experienced significant weight decrease at 7 days (Δ -0.586 kg, p = 0.048). There were no between-treatment differences in clinical congestion score, biomarkers, inferior vena cava diameter, or the presence of lung ultrasound B-lines. At 30 days, 26.5% of the patients in the iv Furosemide-HSS group versus 33.3% in the iv Furosemide group experienced WHF (hazard ratio 0.76, p = 0.330). The incidence of death from any cause or HF hospitalization was 6% of patients in the iv Furosemide-HSS group and 8.3% of patients in the iv Furosemide group (hazard ratio 0.69, p = 0.521). The incidence of worsening kidney function or metabolic derangements was not significantly different in the two arms., Conclusions: A single infusion of iv Furosemide-HSS did not improve 3-h diuresis or congestion parameters in patients with ambulatory WHF. This therapy showed an appropriate safety profile., (© 2024 European Society of Cardiology.)

Background: Genetic disease has recently emerged as a cause of cardiac conduction disorders (CCDs), but the diagnostic yield of genetic testing and the contribution of the different genes to CCD is still unsettled., Objectives: This study sought to determine the diagnostic yield of genetic testing in young adults with CCD of unknown etiology requiring pacemaker implantation. We also studied the prevalence of rare protein-altering variants across individual genes and functional gene groups., Methods: We performed whole exome sequencing in 150 patients with CCD of unknown etiology who had permanent pacemaker implanted at age ≤60 years at 14 Spanish hospitals. Prevalence of rare protein-altering variants in patients with CCD was compared with a reference population of 115,522 individuals from gnomAD database (control subjects)., Results: Among 39 prioritized genes, patients with CCD had more rare protein-altering variants than control subjects (OR: 2.39; 95% CI: 1.75-3.33). Significant enrichment of rare variants in patients with CCD was observed in all functional gene groups except in the desmosomal genes group. Rare variants in the nuclear envelope genes group exhibited the strongest association with CCD (OR: 6.77; 95% CI: 3.71-13.87). Of note, rare variants in sarcomeric genes were also enriched (OR: 1.73; 95% CI: 1.05-3.10). An actionable genetic variant was detected in 21 patients (14%), with LMNA being the most frequently involved gene (4.6%)., Conclusions: Unrecognized rare genetic variants increase the risk of CCD in young adults with CCD of unknown etiology. Genetic testing should be performed in patients age ≤60 years with CCD of unknown etiology. The role of genetic variants in sarcomeric genes as a cause of CCD should be further investigated., Competing Interests: Funding Support and Author Disclosures This study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects "PI17/01941 and PI20/01379” (cofunded by European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future"). The CNIC is supported by the ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). The Hospital Universitario Puerta de Hierro, the Hospital Gregorio Marañón, and the Vall Hebron Hospital are members of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart. Dr Ochoa is employee of Health in Code. Dr Braza-Boïls is supported by Marató TV3 (736/C/2020) and Health Research Institute La Fe. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Hypertonic saline solution (HSS) plus intravenous (IV) loop diuretic appears to enhance the diuretic response in patients hospitalized for heart failure (HF). The efficacy and safety of this therapy in the ambulatory setting have not been evaluated. We aimed to describe the design and baseline characteristics of the SALT-HF trial participants., Methods and Results: 'Efficacy of Saline Hypertonic Therapy in Ambulatory Patients with HF' (SALT-HF) trial was a multicenter, double-blinded, and randomized study involving ambulatory patients who experienced worsening heart failure (WHF) without criteria for hospitalization. Enrolled patients had to present at least two signs of volume overload, use ≥ 80 mg of oral furosemide daily, and have elevated natriuretic peptides. Patients were randomized 1:1 to treatment with a 1-h infusion of IV furosemide plus HSS (2.6-3.4% NaCl depending on plasmatic sodium levels) versus a 1-h infusion of IV furosemide at the same dose (125-250 mg, depending on basal loop diuretic dose). Clinical, laboratory, and imaging parameters were collected at baseline and after 7 days, and a telephone visit was planned after 30 days. The primary endpoint was 3-h diuresis after treatment started. Secondary endpoints included (a) 7-day changes in congestion data, (b) 7-day changes in kidney function and electrolytes, (c) 30-day clinical events (need of IV diuretic, HF hospitalization, cardiovascular mortality, all-cause mortality or HF-hospitalization)., Results: A total of 167 participants [median age, 81 years; interquartile range (IQR), 73-87, 30.5% females] were randomized across 13 sites between December 2020 and March 2023. Half of the participants (n = 82) had an ejection fraction >50%. Most patients showed a high burden of comorbidities, with a median Charlson index of 3 (IQR: 2-4). Common co-morbidities included diabetes mellitus (41%, n = 69), atrial fibrillation (80%, n = 134), and chronic kidney disease (64%, n = 107). Patients exhibited a poor functional NYHA class (69% presenting NYHA III) and several signs of congestion. The mean composite congestion score was 4.3 (standard deviation: 1.7). Ninety per cent of the patients (n = 151) presented oedema and jugular engorgement, and 71% (n = 118) showed lung B lines assessed by ultrasound. Median inferior vena cava diameter was 23 mm, (IQR: 21-25), and plasmatic levels of N-terminal-pro-B-type natriuretic peptide (NTproBNP) and antigen carbohydrate 125 (CA125) were increased (median NT-proBNP 4969 pg/mL, IQR: 2508-9328; median CA125 46 U/L, IQR: 20-114)., Conclusions: SALT-HF trial randomized 167 ambulatory patients with WHF and will determine whether an infusion of hypertonic saline therapy plus furosemide increases diuresis and improves decongestion compared to equivalent furosemide administration alone., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Albuminuria could potentially emerge as a novel marker of congestion in acute heart failure. However, the current evidence linking albuminuria and congestion in patients with congestive heart failure (CHF) remains somewhat scarce. This study aimed to evaluate the prevalence of albuminuria in a cohort of patients with CHF, identify the independent factors associated with albuminuria and analyse the correlation with different congestion parameters., Methods: This is a subanalysis of the Spanish Cardiorenal Registry, in which we enrolled 864 outpatients with heart failure and a value of urinary albumin:creatinine ratio (UACR) at the first visit., Results: The median age was 74 years, 549 (63.5%) were male and 438 (50.7%) had a reduced left ventricular ejection fraction. A total of 350 patients (40.5%) had albuminuria. Among these patients, 386 (33.1%) had a UACR of 30-300 mg/g and 64 (7.4%) had a UACR >300 mg/g. In order of importance, the independent variables associated with higher UACR were estimated glomerular filtration rate determined by the Chronic Kidney Disease Epidemiology Collaboration equation ( R 2  = 57.6%), systolic blood pressure ( R 2  = 21.1%), previous furosemide equivalent dose (FED; R 2  = 7.5%), antigen carbohydrate 125 (CA125; R 2  = 6.1%), diabetes mellitus ( R 2  = 5.6%) and oedema ( R 2  = 1.9%). The combined influence of oedema, elevated CA125 levels and the FED accounted for 15.5% of the model's variability., Conclusions: In patients with chronic stable heart failure, the prevalence of albuminuria is high. The risk factors of albuminuria in this population are chronic kidney disease and hypertension. Congestion parameters are also associated with increased albuminuria., Competing Interests: M.J.S. and J.N. are members of the CKJ editorial board., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown., Objectives: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development., Methods: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers., Results: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45)., Conclusions: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM., Competing Interests: Funding Support and Author Disclosures This study was funded by the Spanish Society of Cardiology (Grant in Inherited Cardiac Diseases 2022) and the Instituto de Salud Carlos III through the projects “PI18/0004, PI20/0320” (Co-funded by European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”). The CNIC is supported by the ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). The Hospital Universitario Puerta de Hierro, Hospital Clínic, Hospital Vall Hebron, Hospital Virgen del Rocío, Hospital Universitario Gregorio Marañon, and the Hospital Universitario Virgen de la Arrixaca are members of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant ( TBX20tv ) and DCM/LVNC., Methods: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers., Results: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P <0.0001) and 99.76 (95% CI, 34.60-287.62; P <0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias., Conclusions: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv -associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes., Competing Interests: Disclosures Drs Amor-Salamanca, de la Higuera Romero, Cárdenas-Reyes, García-Hernández, Valverde-Gómez, Gómez-Díaz, and Ochoa are employees of Health in Code SL. The other authors report no conflicts.

Introduction and Objectives: Repetitive ambulatory doses of levosimendan are an option as a bridge to heart transplantation (HT), but evidence regarding the safety and efficacy of this treatment is scarce. The objective of the LEVO-T Registry is to describe the profile of patients on the HT list receiving levosimendan, prescription patterns, and clinical outcomes compared with patients not on levosimendan., Methods: We retrospectively reviewed all patients listed for elective HT from 2015 to 2020 from 14 centers in Spain., Results: A total of 1015 consecutive patients were included, of whom 238 patients (23.4%) received levosimendan. Patients treated with levosimendan had more heart failure (HF) admissions in the previous year and a worse clinical profile. The most frequent prescription pattern were fixed doses triggered by the patients' clinical needs. Nonfatal ventricular arrhythmias occurred in 2 patients (0.8%). No differences in HF hospitalizations were found between patients who started levosimendan in the first 30 days after listing and those who did not (33.6% vs 34.5%; P=.848). Among those who did not, 102 patients (32.9%) crossed over to levosimendan after an HF admission. These patients had a rate of 0.57 HF admissions per month before starting levosimendan and 0.21 afterwards. Propensity score matching analysis showed no differences in survival at 1 year after listing between patients receiving levosimendan and those who did not (HR, 1.03; 95%CI, 0.36-2.97; P=.958) or in survival after HT (HR, 0.97; 95%CI, 0.60-1.56; P=.958)., Conclusions: Repetitive levosimendan in an ambulatory setting as a bridge to heart transplantation is commonly used, is safe, and may reduce HF hospitalizations., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: Vaccines against SARS-CoV-2 have been a major scientific and medical achievement in the control of the COVID-19 pandemic. However, very infrequent cases of inflammatory heart disease have been described as adverse events, leading to uncertainty in the scientific community and in the general population., Methods: The Vaccine-Carditis Registry has included all cases of myocarditis and pericarditis diagnosed within 30 days after COVID-19 vaccination since August 1, 2021 in 29 centers throughout the Spanish territory. The definitions of myocarditis (probable or confirmed) and pericarditis followed the consensus of the Centers for Disease Control and the Clinical Practice Guidelines of the European Society of Cardiology. A comprehensive analysis of clinical characteristics and 3-month evolution is presented., Results: From August 1, 2021, to March 10, 2022, 139 cases of myocarditis or pericarditis were recorded (81.3% male, median age 28 years). Most cases were detected in the 1st week after administration of an mRNA vaccine, the majority after the second dose. The most common presentation was mixed inflammatory disease (myocarditis and pericarditis). 11% had left ventricular systolic dysfunction, 4% had right ventricular systolic dysfunction, and 21% had pericardial effusion. In cardiac magnetic resonance studies, left ventricular inferolateral involvement was the most frequent pattern (58%). More than 90% of cases had a benign clinical course. After a 3-month follow-up, the incidence of adverse events was 12.78% (1.44% mortality)., Conclusions: In our setting, inflammatory heart disease after vaccination against SARS-CoV-2 predominantly affects young men in the 1st week after the second dose of RNA-m vaccine and presents a favorable clinical course in most cases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Patients with atrial fibrillation (AF) and heart failure (HF) have a high risk of thromboembolism and other outcomes and anticoagulation is recommended., Hypothesis: This study was aimed to explore the risk factors associated with HF worsening in patients with AF and HF taking rivaroxaban in Spain., Methods: Multicenter, prospective, observational study that included adults with AF and chronic HF, receiving rivaroxaban ≥4 months before entering. HF worsening was defined as first hospitalization or emergency visit because of HF exacerbation., Results: A total of 672 patients from 71 Spanish centers were recruited, of whom 658 (97.9%) were included in the safety analysis and 552 (82.1%) in the per protocol analysis. At baseline, mean age was 73.7 ± 10.9 years, 64.9% were male, CHA 2 DS 2 -VASc was 4.1 ± 1.5, HAS-BLED was 1.6 ± 0.9% and 51.3% had HF with preserved ejection fraction. After 24 months of follow-up, 24.9% of patients developed HF worsening, 11.6% died, 2.9% had a thromboembolic event, 3.1% a major bleeding, 0.5% an intracranial bleeding and no patient had a fatal hemorrhage. Older age, the history of chronic obstructive pulmonary disease, the previous use of vitamin K antagonists, and restrictive or infiltrative cardiomyopathies, were independently associated with HF worsening. Only 6.9% of patients permanently discontinued rivaroxaban treatment., Conclusions: Approximately one out of four patients with HF and AF treated with rivaroxaban developed a HF worsening episode after 2 years of follow-up. The identification of those factors that increase the risk of HF worsening could be helpful in the comprehensive management of this population., (© 2023 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Introduction and Objectives: Patients with combined heart failure (HF) and chronic kidney disease (CKD) have been underrepresented in clinical trials. The prevalence of CKD in these patients and their clinical profile require constant evaluation. This study aimed to analyze the prevalence of CKD, its clinical profile, and patterns of use of evidence-based medical therapies in HF across CKD stages in a contemporary cohort of ambulatory patients with HF., Methods: From October 2021 to February 2022, the CARDIOREN registry included 1107 ambulatory HF patients from 13 HF clinics in Spain., Results: The median age was 75 years, 63% were male, and 48% had heart failure with reduced left ventricular ejection fraction (HFrEF). A total of 654 (59.1%) had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 , and 122 (11%) patients with eGFR ≥ 60 mL/min/1.73 m 2 had a urine albumin-creatinin ratio ≥ 30 mg/g. The most important variables associated with lower eGFR were age (R2=61%) and furosemide dose (R2=21%). The proportion of patients receiving an angiotensin-converting enzyme inhibitor (ACEI)/ angiotensin II receptor blockers (ARB), an angiotensin receptor-neprilysin inhibitor (ARNi), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), or a mineralocorticoid receptor antagonist (MRA) progressively decreased with lower eGFR categories. Notably, 32% of the patients with HFrEF and an eGFR <30 mL/min/1.73 m 2 received the combination of ACEI/ARB/ARNi+beta-blockers+MRA+SGLT2i., Conclusions: In this contemporary HF registry, 70% of patients had kidney disease. Although this population is less likely to receive evidence-based therapies, structured and specialized follow-up approaches within HF clinics may facilitate the adoption of these life-saving drugs., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background and Aims: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants., Methods: Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC)., Results: Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09)., Conclusions: Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction and Objectives: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) induce short-term changes in renal function and hemoglobin. Their pathophysiology is incompletely understood. We aimed to evaluate the relationship between 1- and 3-month estimated glomerular filtration rate (eGFR) and hemoglobin changes following initiation of dapagliflozin in patients with stable heart failure with reduced ejection fraction (HFrEF)., Methods: This is a post hoc analysis of a randomized clinical trial that evaluated the effect of dapagliflozin on 1- and 3-month peak oxygen consumption in outpatients with stable HFrEF (DAPA-VO 2 trial, NCT04197635). We used linear mixed regression analysis to assess the relationship between eGFR and hemoglobin changes across treatment arms., Results: A total of 87 patients were evaluated in this substudy. The mean age was 67.0± 10.5 years, and 21 (24.1%) were women. The mean baseline eGFR and hemoglobin were 66.9±20.7mL/min/1.73m 2 and 14.3±1.7g/dL, respectively. Compared with placebo, eGFR did not significantly change at either time points in the dapagliflozin group, but hemoglobin significantly increased at 1 and 3 months. At 1 month, the hemoglobin increase was related to decreases in eGFR only in the dapagliflozin arm (P <.001). At 3 months, there was no significant association in either treatment arms (P=.123). Changes in eGFR were not associated with changes in peak oxygen consumption, quality of life, or natriuretic peptides., Conclusions: In patients with stable HFrEF, 1-month changes in eGFR induced by dapagliflozin are inversely related to changes in hemoglobin. This association was no longer significant at 3 months., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: Arrhythmogenic cardiomyopathy (ACM) is a hereditary heart disease defined by the progressive replacement of the ventricular myocardium with fibroadipose tissue, which can act as a substrate for arrhythmias, sudden death, or even give rise to heart failure (HF). Sudden death is frequently the first manifestation of the disease, particularly among young patients. The aim of this study is to describe a new pathogenic variant in the PKP2 gene ., Methods: A descriptive observational study that included eight initially non-interrelated families with a diagnosis of ACM undergoing follow-up at our HF and Familial Cardiomyopathies Unit, who were carriers of the NM&#95;004572.3:c.775&#95;776insG; p.(Glu259Glyfs*77) variant in the PKP2 gene . The genetic testing employed next-generation sequencing for the index cases and the Sanger method for the targeted study with family members. We compiled personal and family histories, demographic and clinical characteristics, data from the additional tests at the time of diagnosis, and arrhythmic events at diagnosis and during follow-up., Results: We included 47 subjects, of whom 8 were index cases (17%). Among the evaluated family members, 16 (34%) were carriers of the genetic variant, 3 of whom also had a diagnosis of ACM. The majority were women (26 patients; 55.3%), with a mean age on diagnosis of 48.9 ± 18.6 years and a median follow-up of 39 [24-59] months. Worthy of note are the high incidences of arrhythmic events as the form of presentation and in follow-up (21.5% and 20.9%, respectively), and the onset of HF in 25% of the sample. The most frequent ventricular involvements were right (four patients, 16.7%) and biventricular (four patients, 16.7%); we found no statistical differences in any of the variables analysed., Conclusions: This variant is a pathogenic variant of gene PKP2 that has not previously been described and is not present in the control groups associated with ACM. It has incomplete penetrance, a highly variable phenotypic expressivity, and was identified in eight families of our geographical area in Malaga (Andalusia, Spain), suggesting a founder effect in this area and describe the clinical and risk characteristics.

Purpose of the Work: Although sex-specific differences in heart failure (HF) or kidney disease (KD) have been analyzed separately, the predominant cardiorenal phenotype by sex has not been described. This study aims to explore the sex-related differences in cardiorenal syndrome (CRS) in a contemporary cohort of outpatients with HF., Findings: An analysis of the Cardiorenal Spanish registry (CARDIOREN) was performed. CARDIOREN Registry is a prospective multicenter observational registry including 1107 chronic ambulatory HF patients (37% females) from 13 Spanish HF clinics. Estimated Glomerular Filtration Rate (eGFR) < 60 ml/min/1.73 m 2 was present in 59.1% of the overall HF population, being this prevalence higher in the female population (63.2% vs. 56.6%, p = 0.032, median age: 81 years old, IQR:74-86). Among those with kidney dysfunction, women displayed higher odds of showing HF with preserved ejection fraction (HFpEF) (odds ratio [OR] = 4.07; confidence interval [CI] 95%: 2.65-6.25, p < 0.001), prior valvular heart disease (OR = 1.76; CI 95%:1.13-2.75, p = 0.014), anemia (OR: 2.02; CI 95%:1.30-3.14, p = 0.002), more advanced kidney disease (OR for CKD stage 3: 1.81; CI 95%:1.04-3.13, p = 0.034; OR for CKD stage 4: 2.49, CI 95%:1.31-4.70, p = 0.004) and clinical features of congestion (OR:1.51; CI 95%: 1.02-2.25, p = 0.039). On the contrary, males with cardiorenal disease showed higher odds of presenting HF with reduced ejection fraction (HFrEF) (OR:3.13; CI 95%: 1.90-5.16, p < 0.005), ischemic cardiomyopathy (OR:2.17; CI 95%: 1.31-3.61, p = 0.003), hypertension (OR = 2.11; CI 95%:1.18-3.78, p = 0.009), atrial fibrillation (OR:1.71; CI 95%: 1.06-2.75, p = 0.025), and hyperkalemia (OR:2.43, CI 95%: 1.31-4.50, p = 0.005). In this contemporary registry of chronic ambulatory HF patients, we observed sex-related differences in patients with combined heart and kidney disease. The emerging cardiorenal phenotype characterized by advanced CKD, congestion, and HFpEF was predominantly observed in women, whereas HFrEF, ischemic etiology, hypertension, hyperkalemia, and atrial fibrillation were more frequently observed in men., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Curcumin (CCM) is a molecule of particular interest in health applications due to its wide spectrum of benefits for humans. However, its water-insoluble character and low bioavailability have so far prevented its extended use as a therapeutic agent. Incorporation of CCM in drug delivery vehicles (liposomes, vesicles, exosomes, etc .) is expected to contribute to increasing its bioavailability. Studies of the affinity of CCM with the components of the membrane systems of such vehicles and determination of factors that may enhance curcumin entrapment in biological membranes are of fundamental importance. To that end, here we take advantage of the nanoarchitectonic capabilities of the Langmuir technique for the construction of model cell membranes and determination of thermodynamic properties in mixed films. The obtained results may serve to: (i) provide some light on the miscibility of CCM with the components in the cell membrane and (ii) determine the optimal conditions for the fabrication of membrane systems incorporating CCM. For that, binary and ternary mixed Langmuir films of CCM, DPPC (1,2-dipalmitoyl- sn-glycero -3-phosphocholine) and CHOL (cholesterol) have been prepared. Whilst binary mixtures of DPPC and CCM exhibit poor miscibility and even phase segregation, CHOL has shown itself as a key element to promote the incorporation of CCM in the phospholipidic membrane containing DPPC. Both the thermodynamic studies of the ternary Langmuir films and the Atomic Force Microscopy (AFM) images of Langmuir-Blodgett films have shown that ternary mixed films with a molar fraction composition of x DPPC / x CHOL / x CCM = 0.4/0.4/0.2 exhibit good miscibility, stability, and result in monolayers with a very homogeneous topography.

Background: Fabry disease (FD) is an X-linked condition caused by variants in the GLA gene. Since females have two X chromosomes, they were historically thought to be carriers. Although increased knowledge has shown that females often develop the disease, data from Spain and other countries reported that females were undertreated. The aim of this study was to provide a wider and more recent description of the disease characteristics and associated management of females with a GLA variant in a Spanish cohort., Results: Ninety-seven females from 12 hospitals were included in this retrospective study. Mean age was 50.1 ± 17.2 years. Median follow-up time from GLA variant identification was 36.1 months, and most (70.1%) were identified through family screening. Variants associated with classic/non-classic phenotypes were similarly distributed (40.2%/53.6%). Missense variants were the most prevalent (n = 84, 86.6%). In the overall group, 70.4% had major organ involvement (i.e., cardiac, renal, cerebrovascular, peripheral nervous system or gastrointestinal), and 47.3% also had typical Fabry signs (angiokeratoma, cornea verticillata or increased plasma lyso-Gb3). Cardiac involvement was the most prevalent (49.5%) and the main reason for treatment initiation. A total of 33 (34%) patients received disease-specific therapy, 55% of whom were diagnosed by family screening. Females carrying variants associated with a classic phenotype had higher frequencies of clinical manifestations (92.3%) and were predominant in the treated subgroup (69.7%). Despite this, there were 34 untreated females (56.7% of total untreated), with both phenotypes represented, who had major organ involvement, with 27 of cardiac, renal or cerebrovascular nature. Age or comorbidities in this subgroup were comparable to the treated subgroup (P = 0.8 and P = 0.8, respectively)., Conclusions: Efforts have been made in recent years to diagnose and treat timely Fabry females in Spain. A high percentage of females with pathogenic variants, regardless of their associated phenotype, will likely develop disease. A proportion of females with severe disease in this cohort received specific treatment. Still a significant number of females, even with same profile as the treated ones, who may be eligible for treatment according to European recommendations, remained untreated. Reasons for this merit further investigation., (© 2023. The Author(s).)

Introduction: Cardioembolic stroke, associated to nonvalvular atrial fibrillation (NVAF), accounts for approximately one in every four strokes. Cardioembolic stroke has a bad prognosis and is associated with a significant rate of recurrence., Areas Covered: This article reviews current pharmacotherapeutic options for prevention of stroke in NVAF, paying special attention to their use in particular clinical settings (e.g. cardioversion, catheter ablation). We also aim to review new drug candidates that have entered clinical studies in this indication., Expert Opinion: Oral anticoagulant therapy (OAT) remains the mainstay for ischemic stroke prophylaxis in NVAF in patients at risk. Several oral (asundexian, milvexian) and parenteral (abelacimab, osocimab, xisomab, IONIS-FXI RX , fesomersen) factor XIa inhibitors are under development. These new compounds appear to be associated with a low bleeding tendency and have the potential to complement current existing alternatives for anticoagulation. However, it is also of paramount importance to implement interventions to improve adherence to available anticoagulants, which is currently suboptimal. Non-anticoagulant drugs, such as colchicine, metformin and dronedarone, also being investigated to reduce the burden of NVAF and cardioembolic stroke. Additional clinical data are needed to more clearly define the role of these drugs for stroke prevention in NVAF.

Background: Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described., Objectives: We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression., Methods: We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 ± 19.2 years) recruited from 29 international centers., Results: At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% ± 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of ≤35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants., Conclusions: MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare., Competing Interests: Funding Support and Author Disclosures This study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects PI18/0004, PI20/0320, and PT17/0015/0043 (cofunded by European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). The Hospital Universitario Puerta de Hierro, the Hospital Sant Joan de Déu, and the Hospital Universitario Virgen de la Arrixaca are members of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart. Dr de Frutos receives grant support from ISCIII (CM20/00101). Genetic examinations of Polish patients were funded with DETECTIN-HF grant from the ERA-CVD framework, NCBiR. Dr Baas has received funding from CVON2020B005 DOUBLE-DOSE, Dutch Heart Foundation (Dekker 2015T041). Dr Fatkin has received funding from Victor Chang Cardiac Research Institute and NSW Health. Dr Lopes is funded by an MRC UK Clinical Academic Research Partnership award (MR/T005181/1). Dr Meder has received funding from the Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research) and Informatics for Life (Klaus Tschira Foundation). Dr Kubanek has received grant support from the Ministry of Health, Czech Republic (NV19-08-00122) and IPO (Institute for Clinical and Experimental Medicine–IKEM, IN 00023001). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction and Objectives: Optimal medical therapy decreases mortality and heart failure (HF) hospitalizations in HF patients with reduced left ventricular ejection fraction. Women have been underrepresented in clinical trials and not specifically evaluated. This study aimed to compare the safety and effectiveness of drug titration in women vs men., Methods: This post hoc gender study of the ETIFIC multicenter randomized trial included hospitalized patients with new-onset HF with reduced ejection fraction and New York Heart Association II-III and no contraindications to beta-blockers. A structured 4-month titration process was implemented in HF clinics. The primary endpoint was the mean relative dose (% of target dose) of beta-blockers achieved by women vs men. Secondary endpoints included the mean relative doses of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists, adverse events, and other clinical outcomes at 6 months., Results: A total of 320 patients were included, 83 (25.93%) women and 237 (74.06%) men (76 vs 213 analyzed). The mean±standard deviation of the relative doses achieved by women vs men were as follows: beta-blockers 62.08%±30.72% vs 64.4%±32.77%, with a difference of-2.32% (95%CI,-10.58-5.94), P = .580; and mineralocorticoid receptor antagonists 79.85%±27.72% vs 67.29%±31.43%, P =.003. No other differences in drug dosage were found. Multivariate analysis showed nonsignificant differences. CV mortality was 1 (1.20%) vs 3 (1.26%), P=1, and HF hospitalizations 0 (0.00%) vs 10 (4.22%), P=.125., Conclusions: In a post hoc analysis from the HF-titration ETIFIC trial, we found nonsignificant gender differences in drug dosage, cardiovascular mortality, and HF hospitalizations. Trial registry number: NCT02546856., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Aims: Genotype and left ventricular scar on cardiac magnetic resonance (CMR) are increasingly recognized as risk markers for adverse outcomes in non-ischaemic dilated cardiomyopathy (DCM). We investigated the combined influence of genotype and late gadolinium enhancement (LGE) in assessing prognosis in a large cohort of patients with DCM., Methods and Results: Outcomes of 600 patients with DCM (53.3 ± 14.1 years, 66% male) who underwent clinical CMR and genetic testing were retrospectively analysed. The primary endpoints were end-stage heart failure (ESHF) and malignant ventricular arrhythmias (MVA). During a median follow-up of 2.7 years (interquartile range 1.3-4.9), 24 (4.00%) and 48 (8.00%) patients had ESHF and MVA, respectively. In total, 242 (40.3%) patients had pathogenic/likely pathogenic variants (positive genotype) and 151 (25.2%) had LGE. In survival analysis, positive LGE was associated with MVA and ESHF (both, p < 0.001) while positive genotype was associated with ESHF (p = 0.034) but not with MVA (p = 0.102). Classification of patients according to genotype (G+/G-) and LGE presence (L+/L-) revealed progressively increasing events across L-/G-, L-/G+, L+/G- and L+/G+ groups and resulted in optimized MVA and ESHF prediction (p < 0.001 and p = 0.001, respectively). Hazard ratios for MVA and ESHF in patients with either L+ or G+ compared with those with L-/G- were 4.71 (95% confidence interval: 2.11-10.50, p < 0.001) and 7.92 (95% confidence interval: 1.86-33.78, p < 0.001), respectively., Conclusion: Classification of patients with DCM according to genotype and LGE improves MVA and ESHF prediction. Scar assessment with CMR and genotyping should be considered to select patients for primary prevention implantable cardioverter-defibrillator placement., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Hyperkalaemia is a growing concern in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) as it limits the use of some prognostic-modifying drugs and has a negative impact on prognosis. The objective of the present study was to estimate the prevalence of hyperkalaemia in outpatients with HFrEF and its impact on achieving optimal medical treatment. For this purpose, a multicentre, prospective, and observational study was carried out on consecutive HFrEF patients who were monitored as outpatients in heart failure (HF) units and who, in the opinion of their doctor, received optimal medical treatment. A total of 565 HFrEF patients were included from 16 specialised HF units. The mean age was 66 ± 12 years, 78% were male, 45% had an ischemic cause, 39% had atrial fibrillation, 43% were diabetic, 42% had a glomerular filtration rate < 60 mL/min/1.7 m2, and the mean left ventricular ejection fraction was 31 ± 7%. Treatment at the study entry included: 76% on diuretics, 13% on ivabradine, 7% on digoxin, 18.9% on angiotensin-conversing enzyme inhibitors (ACEi), 11.3% on angiotensin receptors blockers (ARBs), 63.8% on angiotensin-neprilysin inhibitors (ARNi), 78.5% on mineralocorticoid receptor antagonists (MRAs), and 92.9% on beta-blockers. Potassium levels in the baseline analysis were: ≤5 mEq/L = 80.5%, 5.1−5.4 mEq/L = 13.8%, 5.5−5.9 mEq/L = 4.6%, and ≥6 mEq/L = 1.06%. Hyperkalaemia was the reason for not prescribing or reaching the target dose of an MRAs in 34.8% and 12.5% of patients, respectively. The impact of hyperkalaemia on not prescribing or dropping below the target dose in relation to ACEi, ARBs, and ARNi was significantly less. In conclusion, hyperkalaemia is a frequent problem in the management of patients with HFrEF and a limiting factor in the optimisation of medical treatment.

Background: The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled., Objectives: The study sought to assess the prognostic impact of disease-causing genetic variants in DCM., Methods: Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR)., Results: After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene., Conclusions: In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene., Competing Interests: Funding Support and Author Disclosures This work was supported by grants from the following institutions: the Instituto de Salud Carlos III (AC16/0014, PI18/0004, PI20/0320) and the European Union (GENPROVIC project from ERA-CVD framework). The Hospital Universitario Puerta de Hierro and the Hospital Universitario Virgen de la Arrixaca are members of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart). All authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Over 70 genes that encode different cell components have been involved in the aetiology of dilated cardiomyopathy. Genotype-phenotype interactions are an unsolved problem, and to a large extent the effects of mutations in the expression mechanisms involved in the disease remain unknown, although associations are increasingly being established which have clinical and prognostic implications., Methods and Results: The objective of our work was to describe our population that has cardiomyopathy associated with mutations in the gene RBM20, and study the genotype-phenotype relationship. We studied 8 cases undergoing follow-up at our Unit, and collected data for demographic, clinical and diagnostic testing variables. The mean age on diagnosis was 55 years [52-59], with a median follow-up of 31.5 months [26.0-67.3]. It is worth noting that 62.5% of the patients in our group had a history of cardiomyopathy in first degree relatives, and 37.5% of them had a family history of sudden death. One of the genetic variations of the sample was shared by three subjects who had no apparent family relationship with each other, and this variation had not been described in controls. It is also interesting that arrhythmic events were found in 37.5% of the sample, and 50% of patients had an indication for implantable cardiac defibrillator., Conclusion: This is the first analysis of patients with RBM20 mutations conducted in our country, and it indicates a profile with prominent arrhythmogenesis, a high penetrance of familial cardiomyopathy, and sudden death., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background and Objectives: To date, in Spain, there are no studies that have evaluated the prevalence of hypertrophic cardiomyopathy in the general population. The aim of this study was to assess the prevalence of hypertrophic cardiomyopathy in a large sample of the working population of Spain., Materials and Methods: The study included 13,179 workers (73% men; mean age: 40 years) from 5 regions of Spain who, between May 2008 and November 2010, had a medical examination with an electrocardiogram. The workers with suggestive abnormalities in the electrocardiogram or a predisposing medical history (exertional syncope or sudden death of a family member younger than 50 years) were referred for an echocardiographic evaluation. We defined hypertrophic cardiomyopathy as a parietal thickness ≥13mm in any segment of the left ventricle. We estimated the prevalence of hypertrophic cardiomyopathy in the entire sample and in the workers without hypertension., Results: A total of 1008 workers were selected for the echocardiogram, although only 496 (49.2% of those selected) of these attended the appointment. After the echocardiogram, we detected 16 cases of hypertrophic cardiomyopathy, estimating a prevalence of 0.24% for the entire sample. In the subgroup of workers with no hypertension, we observed 10 cases of hypertrophic cardiomyopathy, which corresponds to an estimated prevalence of 0.19%., Conclusions: In our sample of the working population in Spain, the estimated prevalence of hypertrophic cardiomyopathy was 0.24%. In the subgroup of patients with no hypertension, the estimated prevalence was 0.19%., (Copyright © 2021 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Introduction and Objectives: Beta-blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin-II-receptor-blockers (ARB), and mineralocorticoid-receptor antagonists decrease mortality and heart failure (HF) hospitalizations in HF patients with reduced left ventricular ejection fraction. The effect is dose-dependent. Careful titration is recommended. However, suboptimal doses are common in clinical practice. This study aimed to compare the safety and efficacy of dose titration of the aforementioned drugs by HF nurses vs HF cardiologists., Methods: ETIFIC was a multicenter (n=20) noninferiority randomized controlled open label trial. A total of 320 hospitalized patients with new-onset HF, reduced ejection fraction and New York Heart Association II-III, without beta-blocker contraindications were randomized 1:1 in blocks of 4 patients each stratified by hospital: 164 to HF nurse titration vs 156 to HF cardiologist titration (144 vs 145 analyzed). The primary endpoint was the beta-blocker mean relative dose (% of target dose) achieved at 4 months. Secondary endpoints included ACE inhibitors, ARB, and mineralocorticoid-receptor antagonists mean relative doses, associated variables, adverse events, and clinical outcomes at 6 months., Results: The mean±standard deviation relative doses achieved by HF nurses vs HF cardiologists were as follows: beta-blockers 71.09%±31.49% vs 56.29%±31.32%, with a difference of 14.8% (95%CI, 7.5-22.1), P <.001; ACE inhibitors 72.61%±29.80% vs 56.13%±30.37%, P <.001; ARB 44.48%±33.47% vs 43.51%±33.69%, P=.93; and mineralocorticoid-receptor antagonists 71%±32.12% vs 70.47%±29.78%, P=.86; mean±standard deviation visits were 6.41±2.82 vs 2.81±1.58, P <.001, while the number (%) of adverse events were 34 (23.6) vs 30 (20.7), P=.55; and at 6 months HF hospitalizations were 1 (0.69) vs 9 (5.51), P=.01., Conclusions: ETIFIC is the first multicenter randomized trial to demonstrate the noninferiority of HF specialist-nurse titration vs HF cardiologist titration. Moreover, HF nurses achieved higher beta-blocker/ACE inhibitors doses, with more outpatient visits and fewer HF hospitalizations. Trial registry number: NCT02546856., (Copyright © 2020 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Aims: Maximum oxygen uptake (VO 2max ) is an essential parameter to assess functional capacity of patients with heart failure (HF). We aimed to identify clinical factors that determine its value, as they have not been well characterized yet., Methods: We conducted a retrospective, observational, single-centre study of 362 consecutive patients with HF who underwent cardiopulmonary exercise testing (CPET) as part of standard clinical assessment since 2009-2019. CPET was performed on treadmill, according to Bruce's protocol (n = 360) or Naughton's protocol (n = 2). We performed multivariable linear regression analyses in order to identify independent clinical predictors associated with peak VO 2max ., Results: Mean age of study patients was 57.3 ± 10.9 years, mean left ventricular ejection fraction was 32.8 ± 14.2%, and mean VO 2max was 19.8 ± 5.2 mL/kg/min. Eighty-nine (24.6%) patients were women, and 114 (31.5%) had ischaemic heart disease. Multivariable linear regression analysis identified six independent clinical predictors of VO 2max , including NYHA class (B coefficient = -2.585; P < 0.001), age (B coefficient per 1 year = -0.104; P < 0.001), tricuspid annulus plane systolic excursion (B coefficient per 1 mm = +0.209; P < 0.001), body mass index (B coefficient per 1 kg/m 2  = -0.172; P = 0.002), haemoglobin (B coefficient per 1 g/dL = +0.418; P = 0.007) and NT-proBNP (B coefficient per 1000 pg/mL = -0.142; P = 0.019)., Conclusions: The severity of HF (NYHA class, NT-proBNP) as well as age, body composition and haemoglobin levels influence significantly exercise capacity. In patients with HF, the right ventricular systolic function is of greater importance for the physical capacity than the left ventricular systolic function., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction and Objectives: According to sudden cardiac death guidelines, an implantable cardioverter-defibrillator (ICD) should be considered in patients with LMNA-related dilated cardiomyopathy (DCM) and ≥ 2 risk factors: male sex, left ventricular ejection fraction (LVEF) <45%, nonsustained ventricular tachycardia (NSVT), and nonmissense genetic variants. In this study we aimed to describe the clinical characteristics of carriers of LMNA genetic variants among individuals from a Spanish cardiac-laminopathies cohort (REDLAMINA registry) and to assess previously reported risk criteria., Methods: The relationship between risk factors and cardiovascular events was evaluated in a cohort of 140 carriers (age ≥ 16 years) of pathogenic LMNA variants (54 probands, 86 relatives). We considered: a) major arrhythmic events (MAE) if there was appropriate ICD discharge or sudden cardiac death; b) heart failure death if there was heart transplant or death due to heart failure., Results: We identified 11 novel and 21 previously reported LMNA-related DCM variants. LVEF <45% (P=.001) and NSVT (P <.001) were related to MAE, but not sex or type of genetic variant. The only factor independently related to heart failure death was LVEF <45% (P <.001)., Conclusions: In the REDLAMINA registry cohort, the only predictors independently associated with MAE were NSVT and LVEF <45%. Therefore, female carriers of missense variants with either NSVT or LVEF <45% should not be considered a low-risk group. It is important to individualize risk stratification in carriers of LMNA missense variants, because not all have the same prognosis., (Copyright © 2020 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic has changed how we view our consultations. To reduce the risk of spread in the most vulnerable patients (those with heart disease) and health personnel, most face-to-face consultations have been replaced by telemedicine consultations. Although this change has been rapidly introduced, it will most likely become a permanent feature of clinical practice. Nevertheless, there remain serious doubts about organizational and legal issues, as well as the possibilities for improvement etc. In this consensus document of the Spanish Society of Cardiology, we attempt to provide some keys to improve the quality of care in this new way of working, reviewing the most frequent heart diseases attended in the cardiology outpatient clinic and proposing some minimal conditions for this health care process. These heart diseases are ischemic heart disease, heart failure, and arrhythmias. In these 3 scenarios, we attempt to clarify the basic issues that must be checked during the telephone interview, describe the patients who should attend in person, and identify the criteria to refer patients for follow-up in primary care. This document also describes some improvements that can be introduced in telemedicine consultations to improve patient care., (© 2020 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: The aim of the current survey was to describe the functioning of cardio-oncology (C-O) units in Spain., Methods: All members of the Spanish Society of Cardiology pertaining to scientific communities related to C-O received questionnaires on the existence of specific programs at their institutions. A second, more extensive questionnaire was sent to the centers which reported C-O organization., Results: We identified 56 centers with C-O programs of which 32 (62.5%) replied to the extended questionnaire. 28% of all centers reported having a multidisciplinary unit involving specialists in several areas. More than 80% of the centers developed surveillance protocols locally adapted which included advanced echocardiographic techniques (68%) or troponin (82%)., Conclusions: The number of institutions with C-O programs is still limited but higher than reported in a survey in 2017. Development of multidisciplinary units of C-O should be promoted to improve the cardiovascular health of cancer patients.

Introduction and Objectives: Hyperkalemia is a growing concern in the treatment of patients with heart failure and reduced ejection fraction because it limits the use of effective drugs. We report estimates of the magnitude of this problem in routine clinical practice in Spain, as well as changes in potassium levels during follow-up and associated factors., Methods: This study included patients with acute (n=881) or chronic (n=3587) heart failure recruited in 28 Spanish hospitals of the European heart failure registry of the European Society of Cardiology and followed up for 1 year. Various outcomes were analyzed, including changes in serum potassium levels and their impact on treatment., Results: Hyperkalemia (K + > 5.4 mEq/L) was identified in 4.3% (95%CI, 3.7%-5.0%) and 8.2% (6.5%-10.2%) of patients with chronic and acute heart failure, respectively, and was responsible for 28.9% of all cases of contraindication to mineralocorticoid receptor antagonist use and for 10.8% of all cases of failure to reach the target dose. Serum potassium levels were not recorded in 291 (10.8%) of the 2693 chronic heart failure patients with reduced ejection fraction. During follow-up, potassium levels increased in 179 of 1431 patients (12.5%, 95%CI, 10.8%-14.3%). This increase was directly related to age, diabetes, and history of stroke and was inversely related to history of hyperkalemia., Conclusions: This study highlights the magnitude of the problem of hyperkalemia in patients with heart failure in everyday clinical practice and the need to improve monitoring of this factor in these patients due to its interference with the possibility of receiving optimal treatment., (Copyright © 2019 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Heart failure is a complex entity, with high morbidity and mortality. The clinical course and outcome are uncertain and difficult to predict. This document, instigated by the Heart Failure and Geriatric Cardiology Working Groups of the Spanish Society of Cardiology, addresses various aspects related to palliative care, where most cardiovascular disease will eventually converge. The document also establishes a consensus and a series of recommendations with the aim of recognizing and understanding the need to implement and progressively apply palliative care throughout the course of the disease, not only in the advanced stages, thus improving the care provided and quality of life. The purpose is to improve and adapt treatment to the needs and wishes of each patient, who must have adequate information and participate in decision-making., (Copyright © 2019 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Inotropes aim at increasing cardiac output by enhancing cardiac contractility. They constitute the third pharmacological pillar in the treatment of patients with decompensated heart failure, the other two being diuretics and vasodilators. Three classes of parenterally administered inotropes are currently indicated for decompensated heart failure, (i) the beta adrenergic agonists, including dopamine and dobutamine and also the catecholamines epinephrine and norepinephrine, (ii) the phosphodiesterase III inhibitor milrinone and (iii) the calcium sensitizer levosimendan. These three families of drugs share some pharmacologic traits, but differ profoundly in many of their pleiotropic effects. Identifying the patients in need of inotropic support and selecting the proper inotrope in each case remain challenging. The present consensus, derived by a panel meeting of experts from 21 countries, aims at addressing this very issue in the setting of both acute and advanced heart failure., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Acute and advanced heart failure are associated with substantial adverse short- and longer-term prognosis. Both conditions necessitate complex treatment choices to restore haemodynamic stability and organ perfusion, relieve congestion, improve symptoms and allow the patient to leave the hospital and achieve an adequate quality of life. Among the available intravenous vasoactive therapies, inotropes constitute an option when an increase in cardiac contractility is needed to reverse a low output state. Within the inotrope category, levosimendan is well suited to the needs of both sets of patients since, in contrast to conventional adrenergic inotropes, it has not been linked in clinical trials or wider clinical usage with increased mortality risk and retains its efficacy in the presence of beta-adrenergic receptor blockade; it is further believed to possess beneficial renal effects. The overall haemodynamic profile and clinical tolerability of levosimendan, combined with its extended duration of action, have encouraged its intermittent use in patients with advanced heart failure. This paper summarises the key messages derived from a series of 12 tutorials held at the Heart Failure 2019 congress organised in Athens, Greece, by the Heart Failure Association of the European Society of Cardiology., Competing Interests: Disclosure: PP is a full-time employee of Orion Pharma. In the past 5 years, all other authors have received honoraria from Orion Pharma for educational lectures. This project did not receive any financial support, apart from logistical expenses related to the organisation of the hands-on tutorials at the annual meeting of the Heart Failure Association of the European Society of Cardiology in Athens, Greece on 26–27 May 2019, which were covered by Orion Pharma. The lecturers and programme were approved by the congress organisers., (Copyright © 2019, Radcliffe Cardiology.)