Sex-based Differences in Heart Failure Biomarkers.

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.

Late gadolinium enhancement distribution patterns in non-ischaemic dilated cardiomyopathy: genotype-phenotype correlation.

AIMS: Late gadolinium enhancement (LGE) is frequently found in patients with dilated cardiomyopathy (DCM); there is little information about its frequency and distribution pattern according to the underlying genetic substrate. We sought to describe LGE patterns according to genotypes and to analyse the risk of major ventricular arrhythmias (MVA) according to patterns. METHODS AND RESULTS: Cardiac magnetic resonance findings and LGE distribution according to genetics were performed in a cohort of 600 DCM patients followed at 20 Spanish centres. After exclusion of individuals with multiple causative gene variants or with variants in infrequent DCM-causing genes, 577 patients (34% females, mean age 53.5 years, left ventricular ejection fraction 36.9 ± 13.9%) conformed to the final cohort. A causative genetic variant was identified in 219 (38%) patients, and 147 (25.5%) had LGE. Significant differences were found comparing LGE patterns between genes (P < 0.001). LGE was absent or rare in patients with variants in TNNT2, RBM20, and MYH7 (0, 5, and 20%, respectively). Patients with variants in DMD, DSP, and FLNC showed a predominance of LGE subepicardial patterns (50, 41, and 18%, respectively), whereas patients with variants in TTN, BAG3, LMNA, and MYBPC3 showed unspecific LGE patterns. The genetic yield differed according to LGE patterns. Patients with subepicardial, lineal midwall, transmural, and right ventricular insertion points or with combinations of LGE patterns showed an increased risk of MVA compared with patients without LGE. CONCLUSION: LGE patterns in DCM have a specific distribution according to the affected gene. Certain LGE patterns are associated with an increased risk of MVA and with an increased yield of genetic testing.

The Novel Variant NP_00454563.2 (p.Glu259Glyfs*77) in Gene PKP2 Associated with Arrhythmogenic Cardiomyopathy in 8 Families from Malaga, Spain.

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_004572.3:c.775_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.

Análisis de la actividad de la consulta de enfermería telefónica a demanda para pacientes con insuficiencia cardíaca / Analysis of the activity of the telephone nursing consultation on demand for patients with heart failure

Objetivo: Analizar los motivos más frecuentes de demanda telefónica en la consulta de la enfermera de insuficiencia cardiaca y evaluar la capacidad de resolución de respuesta tras la llamada. Método: Estudio descriptivo, retrospectivo, de todas las llamadas telefónicas registradas entre junio de 2020 y abril de 2021 en una consulta específica de enfermería para la atención a la insuficiencia cardiaca. De las historias clínicas electrónicas se extrajeron las principales variables sociodemográficas y clínicas, el motivo de llamada y la acción realizada por la enfermera, para su posterior análisis descriptivo. Resultados: Se analizaron 643 llamadas, 354 (55,1%) de las cuales fueron realizadas por los pacientes. El motivo de llamada más frecuente fue para consultar síntomas: 45,8% (n=162). El 71,6% (n=116) de las consultas se solucionaron ajustando el tratamiento farmacológico por teléfono, el 24,7% (n=40) precisaron una visita presencial en la consulta de la enfermera, necesitaron atención en urgencias 22 (13,6%) pacientes: 5 por empeoramiento de la insuficiencia cardiaca. Los pacientes que consultaron por síntomas presentaban peor clase funcional (p=0,007) y habían sido derivados desde hospitalización (p=0,023). Conclusiones: La consulta telefónica se mostró útil para pacientes con insuficiencia cardiaca, siendo principalmente demandada por usuarios que presentan síntomas de empeoramiento de su enfermedad.(AU)

Objective: Analyzing the most frequent reasons for telephone demand in the heart failure nurse's consultation and to evaluate the response resolution capacity after the call. Method: Descriptive, retrospective study of all telephone calls recorded between June 2020 and April 2021 in a specific nursing consultation for heart failure care. The main sociodemographic and clinical variables, reason for calling and action carried out by the nurse were extracted from the electronic medical records, for its subsequent descriptive analysis. Results: A total of 643 calls were analyzed, 354 (55.1%) were made by the patients. The most frequent reason for calling was to consult symptoms: 45.8% (n=162). 71.6% (n=116) of the consultations were resolved by adjusting the pharmacological treatment by telephone, 24.7% (n=40) required a face-to-face visit in the nurse's consultation, 22 (13.6%) needed emergency care: 5 due to worsening heart failure. The patients who consulted for symptoms had a worse functional class (P=.007) and had been referred from hospitalization (P=.023). Conclusions: The telephone consultation was shown to be useful for patients with heart failure, being mainly demanded by users who present symptoms of worsening of their disease.(AU)

Analysis of the activity of the telephone nursing consultation on demand for patients with heart failure.

OBJECTIVE: Analyzing the most frequent reasons for telephone demand in the heart failure nurse's consultation and to evaluate the response resolution capacity after the call. METHOD: Descriptive, retrospective study of all telephone calls recorded between June 2020 and April 2021 in a specific nursing consultation for heart failure care. The main sociodemographic and clinical variables, reason for calling and action carried out by the nurse were extracted from the electronic medical records. For its subsequent descriptive análisis. RESULTS: 643 calls were analyzed, 354 (55.1%) were made by the patients. The most frequent reason for calling was to consult symptoms 45.8% (n = 162). 71.6% (n = 116) of the consultations were resolved by adjusting the pharmacological treatment by telephone, 24.7% (n = 40) required a face-to-face visit in the nurse's consultation, 22 (13.6%) needed emergency care. 5 due to worsening heart failure. The patients who consulted for symptoms had a worse functional class (p = 0.007) and had been referred from hospitalization (p = 0.023). CONCLUSIONS: The telephone consultation was shown to be useful for patients with heart failure, being mainly demanded by users who present symptoms of worsening of their disease.

Case report on ambulatory pulmonary pressure monitoring: an attempt to reduce readmissions for heart failure with preserved ejection fraction.

Background: Despite many recent advances in heart failure (HF) therapies, there remains an unmet need in patients with HF with preserved ejection fraction (HFpEF) for adequate treatment and follow-up, with the potential to reduce associated mortality and morbidity. Increased intracardiac and intrapulmonary pressures have been shown to precede the onset of symptoms of decompensated HF by several days or even weeks, so there have been several attempts to influence the prognosis of HF by monitoring through various methods. One of these is ambulatory pulmonary pressure monitoring to guide treatment in anticipation of decompensation. Case summary: We present the case of a 65-year-old woman with rheumatic valve disease and mechanical aortic and mitral prosthesis since 2003 and pacemaker since 2014, with development of severe tricuspid regurgitation in 2018 and with new valve implantation and multiple decompensations of HFpEF despite optimal medical treatment. Under follow-up in the Heart Failure Unit and after multiple unsuccessful treatment adjustments, it was decided to implant a pulmonary artery pressure monitoring device-CardioMEMS®-in order to optimize patient follow-up and treatment. The procedure was carried out without complications and early optimization of treatment was possible, resulting in a significant reduction in decompensations and admissions for HF. Discussion: Ambulatory pulmonary pressure monitoring is shown to be a safe and effective option to anticipate treatment of heart failure decompensation even with preserved left ventricular ejection fraction, with a significantly positive impact on hospital readmissions and consequent benefit on morbidity and mortality.

Association of Genetic Variants With Outcomes in Patients With Nonischemic Dilated Cardiomyopathy.

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.

Circulating circRNA as biomarkers for dilated cardiomyopathy etiology.

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure. The multidisciplinary nature of testing - involving genetics, imaging, or cardiovascular techniques - makes its diagnosis challenging. Novel and reliable biomarkers are needed for early identification and tailored personalized management. Peripheral circular RNAs (circRNAs), a leading research topic, remain mostly unexplored in DCM. We aimed to assess whether peripheral circRNAs are expressed differentially among etiology-based DCM. The study was based on a case-control multicentric study. We enrolled 130 subjects: healthy controls (n = 20), idiopathic DCM (n = 30), ischemic DCM (n = 20), and familial DCM patients which included pathogen variants of (i) LMNA gene (n = 30) and (ii) BCL2-associated athanogene 3 (BAG3) gene (n = 30). Differentially expressed circRNAs were analyzed in plasma samples by quantitative RT-PCR and correlated to relevant systolic and diastolic parameters. The pathophysiological implications were explored through bioinformatics tools. Four circRNAs were overexpressed compared to controls: hsa_circ_0003258, hsa_circ_0051238, and hsa_circ_0051239 in LMNA-related DCM and hsa_circ_0089762 in the ischemic DCM cohort. The obtained areas under the curve confirm the discriminative capacity of circRNAs. The circRNAs correlated with some diastolic and systolic echocardiographic parameters with notable diagnostic potential in DCM. Circulating circRNAs may be helpful for the etiology-based diagnosis of DCM as a non-invasive biomarker. KEY MESSAGES: The limitations of cardiac diagnostic imaging and the absence of a robust biomarker reveal the need for a diagnostic tool for dilated cardiomyopathy (DCM). The circular RNA (circRNA) expression pattern is paramount for categorizing the DCM etiologies. Our peripheral circRNAs fingerprint discriminates between various among etiology-based DCM and correlates with some echocardiographic parameters. We provide a potential non-invasive biomarker for the etiology-based diagnosis of LMNA-related DCM and ischemic DCM.

Phenotype and progression among patients with dilated cardiomyopathy and RBM20 mutations.

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.

Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure.

Importance: Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia. Objective: To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). Design, Setting, and Participants: This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. Main Outcomes and Measures: The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. Results: In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). Conclusions and Relevance: The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

A new approach to the treatment of advanced heart failure: a case report.

BACKGROUND: Autonomic imbalance characterized by sympathetic predominance and decreased parasympathetic transmission is a classic feature of heart failure (HF) with reduced left ventricular ejection fraction, leading to disease progression, exercise intolerance, ventricular remodelling, arrhythmias, and premature death. The underlying mechanisms to these processes are not yet fully understood, but the current treatments influence this dysregulation, towards an inhibition of sympathetic hyperactivation. New therapies, such as the stimulation of carotid baroreceptors, enhance this inhibition to restore autonomic balance and to be able to cope with these mechanisms. CASE SUMMARY: We report the case of a 76-year-old male with advanced HF at an advanced stage, refractory to optimal treatment, and included in a programme of ambulatory infusions of Levosimendan as compassionate treatment. The patient presented with multiple episodes of decompensated HF secondary to ventricular arrhythmias. A multidisciplinary team decided to implant a baroreceptor stimulator device (Barostim Neo) in order to improve HF symptoms and quality of life, as well as trying to decrease the burden of arrhythmias. The procedure was performed with no complications and good therapeutic response, resulting in a significant reduction of arrhythmias. DISCUSSION: Treatment with a baroreceptor stimulating device is presented as a safe and effective option in our patients with advanced HF refractory to conventional treatment, to improve their quality of life and reduce symptoms; in addition to appearing as a promising option in those with arrhythmic events, which are difficult to control with usual treatments and procedures.

Predictores de riesgo en una cohorte española con cardiolaminopatías. Registro REDLAMINA / Risk predictors in a Spanish cohort with cardiac laminopathies. The REDLAMINA registry

Introducción y objetivos Según las guías de muerte súbita, se debe considerar un desfibrilador automático implantable (DAI) para los pacientes con miocardiopatía dilatada debida a variantes en el gen de la lamina (LMNA) con al menos 2 factores: varones, fracción de eyección del ventrículo izquierdo (FEVI) <45%, taquicardia ventricular no sostenida (TVNS) y variantes no missense. Nuestro objetivo es describir las características clínicas de una cohorte española de pacientes con cardiolaminopatías (registro REDLAMINA) y evaluar los criterios de riesgo vigentes. Métodos Se evaluó la relación entre factores de riesgo y eventos cardiovasculares en una cohorte de 140 portadores de variantes en LMNA (54 probandos, 86 familiares, edad ≥ 16 años). Se consideró: a) evento arrítmico mayor (EAM) si hubo descarga apropiada del DAI o muerte súbita, y b) muerte por insuficiencia cardiaca, incluidos los trasplantes. Resultados Se identificaron 11 variantes nuevas y 21 previamente publicadas. La FEVI <45% (p=0,001) y la TVNS (p <0,001) se relacionaron con los EAM, pero no el sexo o el tipo de variante (missense frente a no missense). La FEVI <45% (p <0,001) fue el único factor relacionado con la muerte por insuficiencia cardiaca. Conclusiones En el registro REDLAMINA, los únicos 2 predictores asociados con EAM fueron la TVNS y la FEVI <45%. No se debería considerar grupo de bajo riesgo a las portadoras de variantes missense con TVNS o FEVI <45%. Es importante individualizar la estratificación del riesgo de los portadores de variantes missense en LMNA, porque no todas tienen el mismo pronóstico. (AU)

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. (AU)

Risk predictors in a Spanish cohort with cardiac laminopathies. The REDLAMINA registry.

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.