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INTRODUCTION AND OBJECTIVES The effect of a centrifugal continuous-flow left ventricular assist device (cfLVAD) on hemodynamic left ventricular unloading (HLVU) and the clinical conditions that interfere with hemodynamic optimization are not well defined. METHODS We retrospectively evaluated the likelihood of incomplete HLVU, defined as high pulmonary capillary wedge pressure (hPCWP)> 15mmHg in 104 ambulatory cfLVAD patients when the current standard recommendations for cfLVAD rotor speed setting were applied. We also evaluated the ability of clinical, hemodynamic and echocardiographic variables to predict hPCWP in ambulatory cfLVAD patients. RESULTS Twenty-eight percent of the patients showed hPCWP. The variables associated with a higher risk of hPCWP were age, central venous pressure, absence of treatment with renin-angiotensin-aldosterone system inhibitors, and brain natriuretic peptide levels. Patients with optimal HLVU had a 15.2±14.7% decrease in postoperative indexed left ventricular end-diastolic diameter compared with 8.9±11.8% in the group with hPCWP (P=.041). Independent predictors of hPCWP included brain natriuretic peptide and age. Brain natriuretic peptide

Resumen Introduccion y objetivos Los efectos hemodinamicos del dispositivo de asistencia ventricular izquierda de flujo continuo (DAVI-fc) en la descarga hemodinamica del ventriculo izquierdo (DHVI) y los factores clinicos que interfieren en su optimizacion no estan bien definidos. Metodos Se estudio de manera retrospectiva la prevalencia de altas presiones capilares enclavadas (hPCWP) del ventriculo izquierdo en 104 pacientes cuyos parametros del DAVI-fc se optimizaron siguiendo las actuales recomendaciones clinicas. Asimismo se analizo el valor de diferentes variables clinicas, hemodinamicas y ecocardiograficas para predecir el grado de DHVI en pacientes ambulatorios portadores de un DAVI-fc. Resultados El 28% de los pacientes presentaron hPCWP. La edad, la presion venosa central y la ausencia de tratamiento con inhibidores del sistema renina-angiotesiona-aldosterona y peptido natriuretico cerebral se asociaron con mayor riesgo de hPCWP. Los pacientes con DHVI optima presentaron una disminucion del diametro indexado del ventriculo izquierdo del 15,2 ± 14,7% en comparacion con el 8,9 ± 11,8% del grupo con hPCWP (p = 0,041). El peptido natriuretico cerebral Conclusiones Una DHVI optima es posible hasta en el 72% de los pacientes portadores de DAVI-fc cuando se siguen las actuales recomendaciones para la optimizacion de los parametros del DAVI-fc. La edad, la presion venosa central y el tratamiento con inhibidores del sistema renina-angiotesiona-aldosterona tienen un efecto importante a la hora de lograr este objetivo. La concentracion de peptido natriuretico cerebral y la magnitud del remodelado inverso del ventriculo izquierdo son metodos no invasivos utiles para evaluar la DHVI.

OBJECTIVES Early right-sided heart failure (RHF) was seen in 22% of recipients of a left ventricular assist device (LVAD) in the European Registry for Patients with Mechanical Circulatory Support (EUROMACS). However, the optimal treatment of post-LVAD RHF is not well known. Levosimendan has proven to be effective in patients with cardiogenic shock and in those with end-stage heart failure. We sought to evaluate the efficacy of levosimendan on post-LVAD RHF and 30-day and 1-year mortality. METHODS The EUROMACS Registry was used to identify adults with mainstream continuous-flow LVAD implants who were treated with preoperative levosimendan compared to a propensity matched control cohort. RESULTS In total, 3661 patients received mainstream LVAD, of which 399 (11%) were treated with levosimendan pre-LVAD. Patients given levosimendan had a higher EUROMACS RHF score [4 (2– 5.5) vs 2 (2– 4); P CONCLUSIONS In this analysis of the EUROMACS registry, we found no evidence for an association between levosimendan and early RHF or death, albeit patients taking levosimendan had much higher risk profiles. For a definitive conclusion, a multicentre, randomized study is warranted.

Background The out-of-hospital cardiac arrest (OHCA) in the young may be associated with a genetic predisposition which is relevant even for genetic counseling of relatives. The identification of genetic variants depends on the availability of intact genomic DNA. DNA from autopsy may be not available due to low autopsy frequencies or not suitable for high-throughput DNA sequencing (NGS). The emergency medical service (EMS) plays an important role to save biomaterial for subsequent molecular autopsy. It is not known whether the DNA integrity of samples collected by the EMS is better suited for NGS than autopsy specimens. Material and methods DNA integrity was analyzed by standardized protocols. Fourteen blood samples collected by the EMS and biomaterials from autopsy were compared. We collected 172 autopsy samples from different tissues and blood with postmortem intervals of 14–168 h. For comparison, DNA integrity derived from blood stored under experimental conditions was checked against autopsy blood after different time intervals. Results DNA integrity and extraction yield were higher in EMS blood compared to any autopsy tissue. DNA stability in autopsy specimens was highly variable and had unpredictable quality. In contrast, collecting blood samples by the EMS is feasible and delivered comparably the highest DNA integrity. Conclusions Isolation yield and DNA integrity from blood samples collected by the EMS is superior in comparison to autopsy specimens. DNA from blood samples collected by the EMS on scene is stable at room temperature or even for days at 4 °C. We conclude that the EMS personnel should always save a blood sample of young fatal OHCA cases died on scene to enable subsequent genetic analysis.

Objectives Left atrial appendage (LAA) amputation concomitant to coronary artery bypass grafting (CABG) has become an increasingly performed technique in patients with atrial fibrillation (AF) or with sinus rhythm and a CHA2DS2-VASc score ≥2. However, LAA amputation has come under suspicion to cause postoperative atrial fibrillation (POAF) due to left atrial (LA) dilation. This study aims to assess this assumption in patients undergoing CABG in off-pump technique with and without amputation of the LAA. Methods Patients who underwent isolated CABG in off-pump technique without history of AF were retrospectively examined. Cohorts were divided according to the concomitant execution of LAA amputation. LA volume was measured by transthoracic echocardiography and rhythm was analyzed by electrocardiography, medication protocol, and visit documentation. Propensity score (PS) matching was performed based on 20 preoperative risk variables to correct for selection bias. Results A total of 1,522 patients were enrolled, with 1,267 in the control group and 255 in the LAA amputation group. Occurrence of POAF was compared in 243 PS-matched patient pairs. Neither the unmatched cohort (odds ratio [OR] 0.82; 95% confidence interval or CI [0.61; 1.11], p = 0.19) nor the PS-matched cohort (OR 0.94; 95% CI [0.62; 1.41], p = 0.75) showed significant differences in POAF occurrence. Subgroup analysis of sex, use of β-blockers, pulmonary disease, ejection fraction, and CHA2DS2-VASc-Score also showed no tendencies. LA volume did not change significantly (p = 0.18, 95% CI [−0.29; 1.51]). Conclusion Surgical amputation of the LAA concomitant to CABG did not lead to LA dilation and has no significant impact on the occurrence of POAF.

BACKGROUND Genetics of sudden cardiac deaths (SCD) remains frequently undetected. Genetic analysis is recommended in undefined selected cases in the 2021 ERC-guideline. The emergency medical service and physicians (EMS) may play a pivotal role for unraveling SCD by saving biomaterial for later molecular autopsy. Since for high-throughput DNA-sequencing (NGS) high quality genomic DNA is needed. We investigated in a prospective proof-of-concept study the role of the EMS for the identification of genetic forms of SCDs in the young. METHODS We included patients aged 1-50 years with need for cardiopulmonary resuscitation attempts (CPR). Cases with non-natural deaths were excluded. In two German counties with 562,904 residents 39,506 services were analysed. Paired end panel-sequencing was performed, and variants were classified according to guidelines of the American College of Medical Genetics (ACMG). RESULTS 769 CPR-attempts were recorded (1.95% of all EMS-services; CPR-incidence 68/100,000). In 103 cases CPR were performed in patients

OBJECTIVES The development of late-onset right ventricular failure (LoRVF) that occurs months after a continuous-flow left ventricular assist device (LVAD) is implanted is a clinical problem that warrants investigation. Our goal was to study the incidence, clinical manifestations and prognosis of LoRVF in a population of patients who received an LVAD as bridge to transplantation. METHODS Data were analysed from 97 consecutive patients who received an LVAD as bridge to transplantation and underwent a right heart catheterization at least 3 months after receiving an LVAD implantation. LoRVF was defined if both haemodynamic criteria of a central venous pressure >16 mmHg and a cardiac index RESULTS LoRVF was diagnosed in 13% of patients after a median time of 11 months. Patients with LoRVF presented preoperative worse right ventricular (RV) dilatation and severe tricuspid regurgitation. LORVF was also associated with postoperative RV dilatation, moderate to severe tricuspid regurgitation and lower tricuspid annular plane systolic excursion. LoRVF resulted in increased brain natriuretic peptide levels and the need for diuretics, lower haemoglobin levels and a higher rate of atrial fibrillation and gastrointestinal bleeding. The rate of hospitalizations for heart failure in patients with LoRVF was 46%, and 15% required an urgent transplantation due to refractory RV failure. LoRVF decreased global survival and survival free from hospitalizations for heart failure (P CONCLUSIONS LoRVF after the implantation of an LVAD as bridge to transplantation is associated with higher morbidity and lower survival. The results suggest that the routine use of a right heart catheterization and transthoracic echocardiography may contribute to an early diagnosis before further severe complications due to refractory RV failure might occur. ID number of the IRB approval AZ-2019-521 on 10 July 2019.

OBJECTIVES Data on the impact and course of uncorrected tricuspid regurgitation (TR) during left ventricular assist device (LVAD) implantation are scarce and inconsistent. This study explores the clinical impact and natural course of uncorrected TR in patients after LVAD implantation. METHODS The European Registry for Patients with Mechanical Circulatory Support was used to identify adult patients with LVAD implants without concomitant tricuspid valve surgery. A mediation model was developed to assess the association of TR with 30-day mortality via other risk factors. Generalized mixed models were used to model the course of post-LVAD TR. Joint models were used to perform sensitivity analyses. RESULTS A total of 2496 procedures were included (median age: 56 years; men: 83%). TR was not directly associated with higher 30-day mortality, but mediation analyses suggested an indirect association via preoperative elevated right atrial pressure and creatinine (P = 0.035) and bilirubin (P = 0.027) levels. Post-LVAD TR was also associated with increased late mortality [hazard ratio 1.16 (1.06–1.3); P = 0.001]. On average, uncorrected TR diminished after LVAD implantation. The probability of having moderate-to-severe TR immediately after an implant in patients with none-to-mild TR pre-LVAD was 10%; in patients with moderate-to-severe TR pre-LVAD, it was 35% and continued to decrease in patients with moderate-to-severe TR pre-LVAD, regardless of pre-LVAD right ventricular failure or pulmonary hypertension. CONCLUSIONS Uncorrected TR pre-LVAD and post-LVAD is associated with increased early and late mortality. Nevertheless, on average, TR diminishes progressively without intervention after an LVAD implant. Therefore, these data suggest that patient selection for concomitant tricuspid valve surgery should not be based solely on TR grade.

Purpose Time of drug administration may significantly influence its effect. The aim of the present study was to investigate the effect of ASA (administrated in the morning or in the evening) on the anti-hypertensive effect and diurnal blood pressure profile in the high-risk group of cardiovascular patients. Methods All patients (n = 114) had been diagnosed with coronary heart disease and arterial hypertension prior to the enrolment and had been treated with 75 mg per day of ASA in the morning. The patients were randomly assigned to one of the two study groups receiving 75 mg of ASA per day in a single antiplatelet therapy for 3 months in the morning (n = 58) or in the evening (n = 56). The control group (n = 61) consisted of patients with arterial hypertension but without coronary heart disease, not receiving ASA. In all the patients, during each visit, clinical blood pressure (BP) and ambulatory blood pressure measurements (ABPM) were performed. Results There was a significant reduction in 24-h BP and blood pressure at night in the ASA group evening group compared with the ASA morning group and the control group. Conclusions The present study demonstrated that compared with the use of ASA in the morning, its administration in the evening may lead to favourable drop in the ABPM and an improvement of the diurnal profile in the high-risk group of cardiovascular patients who are not naïve to ASA.

Background The clinical profile of left ventricular assist device (LVAD) candidates is rapidly changing, with increasing proportion of patients in more stable clinical conditions. However, early postoperative right ventricular failure (eRVF) is still one of the cornerstones associated with increased mortality and the preoperative recognition of associated risk factors remains challenging. The aim of this study was to identify predictive parameters for eRVF after LVAD implantation in patients with preoperative intermediate Intermacs (InM) risk profile 3-5. Methods Preoperative laboratory, echocardiography, and right heart catheterization data collected from 80 patients with InM profile 3-5 before LVAD implantation were retrospectively tested with respect to their ability to predict the risk for eRVF after the implantation of a continuous-flow LVAD. Results Preoperative higher bilirubin and blood urea nitrogen (BUN) levels, higher Model for End-stage Liver Disease score, lower estimated glomerular filtration rate, and higher central venous pressure to pulmonary capillary wedge pressure ratio (CVP/PCWP) were associated to higher risk of eRVF. Regarding the echocardiographic assessment, higher end diastolic linear dimensions of the RV, higher basal end diastolic RV linear dimension to LV ratio, severe tricuspid regurgitation, lower tricuspid annular plane systolic excursion, and lower RV fractional area contraction identified patients with higher risk for eRVF. In the multivariable analysis, a CVP/CPWP > 0.55 (odds ratio [OR]: 4, 95% confidence interval [CII]: 1.4-11.8;P = .01) and BUN > 44.5 mg/dL (OR: 6.6, 95% CI: 1.51-23; P = .011) independently predicted the risk of eRVF. Conclusion Preoperative BUN > 44.5 mg/dL and CVP/PCWP > 0.55 are associated to an increased risk of eRVF following LVAD implantation in intermediate InM patients.

Assessing hemodynamics, especially central venous pressure (CVP), is essential in heart failure (HF). Right heart catheterization (RHC) is the gold-standard, but non-invasive methods are also needed. However, the role of 2-dimensional echocardiography (2DE) remains uncertain, and 3-dimensional echocardiography (3DE) is not always available. This study investigated standardized and breathing-corrected assessment of inferior vena cava (IVC) volume using echocardiography (2DE and 3DE) versus CVP determined invasively using RHC. Sixty consecutive HF patients were included (82% male, age 54 ± 11 years, New York Heart Association class 2.23 ± 0.8, ejection fraction 46 ± 18.4%, brain natriuretic peptide 696.93 ± 773.53 pg/mL). All patients underwent Swan-Ganz RHC followed by 2DE and 3DE, and IVC volume assessment. On 2DE, mean IVC size was 18.3 ± 5.5 mm and 13.8 ± 6 mm in the largest deflection and shortest distention, respectively. Mean CVP from RHC was 9.3 ± 5.3 mmHg. Neither 2DE nor 3DE showed acceptable correlation with invasively measured CVP; IVC volume acquisition showed optimal correlation with RHC CVP (0.64; 95% confidence interval 0.46–0.77), with better correlation when mitral valve early diastole E wave and right ventricular end-diastolic diameter were added. Using a CVP cut-point of 10 mmHg, receiver operating characteristic curve showed true positivity (specificity) of 0.90 and sensitivity of 62% for predicting CVP. A validation study confirmed these findings and verified the high predictive value of IVC volume assessment. Neither 2DE nor 3DE alone can reliably mirror CVP, but IVC volume acquisition using echocardiography allows non-invasive and adequate approximation of CVP. Correlation with invasively measured pressure was strongest when CVP is > 10 mmHg.

Aims We aimed to unravel the genetic, molecular and cellular pathomechanisms of DSC2 truncation variants leading to arrhythmogenic cardiomyopathy (ACM). Methods and results We report a homozygous 4-bp DSC2 deletion variant c.1913_1916delAGAA, p.Q638LfsX647hom causing a frameshift carried by an ACM patient. Whole exome sequencing and comparative genomic hybridization analysis support a loss of heterozygosity in a large segment of chromosome 18 indicating segmental interstitial uniparental isodisomy (UPD). Ultrastructural analysis of the explanted myocardium from a mutation carrier using transmission electron microscopy revealed a partially widening of the intercalated disc. Using qRT-PCR we demonstrated that DSC2 mRNA expression was substantially decreased in the explanted myocardial tissue of the homozygous carrier compared to controls. Western blot analysis revealed absence of both full-length desmocollin-2 isoforms. Only a weak expression of the truncated form of desmocollin-2 was detectable. Immunohistochemistry showed that the truncated form of desmocollin-2 did not localize at the intercalated discs. In vitro, transfection experiments using induced pluripotent stem cell derived cardiomyocytes and HT-1080 cells demonstrated an obvious absence of the mutant truncated desmocollin-2 at the plasma membrane. Immunoprecipitation in combination with fluorescence measurements and Western blot analyses revealed an abnormal secretion of the truncated desmocollin-2. Conclusion In summary, we unraveled segmental UPD as the likely genetic reason for a small homozygous DSC2 deletion. We conclude that a combination of nonsense mediated mRNA decay and extracellular secretion is involved in DSC2 related ACM.

Left-atrial (LA) strain is the result of complex hemodynamics, increasingly assessed by feature-tracking cardiovascular magnetic resonance (CMR). We investigate the value of multi-parametric regression (MPR) analyses and the influence of the heart rate on LA-strain. As LA-strain data remains limited, CMR-quantified sex- and age-dependent normal values were derived. After following a health assessment questionnaire, 183 healthy volunteers (11-70 years, 97 females, median 32.9±28.3 years) were recruited for LA-strain assessment. LA volumetric data, left ventricular strain, transmitral and pulmonary venous blood flow parameters were utilized to create clusters for MPR analyses for all subjects and heart rate-specific subgroups (range: 60–75 beats-per-minute, N=106). In comparison to the total cohort, subgroups showed no gender differences (p>0.05) for LA reservoir, conduit and booster strains (all: 47.3±12.7%; 29.0±15.5%; 17.6±5.4%) and strain rates (all: 2.1±1.0 s−1; -2.9 ± 1.5 s−1; -2.3 ± 1.0 s−1). MPR analyses identified parameter clusters with large effect size (|R²|≥0.26) for reservoir-, conduit- and booster strain and corresponding active and passive cardiac functional parameters. Increased correlations for the subgroup were found. In contrast to previous studies, heart rate selected subgroups showed no gender differences in LA-strain. MPR analyses improve characterization of LA-strain at selected heart rates.

Left-atrial (LA) strain is the result of complex hemodynamics, which may be better characterized using a multiparametric approach. Cardiovascular magnetic resonance (CMR) feature tracking was used to perform a comprehensive LA strain assessment of 183 enrolled healthy volunteers (11–70 years, 97 females, median 32.9 ± 28.3 years). Novel strain dependencies were assessed using multi-parametric regression (MPR) analyses. LA volumetric data, left ventricular strain, transmitral and pulmonary venous blood flow parameters were utilized to create clusters for MPR of all subjects and a heart rate controlled subgroup (pulse: 60–75/min, N = 106). The LA reservoir(r) and conduit(c) strains of the total cohort were significantly elevated (p ≤ 0.001) in women (r: 49.7 ± 12.9%, c: 32.0 ± 11.0%) compared to men (r: 42.9 ± 11.4%, c: 26.1 IQ 10.5%). In contrast, there were no gender-specific differences (p > 0.05) for subgroup LA reservoir, conduit and booster(b) strains (all, r: 47.3 ± 12.7%; c: 29.0 IQ 15.5%; b: 17.6 ± 5.4%) and strain rates (all, 2.1 IQ 1.0 s−1; − 2.9 IQ 1.5 s−1; − 2.3 IQ 1.0 s−1). MPR found large effect sizes (|R2|≥ 0.26) for correlations between strain and various cardiac functional parameters. Largest effect size was found for the association between LA conduit strain and LA indexed booster volume, LA total ejection fraction, left ventricular global radial strain and E-wave (|R2|= 0.437). In addition to providing normal values for sex-dependent LA strain and strain rate, no gender differences were found with modified heart rate. MPR analyses of LA strain/strain rate and various cardiac functional parameters revealed that heart rate control improved goodness-of-fit for the overall model.

Currently, little is known about the genetic background of restrictive cardiomyopathy (RCM). Herein, we screened an index patient with RCM in combination with atrial fibrillation using a next generation sequencing (NGS) approach and identified the heterozygous mutation DES-c.735G>C. As DES-c.735G>C affects the last base pair of exon-3, it is unknown whether putative missense or splice site mutations are caused. Therefore, we applied nanopore amplicon sequencing revealing the expression of a transcript without exon-3 in the explanted myocardial tissue of the index patient. Western blot analysis verified this finding at the protein level. In addition, we performed cell culture experiments revealing an abnormal cytoplasmic aggregation of the truncated desmin form (p.D214-E245del) but not of the missense variant (p.E245D). In conclusion, we show that DES-c.735G>C causes a splicing defect leading to exon-3 skipping of the DES gene. DES-c.735G>C can be classified as a pathogenic mutation associated with RCM and atrial fibrillation. In the future, this finding might have relevance for the genetic understanding of similar cases.

Background Severely reduced right heart function and high operative risk are major challenges in the treatment of tricuspid regurgitation (TR) as both can lead to low cardiac output heart failure (LCO-Hf). Alternative methods and criteria for patient selection are actively being sought. Case summary We report on a 66-year-old patient with severe right heart failure (rHF) with recurrent TR after prior surgical valve repair with a 32-mm-Edwards-MC3 annuloplasty ring (AR). Surgical revision was discarded due to extreme high surgical risk. A right ventricular assist device was discussed but declined by the patient. Percutaneous edge-to-edge repair was not applicable due to massive tethering of the anterior leaflet and complete lack of coadaptation. According to the Heart team decision, percutaneous tricuspid valve-in-ring implantation was performed using a 29-mm Sapien-3 prosthesis (SP3) under moderate balloon overinflation. Despite satisfying positioning, the prosthesis showed massive intravalvular regurgitation due to immobility of the septally oriented cusp, which was most likely caused by eccentric bulging of the prosthesis in the opening region of the AR. Implantation of a second prosthesis leads to a perfectly functional result. Importantly, no major haemodynamic complications ensued. Discussion Although being a potential risk of tricuspid valve repair LCO-hf could not be observed in the present case. Additionally, deformation of the implanted transcatheter aortic valve replacement prosthesis resulting from the regional lack of abutment in AR should be considered as a potential complication. Hence, further careful evaluation of the feasibility of percutaneous tricuspid valve treatment, also in patients with rHF, is needed.

Heart failure is a clinical syndrome of multifactorial aetiology with typical symptoms and diverse prevalence depending on the world region, reaching more than 10% in the population over 70 years of age. The prognosis, in spite of a dynamic improve- ment in medical therapy, remains poor. The only treatment for these patients is heart transplantation, however, its availability is highly limited because of the shortage of donor organs. Mechanical circulatory support can offer an alternative treatment for this patient cohort. In this review the authors discuss the present indications for, as well as results and complications of different types of long-term mechanical circulatory support. The long-term survival in patients receiving this therapy, in spite of many complication, is much better than in those receiving medical treatment. The use of mechanical circulatory support is an established treatment option for many patients with end-stage heart failure. The most important issue for the cardiologist is to identify patients eligible for this therapy in order to give them a chance for a longer life and better quality of life.

Genetics of sudden cardiac deaths (SCD) remains frequently undetected. Genetic analysis is recommended in undefined selected cases in the 2021 ERC-guideline. The emergency medical service and physicians (EMS) may play a pivotal role for unraveling SCD by saving biomaterial for later molecular autopsy. Since for high-throughput DNA-sequencing (NGS) high quality genomic DNA is needed. We investigated in a prospective proof-of-concept study the role of the EMS for the identification of genetic forms of SCDs in the young.We included patients aged 1-50 years with need for cardiopulmonary resuscitation attempts (CPR). Cases with non-natural deaths were excluded. In two German counties with 562,904 residents 39,506 services were analysed. Paired end panel-sequencing was performed, and variants were classified according to guidelines of the American College of Medical Genetics (ACMG).769 CPR-attempts were recorded (1.95% of all EMS-services; CPR-incidence 68/100,000). In 103 cases CPR were performed in patients 50y. 58% died on scene, 26% were discharged from hospital. 24 subjects were included for genotyping. Of these 33% died on scene, 37.5% were discharged from hospital. 25% of the genotyped patients were carriers of (likely) pathogenic (ACMG-4/-5) variants. 67% carried variants with unknown significance (ACMG-3). 2 of them had familial history for arrhythmogenic cardiomyopathy or had to be re-classified as ACMG-4 carriers due to whole exome sequencing.The EMS contributes especially in fatal OHCA-cases to increase the yield of identified genetic conditions by collecting a blood sample on scene. Thus, the EMS can contribute significantly to primary and secondary prophylaxis in affected families.

Cardiovascular diseases are the number one cause of morbidity and mortality worldwide, but the underlying molecular mechanisms remain not well understood. Cardiomyopathies are primary diseases of the heart muscle and contribute to high rates of heart failure and sudden cardiac deaths. Here, we distinguished four different genetic cardiomyopathies based on gene expression signatures. In this study, RNA-Sequencing was used to identify gene expression signatures in myocardial tissue of cardiomyopathy patients in comparison to non-failing human hearts. Therefore, expression differences between patients with specific affected genes, namely \(\it LMNA\) (lamin A/C), \(\it RBM20\) (RNA binding motif protein 20), \(\it TTN\) (titin) and \(\it PKP2\) (plakophilin 2) were investigated. We identified genotype-specific differences in regulated pathways, Gene Ontology (GO) terms as well as gene groups like secreted or regulatory proteins and potential candidate drug targets revealing specific molecular pathomechanisms for the four subtypes of genetic cardiomyopathies. Some regulated pathways are common between patients with mutations in \(\it RBM20\) and \(\it TTN\) as the splice factor RBM20 targets amongst other genes \(\it TTN\), leading to a similar response on pathway level, even though many differentially expressed genes (DEGs) still differ between both sample types. The myocardium of patients with mutations in \(\it LMNA\) is widely associated with upregulated genes/pathways involved in immune response, whereas mutations in \(\it PKP2\) lead to a downregulation of genes of the extracellular matrix. Our results contribute to further understanding of the underlying molecular pathomechanisms aiming for novel and better treatment of genetic cardiomyopathies.

The risk of left ventricular (LV) and right ventricular (RV) maladaptation after surgery for isolated primary mitral regurgitation (PMR) is poorly defined. We aimed to evaluate LV and RV contractile function using speckle-tracking analysis alongside with quantification of exercise tolerance in patients with PMR after mitral valve surgery. All consecutive patients with symptomatic PMR undergoing mitral valve surgery between July 2015 and May 2017 were prospectively enrolled. Sequential echocardiographic studies along with clinical assessment were performed before and three months after surgery. Mean age in 138 patients was 65.8 ± 12.7 years, 48.2% (66) of whom were female. Mean LV ejection fraction decreased from 57 ± 12% to 50 ± 11% (p

Early right ventricular failure (RVF) remains one of the main factors associated with early mortality following continuous-flow left ventricular assist device (LVAD) implantation. However, late-onset RVF (LoRVF) has emerged as an increasing concern, but little is known about its incidence rate and the value of transthoracic echocardiography (TTE) to predict this complication during the LVAD follow-up. Methods and results We retrospectively analyzed the 1-year hemodynamic and clinical data from patients (p) that, between 2016 and 2018, underwent a right heart catheterization (RHC) after LVAD as bridge to transplantation (BTT). 73 p (84% males, 52 ± 12 years, 49% Heart Ware LVAD, 51% Heart Mate 3 LVAD), out of 187 LVAD implants, were studied. According to the Intermacs definition, LoRVF was assigned if the RHC showed a central venous pressure (CVP)>18 mmHg with cardiac index< 2.3 L/min/m2. Isolated LoRVF was assigned if LoRVF was present in the absence of elevated pulmonary capillary wedge pressure (PCWP) ≤15 mmHg. TTE was performed at the time of the RHC and the following parameters were obtained: parasternal long-axis left ventricular end diastolic diameter (LVEDD), basal (RVED1) and mid-cavity (EDRV2) end diastolic RV linear dimension in 4 chamber view, severity of tricuspid regurgitation (TR) and of mitral regurgitation (MR), tricuspid annular plane systolic excursion (TAPSE), and the position of the LVAD inflow cannula (IC). LoRVF was present in 16 p (22% of the studied population): 12 p (75%) presented a PCWP > 15 mmHg and 4 p (25%) presented isolated LoRVF. Symptoms and signs of venous congestion were present in 2/3 of the p with LoRVF and elevated PCWP. On the other hand, all the p with isolated LoRVF presented severe signs of venous congestion, and 50% of them could be successfully transplanted in high urgent status. P with LoRVF showed more dilated RV (RVED1 43.8 ± 9.2 vs 37.7 ± 5.3 mm, p = 0.02) and lower TAPSE (11 ± 2 vs 14 ± 2 mm p mild. Conclusion LoRVF is a frequent complication during LVAD support as BTT and most of the cases are associated with persistent elevated PCWP. Isolated LoRVF, which is not associated with high PCWP, has a bad prognosis. RV evaluation with TTE during the clinical follow-up can be useful to detect LoRVF. However a persistent elevated PCWP is not associated with echocardiographic signs of incomplete unloading of the LV by the LVAD.

Background DES mutations cause different cardiac and skeletal myopathies. Most of them are missense mutations. Methods Using a next-generation sequencing cardiac 174 gene panel, we identified a novel heterozygous in-frame indel mutation (DES-c.493_520del28insGCGT, p.Q165_A174delinsAS) in a Caucasian patient with cardiomyopathy in combination with atrioventricular block and skeletal myopathy. This indel mutation is located in the coding region of the first exon. Family anamnesis revealed a history of sudden cardiac death. We performed cell transfection experiments and in vitro assembly experiments to prove the pathogenicity of this novel DES indel mutation. Results These experiments revealed a severe filament formation defect of mutant desmin supporting the pathogenicity. In addition, we labeled a skeletal muscle biopsy from the mutation carrier revealing cytoplasmic desmin positive protein aggregates. In summary, we identified and functionally characterized a pathogenic DES indel mutation causing cardiac and skeletal myopathy. Conclusion Our study has relevance for the clinical and genetic interpretation of further DES indel mutations causing cardiac or skeletal myopathies and might be helpful for risk stratification.

Severe mitral annulus calcifications significantly hinder surgical repair and replacement of the dysfunctional mitral valve. Herein, we present a novel surgical technique where we created an intra-atrial neomitral ring using a vascular Dacron graft in which a prosthetic valve was implanted. This approach is a simple alternative technique that can be used when anatomic prosthetic valve implantation is not feasible. Major assets of this approach are evasion of extensive debridement, implantation of an adequately sized prosthesis, and prosthetic material availability.

Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T &gt, C, p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations.

Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations.

Early right ventricular failure (RVF) remains a frequent complication and is one of the main factors associated to early mortality following left ventricular assist device (LVAD) implantation. However, late-onset RVF (LoRVF) has emerged as an increasing concern, but little is known about its incidenceand underlying mechanisms. Methods and results We retrospectively analysed the 1-year hemodynamic and clinical data from all patients that, between 2016 and 2018, underwent a right heart catheterization (RHC) after continuous-flow LVAD implantation as bridge to transplantation. Sixty-six patients (84% males, 53±11 years, 60% implanted in Intermacs 1–2, 52% HeartWare LVAD, 48% HM3 LVAD), out of 187 LVAD implants, were studied. LoRVF was defined as central venous pressure>18 mmHg with cardiac index LoRVF was present in 17 patients (25.7%) and 12 (71%) of them manifested concomitant clinical signs of RVF. Eleven of the patients who presented LoRVF (65% of the LoRVF) had a pulmonary capillary wedge pressure (PCWP)>15 mmHg. Isolated LoRVF (LoRVF criteria + PCWP≤15 mmhg) was found in 6 patients (35% of the LoRVF) and accounted for 9% of the studied population. Fifty percent of patients who presented isolated LoRVF could be successfully transplanted in high urgent status due to severe chronic RVF and 1 patient died to refractory RVF. We did not find an association between isolated LoRVF and age, renal function, type of LVAD, persistent increased pulmonary vascular resistances or the previous need of temporary right ventricular support due to early acute RVF following LVAD. There was however a significant association between the presence of atrial fibrillation and isolated LoRVF (p Incidence and prognosis of LoRVF Conclusion Late-onset RVF is a frequent complication during LVAD support as bridge to transplantation. Most of the cases are associated to a lesser degree of left ventricular unloading. The presence of isolated late-onset RVF with normal PCWP has an impact on the long-term prognosis and the need of urgent heart transplantation and is not related to early RVF following LVAD implantation or persistent increased pulmonary vascular resistance.

Background Assessing hemodynamics, in particular central venous pressure (CVP) is essential in heart failure diagnostics, leading individual therapy. Hereby, invasive measurement through Swan-Ganz right heart catheterization (RHC) is considered gold standard for patient evaluation, but catheterization implies risks of invasiveness including bleeding, infection, vessel and nerve injury, as well as patient discomfort. Non-invasive methods are warranted, but no alternative technique is validated yet. Two-dimensional echocardiography (2DE) is believed to be uncertain in this approach as vena cava often shows ellipse-shapes. Therefore, this study sought to investigate standardized and breathing corrected three-dimensional inferior vena cava echocardiography (3DE) to directly compare CVP with right heart catheterization. Methods and results We prospectively included 100 consecutive heart failure patients in this study (mean age 53±12 years, body mass index 27±5, New York Heart Association functional class 2.3±0.6, left ventricular ejection fraction 34.1±12.8%, brain natriuretic peptide 658.13±974.03, 76% male), all underwent Swan-Ganz right-heart catheterization and immediately both 2DE and 3DE (Philips EPIQ 7G) of inferior vena cava. From two-dimensional data the diameter of IVC was measured perpendicularly in long and short-axis. From 3DE data a cross-sectional image of IVC was reconstructed for both vertical and horizontal diameters of IVC as well as the area of IVC. Established 2DE images revealed mean vena cava sizes of 15.9±5.9 mm, while standardized cross-sectional breathing corrected 3DE images showed diameters of 19.8±7.8 mm in longitudinal axis and 15.74±7.8 in short axis. RHC mean CVP was 9.00±5.4 mmHg and correlation of CVP and 2DE measurements failed adequate correlation (2DE 95% CI 0.19–1.61; r=0.25; p=0.312). However, 3DE axis ratio assessment correlated well with invasive CVP and showed reproducible results (3DE 95% CI 0.26–0.69; r=0.89; p Conclusions Standardized 3DE correlates well with invasive CVP while established 2DE usual care assessment does not show reliable CVP correlation. 3DE CVP assessment may represent a more feasible and easily applicable method for CVP measurement, including absence for risks of right heart catheterization. Further studies are ongoing to validate these findings in the future.

The obstructive sleep apnea (OSA) is highly associated with various significant cardiovascular outcomes such as resistant hypertension (RAH). Despite this, as of now the relationship between high night-time blood pressure (BP) and left ventricular hypertrophy (LVH) in patients with OSA and RAH is not fully understood. The aim of this study was to assess the influence of the addition of eplerenone to a standard antihypertensive therapy on parameters of 24-h ambulatory blood pressure measurement (ABPM) as well as on the results of echocardiography and polysomnography in patients with OSA and RAH. The patients were randomly assigned to one of the two study groups: the treatment group, receiving 50 mg/d eplerenone orally for 6 months (n = 51) and the control group, remaining on their standard antihypertensive therapy (n = 51). After that period, a significant reduction in the night-time BP parameters in the treatment group including an increased night blood pressure fall from 4.6 to 8.9% was noted. Additionally, the number of non-dipper patients was reduced by 45.1%. The treatment group also revealed a decrease in left ventricular hypertrophy and in the apnea&ndash, hypopnea index (AHI) with a positive correlation being observed between these two parameters. This study is the first to report the improvement of the circadian BP profile and the improvement of the left ventricle geometry in patients with OSA and RAH following the addition of selective mineralocorticoid receptor antagonists to antihypertensive therapy.

OBJECTIVES Tricuspid regurgitation (TR) is common in patients receiving a left ventricular assist device (LVAD). Controversy exists as to whether concomitant tricuspid valve surgery (TVS) is beneficial in currently treated patients. Therefore, our goal was to investigate the effect of TVS concomitant with a LVAD implant. METHODS The European Registry for Patients with Mechanical Circulatory Support was used to identify adult patients. Matched patients with and without concomitant TVS were compared using a propensity score matching strategy. RESULTS In total, 3323 patients underwent LVAD implantation of which 299 (9%) had TVS. After matching, 258 patients without TVS were matched to 258 patients with TVS. In the matched population, hospital deaths, days on inotropic support, temporary right ventricular assist device implants and hospital stay were comparable, whereas stay in the intensive care unit was higher in the TVS cohort (11 vs 15 days; P = 0.026). Late deaths (P = 0.17), cumulative incidence of unexpected hospital readmission (P = 0.15) and right heart failure (P = 0.55) were comparable between patients with and without concomitant TVS. In the matched population, probability of moderate-to-severe TR immediately after surgery was lower in patients with concomitant TVS compared to patients without TVS (33% vs 70%; P = 0.001). Nevertheless, the probability of moderate-to-severe TR decreased more quickly in patients without TVS (P = 0.030), resulting in comparable probabilities of moderate-to-severe TR within 1.5 years of follow-up. CONCLUSIONS In matched patients, TVS concomitant with LVAD implant does not seem to be associated with better clinical outcomes. Concomitant TVS reduced TR significantly early after LVAD implant; however, differences in probability of TR disappeared during the follow-up period.

Purpose Normalization of hemodynamics plays an important role in achieving an optimal clinical benefit after LVAD Implantation. However the hemodynamic optimization during follow-up continues to be a challenge. We assessed the likelihood of effective hemodynamic unloading of the Left ventricle (HLVU) during LVAD support, when the current standard recommendations for LVAD speed optimization were applied in the clinical practice, and its association with different clinical and echocardiographic (TTE) conditions. Methods Retrospective study that included consecutive patients who had primary received an LVAD as bridge to heart transplantation (BTT) and underwent a right-side catheterization (RHC) at least 3 months after the LVAD implantation as part of the screening process for BTT candidacy.Routinely ambulatory follow-up consisted in clinical, TTE and hematological examination.LVAD rotor speed was optimized during each follow-up visit according to the current clinical recommendations. Results 104 p (87% male, 55+/-6 years, 42% HeartWare LVAD, 58% HM3 LVAD) were studied. Incomplete HLVU was defined if the pulmonary capillary wedge pressure was above 15 mmHg (hPCWP), and it was present in 29 p (28%). Patients with hPCWP were older, had worse postoperative renal function, higher BNP levels, received fewer renin-angiotensin-Aldosteron blocking agents(RAB) and required higher dose of diuretics (p 300 pg/dl could predict hPCWP with 78% accuracy, 74% specificity and a 78% sensitivity (p Conclusion An incomplete HLVU under LVAD support is common in the clinical practice, when the current standard recommendations are applied. Our study highlights the negative effect of age and renal dysfunction in the likehood of effective HLVU and the potential contribution of the RAB to achieve this goal.The BNP levels and the magnitude of the echocardiographic reverse LV remodeling seem to be useful non-invasive tools to evaluate the degree of effective LV unloading during follow-up.

Background Data regarding the effects of vitamin D on cardiac function are inconclusive. Methods In a post-hoc analysis of the EVITA (Effect of vitamin D on mortality in heart failure) trial, we investigated whether a daily vitamin D3 supplement of 4000 IU for three years affects echocardiography parameters like left ventricular end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), and LV ejection fraction (LVEF) in patients with advanced heart failure (HF) and 25‑hydroxyvitamin D levels Results At baseline, values of LVEDD, LVESD, and LVEF were 67.5 ± 10.5 mm, 58.9 ± 12.0 mm, and 30.47 ± 10.2%, respectively. There were no time × treatment interaction effects on LV echocardiographic parameters in the entire study cohort, neither at 12 months nor at 36 months post-randomization (P-values > 0.05). However, in the subgroup of patients aged ≥50 years, vitamin D treatment was associated with an increase in LVEF of 2.73% (95%CI: 0.14 to 5.31%) at 12 months post-randomization (n = 311). The increase was slightly attenuated to 2.60% (95%CI: −2.47 to 7.67%) at 36 months post-randomization (n = 242). Conclusion Our data indicate that vitamin D supplementation does not significantly improve cardiac function in all patients with advanced HF. However, vitamin D probably improves LV function in HF patients aged ≥50 years.

The number of implanted left ventricular assist devices is increasing systematically. Novel systems are being introduced and survival rates are improving, but complications, such as heart failure, leading to high early and late mortality still exist. Echocardiography is the preferred method for assessing the anatomy and function of the right ventricle (RV). In spite of the many methods available for use, including 2- and 3-dimensional techniques, assessment of the RV remains challenging. In this review, we present echocardiographic parameters that are most often used to assess right ventricular anatomy and function, and analyse their ability to predict right heart failure after the implantation of a left ventricular assist device.

OBJECTIVES In end-stage heart failure patients with left-ventricular assist device implantation and tricuspid valve (TV) regurgitation grade >2, the surgical strategy for TV regurgitation is unclear at present. We aimed to compare clinical outcomes in patients receiving left-ventricular assist device (LVAD) implants with or without TV repair (TVR). METHODS We included 58 patients with TV regurgitation grade >2 in our data analysis. Thirty-two patients received TVR during LVAD implantation (TVR+ group), whereas 26 patients did not receive TVR (TVR- group). We assessed demographic and various preoperative clinical and echocardiographic parameters in both groups. The primary end-point was survival up to 1 year. Secondary end-points were the incidence of prolonged mechanical ventilatory support, rethoracotomy, early and late right heart failure and liver or kidney failure. RESULTS Preoperatively, the two groups differed according to heart failure diagnosis, need for inotropic support and haemodynamic/echocardiographic parameters such as transpulmonary gradient, cardiac index and the ratio of the right-ventricular end-diastolic diameter to the left-ventricular end-diastolic diameter. The survival rate up to 1 year was 53.1% in the TVR+ group and 73.1% in the TVR- group (P = 0.176). The propensity score (PS)-adjusted 1-year mortality risk with the TVR- group as a reference was 3.05 for the TVR+ group (95% confidence interval: 0.84-11.11; P = 0.091). Secondary end-points did not differ significantly between study groups. CONCLUSIONS Data indicate that end-stage heart failure patients with TV regurgitation grade >2 undergoing LVAD implants do not benefit from concomitant TVR. Results have to be confirmed by prospective studies.

OBJECTIVES The number of implanted biological valves for treatment of valvular heart disease is growing and a percentage of these patients will eventually undergo a transcatheter valve-in-valve (ViV) procedure. Some of these patients will represent challenging cases. The aim of this study was to develop a feasible algorithm to plan and in vitro simulate a new interventional procedure to improve patient outcome. METHODS In addition to standard diagnostic routine, our algorithm includes 3D printing of the annulus, hydrodynamic measurements and high-speed analysis of leaflet kinematics after simulation of the procedure in different prosthesis positions as well as X-ray imaging of the most suitable valve position to create a 'blueprint' for the patient procedure. RESULTS This algorithm was developed for a patient with a degenerated Perceval aortic sutureless prosthesis requiring a ViV procedure. Different ViV procedures were assessed in the algorithm and based on these results the best option for the patient was chosen. The actual procedure went exactly as planned with help of this algorithm. CONCLUSIONS Here we have developed a new technically feasible algorithm simulating important aspects of a novel interventional procedure prior to the actual procedure. This algorithm can be applied to virtually all patients requiring a novel interventional procedure to help identify risks and find optimal parameters for prosthesis selection and placement in order to maximize safety for the patient.

OBJECTIVES Heart transplantation (HT) and ventricular assist devices (VAD) for the management of end-stage heart failure have not been directly compared. We compare the outcomes and use of resources with these 2 strategies in 2 European countries with different allocation systems. METHODS We studied 83 patients managed by VAD as the first option in Bad Oeynhausen, Germany (Group I) and 141 managed with either HT or medical therapy, as the first option, in Paris, France (Group II). The primary end-point was 2-year survival. Kaplan-Meier analyses were performed after the application of propensity score weights to mitigate the effects of non-random group assignment. The secondary end-points were resource utilization and costs. Subgroup analyses were performed for patients undergoing HT and patients treated with inotropes at the enrolment time. RESULTS The Group I patients were more severely ill and haemodynamically compromised, and 28% subsequently underwent HT vs 55% primary HT in Group II, P

Restrictive cardiomyopathy (RCM) is a rare heart disease characterized by diastolic dysfunction and atrial enlargement. The genetic etiology of RCM is not completely known. We identified by a next-generation sequencing panel the novel CRYAB missense mutation c.326A>G, p.D109G in a small family with RCM in combination with skeletal myopathy with an early onset of the disease. CRYAB encodes αB-crystallin, a member of the small heat shock protein family, which is highly expressed in cardiac and skeletal muscle. In addition to in silico prediction analysis, our structural analysis of explanted myocardial tissue of a mutation carrier as well as in vitro cell transfection experiments revealed abnormal protein aggregation of mutant αB-crystallin and desmin, supporting the deleterious effect of this novel mutation. In conclusion, CRYAB appears to be a novel RCM gene, which might have relevance for the molecular diagnosis and the genetic counseling of further affected families in the future.

OBJECTIVES We investigated the impact of inodilators on the accuracy of E/e' ratio as a surrogate for pulmonary artery occlusion pressure in patients with decompensated end-stage systolic heart failure. SETTING The ratio of early diastolic transmitral flow velocity to tissue Doppler mitral annular early diastolic velocity, E/e', and pulmonary artery occlusion pressure have been shown to be correlated. The validity of E/e' for predicting pulmonary artery occlusion pressure in patients with decompensated end-stage systolic heart failure was recently challenged, but the influence of inodilators was not taken into account, despite the reported influence of these drugs on left ventricular relaxation properties. PATIENTS AND INTERVENTION Invasive hemodynamic monitoring and echocardiographic data were collected prospectively from 39 patients with decompensated end-stage systolic heart failure (92% male), aged 56 ± 13 years. These patients had dilated ventricles with a low cardiac index (1.9 ± 0.6 L/min/m) and high pulmonary artery occlusion pressure (22 ± 8 mm Hg), and 90% required inodilator support during hospitalization. MEASUREMENTS AND MAIN RESULTS The correlation between septal E/e' and pulmonary artery occlusion pressure was good for examinations in the absence of inodilators (n = 21) (r = 0.7; p < 0.001), but no correlation was found when inodilators were used (n = 31). Lateral and mean E/e' were poorly correlated with pulmonary artery occlusion pressure, if at all, in both cases. CONCLUSIONS By modifying ventricular relaxation properties and the influence of filling pressure on e', inodilator agents severely impair the correlation between E/e' and pulmonary artery occlusion pressure in patients with decompensated end-stage systolic heart failure.